CN103637977A

CN103637977A - Drug-containing implants and methods of use thereof

Info

Publication number: CN103637977A
Application number: CN201310587181.8A
Authority: CN
Inventors: S·西格尔; K·维尼
Original assignee: University of Pennsylvania Penn
Current assignee: University of Pennsylvania Penn
Priority date: 2005-07-18
Filing date: 2006-07-18
Publication date: 2014-03-19
Also published as: CA2614601A1; AU2006269927A1; CA2614601C; JP2009501798A; KR20080033991A; KR101283946B1; AU2006269927B2; JP5405825B2; MX2008000573A; EP1909689A4; WO2007011955A3; JP2014001246A; JP6153952B2; EP1909689A2; WO2007011955A2; MX362908B; JP2015078233A

Abstract

The present invention relates to medicated implants and methods of use thereof, and in particular provides implants comprising a therapeutic drug and a polymer comprising polylactic acid (PLA) and optionally polyglycolic acid (PGA).

Description

Drug-containing implants and using method thereof

The application submits on July 18th, 2006, the dividing an application of the Chinese patent application 200680034307.7 that denomination of invention is " drug-containing implants and using method thereof ".

Invention field

The invention provides the implant that comprises curative drug and contain polylactic acid (PLA) and the polymer of optional polyglycolic acid (PGA).The present invention also provides and utilizes implant of the present invention to maintain the Drug therapy level in individuality, with the speed release curative drug of substantial linear, and the method for the treatment of schizophrenia and other diseases and disease.

background of invention

Medicine non-compliance (medication noncompliance) is the maximum determiner of schizophrenic recurrence.Therefore the Therapeutic Method that, helps patient to retain medicine in the time period extending can improve clinical effectiveness substantially.The method of carrying out at present antischizophrinic thing (for example risperidone) administration provides and continues one month or shorter dosage.Therefore, providing the method for the treatment level of risperidone and other drug is this area needs.

summary of the invention

In one embodiment, the invention provides biodegradable implant, it comprises: (a) with respect to the quality of described implant, by mass, the curative drug existing with the amount of 10%-60%; (b) with respect to the quality of described implant, by mass, the polymer existing with the amount of 40%-90%, described polymer comprises PLA and optional PGA, and wherein PLA:PGA molar ratio is 50:50 to 100:0.

In another embodiment, the invention provides the Drug therapy level in individuality is maintained by a definite date to the method at least about 1 month, described method comprises to one group of biodegradable implant of described individual administration, this is organized biodegradable implant and is comprised of the one or more independent biodegradable implants that comprise following component: (a) with respect to the quality of described implant, by mass, the curative drug existing with the amount of 10%-60%; (b) with respect to the quality of described implant, by mass, the polymer existing with the amount of 40%-90%, described polymer comprises PLA and optional PGA, wherein PLA:PGA molar ratio is 50:50 to 100:0, if and wherein described independent biodegradable implant outnumber one, they substantially do not have each other difference on their PLA:PGA molar ratio, thereby the Drug therapy level in individuality is maintained by a definite date at least about 1 month.

In another embodiment, the invention provides the Drug therapy level in individuality is maintained by a definite date to the method at least about 3 months, described method comprises: (1) is to the biodegradable implant of described individual administration initial set, the biodegradable implant of wherein said initial set is comprised of the one or more independent biodegradable implants that comprise following component: (a) with respect to the quality of described implant, by mass, the curative drug existing with the amount of 10%-60%; (b) with respect to the quality of described implant, by mass, the polymer existing with the amount of 40%-90%, described polymer comprises PLA and optional PGA, and wherein PLA:PGA molar ratio is 50:50 to 100:0; (2) when approaching the peak point of release of biodegradable implant of described initial set, to described individual administration, maintain the one or more biodegradable implant of group, the wherein said biodegradable implant that maintains group is comprised of other independent biodegradable implant, and the described other PLA:PGA molar ratio of independent biodegradable implant and the independent biodegradable implant of the biodegradable implant of described initial set equate.If the independent biodegradable implant of described initial set outnumber one, they substantially do not have each other difference on PLA:PGA molar ratio, thereby the Drug therapy level in individuality is maintained by a definite date at least about 3 months.

accompanying drawing summary

Fig. 1: as the result of implant, longitudinal inspection of 443 days of the haloperidol level in primates.

Fig. 2: A) put into implant in rabbit operation process.The implant that demonstration is fastened (white arrow).Otch is extended to and can be taken pictures.B) in rabbit, necropsy is presented at the implant of having degraded (black arrow) that ties position between two mosquito forcepss.After taking out implant, do not observe fibrosis.In two width images: scale=20mm.C) PLA in DMSO-d6 and 40% (w/w) haloperidol mixture ¹hNMR spectrum.Illustration: corresponding haloperidol and PLA chemical constitution.D) DMSO-d ₆in rabbit sample, peak is corresponding to the haloperidol peak of seeing in contrast spectrum.E) the rabbit sample in chloroform, consistent with the catabolite of PLA (lactic acid) with the peak at 4.5 places 0.9,1.2,3.9.

Fig. 3: from the haloperidol serum-concentration of polymeric implant in rabbit.Each group shows meansigma methods ± SEM of 5 animals.A) multiple polymer system.B) single polymers system.Each is organized data and shows with Trendline, so that the figure of serum-concentration along with the time to be described.

Fig. 4: the external concentration of accumulation of dish type and clavate implant.The meansigma methods that each point indicating panel or rod repeat for 3 times.

Fig. 5: the stability of risperidone in physiological water solution.A) residue risperidone amount is to the time.The y y-intercept of HPLC is 10.42mg, and the y y-intercept of UV spectrophotography is 10.23mg.Similarly, the linear trend line slope of HPLC is that the linear trend line slope of 0.01, UV spectrophotography is 0.00.B) use HPLC and UV spectrophotometric analysis and compared the value of positive contrast solution in A, and surface area is to the sample (Fig. 6 B) in volume ratio research.The correlation coefficient of these methods is 0.99 (182 sample), and this shows that UV spectrophotography is the accurate measurement method of the levels of drugs in external solution.

Fig. 6: external risperidone discharges along with polymer forms and SA:V ratio and changing: A) polymer forms---from the external risperidone release of accumulation of the 20% carrying capacity implant that comprises 50:50,65:35 or 75:25PLGA.The accumulation that data were expressed as along with the time always discharges %.Each point represents the standard error (SEM) of the meansigma methods ± meansigma methods of 3 implants.Completely discharge and occur in respectively approximately 40,80 and 120 days.B) SA is to volume ratio---and have small radii, therefore the rod of larger SA:V ratio (circle) shows release in vitro faster than the rod (triangle) with relatively large radius, and this is proved by the higher cumulative concentration between 28 to 44 days.Point represents from 4 excellent meansigma methods ± SEM.By HPLC and UV spectrophotometric analysis data, they produce identical result, as shown in Figure 5.

Fig. 7: the cumulative in vitro risperidone from the implant that comprises 85:15PLGA and 10,20,30,40,50 or 60 % by weight drug loading discharges.A) the accumulation risperidone quality (meansigma methods ± SEM) in external solution.B), for clear, show separately the figure of 40% risperidone implant.Comprise that correlation coefficient is that 0.99 Trendline is to illustrate this figure.C) percentage ratio that is total medicine by the cumulative release quality representation of 30,40,50 and 60% risperidone implant, the function being beneficial to release profiles as drug loading compares.The meansigma methods of all types of implants has also been described.These 4 kinds of implants Trendline separately has 0.99 correlation coefficient (R ²).Omit 10% and 20% curve to improve the visibility of double line.D), in order to promote clearness, show separately 40% medicine carrying group.

Fig. 8: risperidone implant increases PPI but do not increase and startle.Implantation latter 14 days and 21 days, risperidone implant increased PPI (p=0.052), and startle, there is no significant change.

Fig. 9: the N40 that risperidone implant increases P20 and blocks amfetamine induction brings out the interruption of current potential.A) amfetamine that risperidone implant improves the P20 amplitude (p=0.03) in C57BL/6J mice and weakens N40 (p=0.02) reduces.

Figure 10: different pharmaceutical is as the release amount (being standardized as total amount) of the function of time.Although all release profiles all meet similar S shape, in initial release region, the ratio of the slope in constant release district (wherein Af/ Δ t is constant) and completely characteristic time (f=1) aspect of release is all very different.

Figure 11: use fitting parameter D and k by haloperidol (A) and ibuprofen (ibuprofene) (B) data fitting in the model shown in equation 4: for (A), k is about 0.1 (1/ day), and D is 0.045.For (B), k is about 0.164 (1/ day), and D is 0.051.

Figure 12: the relation between the diffusion coefficient D that after 14 days, the maxima solubility (with mg/mL) of medicine in water and water enter polymer/drug complex, its calculate Zi by the data fitting of Figure 10 to equation 4.5.3 powers of D and dissolubility are proportional.

Figure 13: biodegradable implant pass continuously medicine model: serum-concentration figure A) being produced by one or more single polymers implants.Trendline represents drug release figure.B) implant the superimposed curves separately of single polymers implant system 4 times.Within every 6 months, again implant this polymer-drug regimen.C) with solid line (sold line), show the total serum concentration being produced by each overlapping implantation (dotted line).For given material, as long as implant, occur in the time place that approaches peak concentration, though level is slightly vibrated, but still maintain in target zone.In all groups, arrow labelling is implanted.

Figure 14: the risperidone serum-concentration being produced by multiple polymer risperidone implant system.A) serum-concentration being produced by one group of 4 rapid release implant.B) serum-concentration being produced by 5 polymer systems, wherein using the polymer of 4 fast degradations (" starting group ") with as maintain every 6 months of group again 1 of implantation continue longer combination of polymers.With solid line, represent total drug level, dot the release profiles of each polymer.After about 1 week, obtain drug target level, at aimed concn, have slight vibration around thereafter.

Figure 15: the insertion of clavate implant and removing.A) by the hole of 4-mm, insert the clavate implant of 1-cm.Illustration is presented at the 1-cm implant before insertion.B) use the trocar, by the hole of 4-mm, insert implant.C) with the implantation position after single needle stitching.D) after 10 minutes, the mice in rearging cage does not have painful sign.E) implant the mice after 2 weeks.Implantation position heals completely, does not record painful sign or adverse events.F) mice of a subgroup is removed implant to evaluate the reversibility of this operation after implanting 2 weeks or 4 weeks.G) at two time points, be all easy to remove implant, and there is no the sign of adhesion or local cicatrix.Illustration---the implant of removing.H) removing implant after 10 minutes, a mice exposes back in its rearging cage.Then put to death the mice in these groups and obtain serum risperidone and 9-OH risperidone level.Aseptic risperidone implant obtains 7.3 serum risperidone level after implanting 2 weeks, after implanting 4 weeks, is 12.8.B) with single needle, sew up rear home position manifestation implant.C) after 10 minutes, the mice in rearging cage does not have painful sign.

Figure 16: the typical section of clavate of the present invention, dish type and cylindrical implant (non exhaustive list).

Figure 17: from the external risperidone concentration of implant, meansigma methods ± S.E.M, n=4.

Figure 18: the release profiles of aseptic and non-sterile implant in mice, each time point aseptic (S) or non-sterile (U) n=4 separately.

Figure 19: the risperidone content the implant of removing from mice, is expressed as the percentage ratio of implant quality.

Risperidone stability in Figure 20: A.pH7.4,6.4,5.4 and 4.4 solution.It is stable that all samples all keeps, test initial 77 days in, have drug quality insignificant every diurnal variation (pH7.4 be 0.06%, pH6.4 be 0.04%, pH5.4 be 0.10% and pH4.4 be 0.00%).B. risperidone is in the stability of pH2.0-7.4.

detailed Description Of The Invention

In one embodiment, the invention provides implantable long-term delivery system, it is for improving the drug compliance (medication adherence) of the disease relevant with the probability of not complying with.In one embodiment, described delivery system is included in the curative drug in implantable clavate structure, and improves drug compliance in the individuality of suffering from the disease relevant with the probability of not complying with.

In different embodiments, term " implantable " comprises and can be inserted into the compositions in (such as subcutaneous, intramuscular etc.) individuality.In another embodiment, described implantable compositions or removable.

In different embodiments, term " for a long time " comprises and is greater than approximately three months, is greater than approximately four months, is greater than approximately five months, is greater than approximately six months, is greater than approximately seven months, is greater than approximately eight months, is greater than approximately nine months, is greater than approximately ten months, is greater than approximately 11 months, is greater than approximately one year or the longer time period.

In one embodiment, term " long-term delivery system " comprises such system, once it is to individual administration, just progressively goal treatment medicine is delivered to individual with the treatment disease relevant with the probability of not complying with effective dose.In other embodiments, can be greater than approximately three months, be greater than approximately four months, be greater than approximately five months, be greater than approximately six months, be greater than approximately seven months, be greater than approximately eight months, be greater than approximately nine months, be greater than approximately ten months, be greater than approximately 11 months, be greater than approximately one year or sending described medicine in longer time period.

In one embodiment, term " improves drug compliance " and refers to improve and suffers from the percentage of time of its disease of goal treatment Drug therapy for the individuality of the disease relevant with the probability of not complying with.

In one embodiment, term " disease relevant with the probability of not complying with " comprises psychosis, such as: schizophrenia, bipolar disorder, dementia, delirium, impulse control disorder, psychotic depression, drug dependence etc.In one embodiment, term " disease relevant with the probability of not complying with " refers to the disease of the individual non-compliance with height ratio.In another embodiment, it comprises judgement or intelligent disease that impact is individual.In another embodiment, this term comprises and has low ratio the disease of the individual compliance of (for example,, in different embodiments, lower than 90%, lower than 80%, lower than 70%, lower than 60%, lower than 50%, lower than 40% with lower than 30%).

In one embodiment, term " curative drug " comprises the medicine that is used for the treatment of the disease relevant with the probability of not complying with.In another embodiment, described curative drug shows the dissolubility increasing in the pH environment reducing.In another embodiment, described curative drug is antidepressants.In another embodiment, described curative drug is antianxiety drugs.In another embodiment, described curative drug is psychosis.In another embodiment, described curative drug is birth control medicine.

In another embodiment, " dissolubility of increase " refers to that dissolubility improves at least 10% under neutral pH.In another embodiment, this term refers to that dissolubility improves at least 20% under neutral pH.In another embodiment, described in, rise at least 30%.In another embodiment, described in, rise at least 40%.In another embodiment, described in, rise at least 50%.In another embodiment, described in, rise at least 60%.In another embodiment, described in, rise at least 70%.In another embodiment, described in, rise at least 80%.In another embodiment, described in, rise at least 100% (2 times).In another embodiment, described in, rise at least 3 times.In another embodiment, described in, rise at least 4 times.In another embodiment, described in, rise at least 5 times.In another embodiment, described in, rise at least 6 times.In another embodiment, described in, rise at least 8 times.In another embodiment, described in, rise at least 3 times.In another embodiment, described in, rise at least 10 times.In another embodiment, described in, rise at least 15 times.In another embodiment, described in, rise at least 20 times.In another embodiment, described in, rise at least 30 times.In another embodiment, described in, rise at least 40 times.In another embodiment, described in, rise at least 50 times.In another embodiment, described in, rise at least 70 times.In another embodiment, described in, rise at least 100 times.In another embodiment, described in, rise at least 150 times.In another embodiment, described in, rise at least 200 times.In another embodiment, described in, rise at least 300 times.In another embodiment, described in, rise at least 500 times.In another embodiment, described in, rise at least 1000 times.In another embodiment, described in, rise to and be at least greater than 1000 times.In another embodiment, described medicine shows insignificant dissolubility under neutral pH.Various probabilities represent independently embodiment of the present invention.

In another embodiment, " the pH environment of reduction " refers to the pH lower than 5.0.In another embodiment, this term refers to the pH lower than 4.5.In another embodiment, this term refers to the pH lower than 4.0.In another embodiment, this term refers to the pH lower than 3.5.In another embodiment, this term refers to the pH lower than 3.0.In another embodiment, this term refers to the pH lower than 2.5.In another embodiment, this term refers to the pH lower than 2.0.In another embodiment, this term refers to 5.0 pH.In another embodiment, this term refers to 4.5 pH.In another embodiment, this term refers to 4.0 pH.In another embodiment, this term refers to 3.5 pH.In another embodiment, this term refers to 3.0 pH.In another embodiment, this term refers to 2.5 pH.In another embodiment, this term refers to 2.0 pH.Various probabilities represent independently embodiment of the present invention.

In another embodiment, the invention provides biodegradable implant, it comprises: (a) with respect to the quality of described implant, by mass, the curative drug existing with the amount of 10%-60%; (b) with respect to the quality of described implant, by mass, the polymer existing with the amount of 40%-90%, described polymer comprises PLA and optional PGA, and wherein PLA:PGA molar ratio is 50:50 to 100:0.

In another embodiment, the implant of method and composition of the present invention is aseptic implant.In another embodiment, described implant needn't be for aseptic.In another embodiment, described implant is substantially aseptic.In another embodiment, described implant sterilizing.In another embodiment, described implant is aseptic, just has a small amount of pollution of introducing between taking out from aseptic packaging and implanting.Various probabilities represent independently embodiment of the present invention.

When for this paper, in one embodiment, term " biodegradable " refers to the material of degrading in biotic environment.In another embodiment, " biodegradable " refers to the material in biotic environment with the limited half-life.In another embodiment, " biodegradable " refers to the material in biotic environment with measurable half-life.In another embodiment, " biodegradable " refers to the material at living organism vivo degradation.In another embodiment, " biodegradable " refers to the material in live organism with the limited half-life.In another embodiment, " biodegradable " refers to the material in live organism with measurable half-life.In another embodiment, term " biodegradable " is equivalent to term (bioerodible) of bioerodable " can ".

In one embodiment, the described half-life is 1 month or shorter.In another embodiment, the described half-life is 2 months or shorter.In another embodiment, the described half-life is 3 months or shorter.In another embodiment, the described half-life is 4 months or shorter.In another embodiment, the described half-life is 5 months or shorter.In another embodiment, the described half-life is 6 months or shorter.In another embodiment, the described half-life is 8 months or shorter.In another embodiment, the described half-life is 10 months or shorter.In another embodiment, the described half-life is 1 year or shorter.In another embodiment, the described half-life is 1.5 years or shorter.In another embodiment, the described half-life is 2 years or shorter.In another embodiment, the described half-life is 3 years or shorter.In another embodiment, the described half-life is 4 years or shorter.In another embodiment, the described half-life is 5 years or shorter.In another embodiment, the described half-life is 7 years or shorter.In another embodiment, the described half-life is 10 years or shorter.Various probabilities represent independently embodiment of the present invention.

In one embodiment, " polymer " refers to by independent unit or the macromole of monomer composition.In another embodiment, described polymer is branched polymer.In another embodiment, described polymer is linear polymer.In another embodiment, described polymer is cross linked polymer.The polymer of any other type that in another embodiment, described polymer is known in the art.Various probabilities represent independently embodiment of the present invention.

PLA:PGA polymer comprises PLA and PGA monomer, and PLA polymer only comprises PLA monomer.The using method of PLA polymer and PLA:PGA polymer and synthetic method are well known in the art, are described in such as people such as Fukushima (Macromol Biosci5 (1): 21-9,2005); People (the Macromol Biosci15 such as Saulnier B; 4 (3): 232-7,2004) and in the people (J Colloid Interface Sci271 (2): 336-41,2004) such as Park SJ.Various probabilities represent independently embodiment of the present invention.

In one embodiment, the implant of method and composition of the present invention is clavate.As provided herein, result demonstration clavate implant of the present invention and disc implant can be used in sending for a long time of risperidone and other drug is provided.In another embodiment, described implant is dish type.In another embodiment, implant is cylindrical.In another embodiment, implant is thin slice.In another embodiment, described implant for example, for being suitable for being retained in any shape in bodily tissue (subcutaneous tissue).In another embodiment, described implant is for being suitable for constitutionally stable any shape in subcutaneous space.In another embodiment, described implant is any shape that is suitable for tolerating in subcutaneous space.In another embodiment, any other shape that described implant is known in the art.

In one embodiment, " clavate " refers to that its cross section is essentially the shape that circular and its length is at least described diameter of section twice.In another embodiment, described cross sectional shape is any other cross sectional shape of the present invention.In another embodiment, described length is at least equally long with the diameter in described cross section.In another embodiment, described length is at least 1.1 times of described diameter of section.In another embodiment, described length is at least 1.2 times of described diameter.In another embodiment, described length is at least 1.3 times of described diameter.In another embodiment, described length is at least 1.4 times of described diameter.In another embodiment, described length is at least 1.5 times of described diameter.In another embodiment, described length is at least 1.6 times of described diameter.In another embodiment, described length is at least 1.7 times of described diameter.In another embodiment, described length is at least 1.8 times of described diameter.In another embodiment, described length is at least 1.9 times of described diameter.In another embodiment, described length is at least 2.2 times of described diameter.In another embodiment, described length is at least 2.5 times of described diameter.In another embodiment, described length is at least 3 times of described diameter.In another embodiment, described length is at least 4 times of described diameter.Various probabilities represent independently embodiment of the present invention.

In one embodiment, " dish type " refers to the circle that is essentially flat.In another embodiment, described in, be shaped as ellipse, square, rectangle etc.In one embodiment, thickness is less than the diameter of circle, ellipse etc.In another embodiment, described thickness is less than 0.9 times of diameter of described shape.In another embodiment, described thickness is less than 0.8 times of described diameter.In another embodiment, described thickness is less than 0.7 times of described diameter.In another embodiment, described thickness is less than 0.6 times of described diameter.In another embodiment, described thickness is less than 0.5 times of described diameter.In another embodiment, described thickness is less than 0.4 times of described diameter.In another embodiment, described thickness is less than 0.3 times of described diameter.In another embodiment, described thickness is less than 0.2 times of described diameter.In another embodiment, described thickness is less than 0.1 times of described diameter.Various probabilities represent independently embodiment of the present invention.

In one embodiment, described clavate, dish type and the cylindrical shape that refers in this article have the circular cross-section of being essentially.In another embodiment, described cross sectional shape is oval-shaped.What in another embodiment, described ellipse needn't be for circle at edge.In another embodiment, described cross sectional shape is any shape in Figure 16.In another embodiment, any other shape that described cross sectional shape is known in the art.Because the present invention shown the rate of releasing drug of implant and its surface area proportional, so in one embodiment, in order to make it have the feature of expectation, do not change rate of release, can revise the shape of implant, it is constant that condition is that surface area maintains.The present invention shown the release persistent period of implant and its SA:V ratio proportional; Therefore, in one embodiment, do not change the persistent period of release in order to make it have the feature of expectation, can revise the shape of implant, condition is that SA:V ratio remains constant.Various shape representations independently embodiment of the present invention.

In another embodiment, " be essentially circular " refers to that it is anyly less than its 150% justifies or be similar to round shape of short diameter to the longest diameter in uniform section.In another embodiment, the longest diameter in each cross section be less than its shortest diameter 145%.In another embodiment, this numeral is 140%.In another embodiment, this numeral is 135%.In another embodiment, this numeral is 130%.In another embodiment, this numeral is 125%.In another embodiment, this numeral is 120%.In another embodiment, this numeral is 115%.In another embodiment, this numeral is 110%.In another embodiment, this numeral is 105%.

In another embodiment, described longest diameter be no more than described in the shortest diameter 150%.In another embodiment, described longest diameter be no more than described in the shortest diameter 145%.In another embodiment, described longest diameter be no more than described in the shortest diameter 140%.In another embodiment, described longest diameter be no more than described in the shortest diameter 135%.In another embodiment, described longest diameter be no more than described in the shortest diameter 130%.In another embodiment, described longest diameter be no more than described in the shortest diameter 125%.In another embodiment, described longest diameter be no more than described in the shortest diameter 120%.In another embodiment, described longest diameter be no more than described in the shortest diameter 115%.In another embodiment, described longest diameter be no more than described in the shortest diameter 110%.In another embodiment, described longest diameter be no more than described in the shortest diameter 105%.

In another embodiment, longest diameter is that meeting basic is any other circular ratio to the ratio of short diameter.In another embodiment, this numeral is any other circular numeral for describing substantially.Various probabilities represent another embodiment of the present invention.

In another embodiment, substantially constant in the length of described area of section on rod of the present invention, dish and cylinder.In another embodiment, described area of section is non-constant.In another embodiment, substantially constant in the length of described sectional dimension on rod of the present invention, dish and cylinder.In another embodiment, described sectional dimension is non-constant.Various probabilities represent independently embodiment of the present invention.

In another embodiment, implant of the present invention has rectangular cross sectional shape.In another embodiment, described cross sectional shape is square.In another embodiment, any other shape that described cross sectional shape is known in the art.

In another embodiment, described implant is monolithic.In another embodiment, described implant is comprised of compared with widgets several (10 or still less) that combine.In another embodiment, described assembly is joined together.Various probabilities represent independently embodiment of the present invention.

Above-mentioned all shapes and cross sectional shape represent respectively independently embodiment of the present invention.

The method of inserting implant is well known in the art.In one embodiment, use the operating theater instruments that is called " trocar ", by the minimum mode of infection, insert implant.In another embodiment, utilization is similar to Norplant (Townsend S " Insertion and removal of Norplant " Netw Fr6:8-9,1991) operation and tool set (trocar and sleeve) used and inserts described implant.In another embodiment, clavate implant is because it is easy to implant and do not have follow-up sense of discomfort that advantage (Figure 15) is provided.In another embodiment, the advantage of clavate implant is to insert their required little otch; For example: in different embodiments, be about 2mm, 3mm, 4mm, 5mm, 6mm or 7mm.In another embodiment, implant is because it can be implanted advantage is provided to out-patient.In another embodiment, with single needle or aseptic stitching described incision site (Figure 15).In another embodiment, by any other operation method known in the art, insert described implant.The whole bag of tricks represents independently embodiment of the present invention.

In another embodiment, implant of the present invention is because individuality needn't provide advantage every a few week acceptance injections, thus raising patient compliance.In another embodiment, the advantage of described implant is because the patient of the raising obtaining is autonomous.In another embodiment, the advantage of described implant is because they do not stimulate at medicine-feeding part.

In another embodiment, the advantage of implant of the present invention is due to they stability under body temperature during passing medicine.

In another embodiment, the advantage of implant of the present invention is due to they corrosions completely, thereby needn't remove retained material.In one embodiment, corrosion is mainly surface erosion.In one embodiment, corrosion is mainly bulk erosion.In another embodiment, corrosion is the combination of exhibiting high surface corrosion and bulk erosion.Various probabilities represent independently embodiment of the present invention.

In another embodiment, the implant of method and composition of the present invention is fastened to (Fig. 2) to help its location, and if desired, remove it.As herein provided, this method of removing is successfully tested in Mouse and rat.In another embodiment, after implant described in palpation, make little otch and with tweezers, fetch the retained material of described implant.

In another embodiment, described implant is removable.In one embodiment, " removable " refers to the ability of removing described implant by operation or other modes.In another embodiment, " removable " refers to the ability of removing residue implant.In another embodiment, " removable " refers to the ability of removing most of surplus implant.In one embodiment, because side effects of pharmaceutical drugs are wherein removed described implant.In another embodiment, because described implant is removed in doctor's decision.In another embodiment, because described implant is removed in patient's decision.In another embodiment, because overdose is removed described implant.In another embodiment, due to expectation, to end any other of therapeutic process former thereby remove described implant.(Figure 15) as herein provided, implant of the present invention whole be easy to remove and keep hesive during passing medicine.In another embodiment, described implant whole be removable during passing medicine.In another embodiment, described implant whole detectable be removable during passing medicine.In another embodiment, described implant is easy to remove during passing medicine whole.In another embodiment, described implant is detectablely easy to remove during passing medicine whole.In another embodiment, described implant whole be hesive during passing medicine.In another embodiment, described implant whole detectable be hesive during passing medicine.Various probabilities represent independently embodiment of the present invention.

In another embodiment, " be easy to remove " to refer to use tweezers or ability that similarly instrument is removed.In another embodiment, described term refers to the ability of not using strong suction to remove.In another embodiment, described term refers to and is removed and must not removes the ability of surrounding tissue.Various probabilities represent independently embodiment of the present invention.

In another embodiment, implant of the present invention shows that internal pH environment is along with depolymerization becomes compositing monomer and the advantage that declines.In another embodiment, pH declines along with degraded and has improved the time dependence release of following medicine and activating agent, described medicine and activating agent insoluble in neutral pH (and being therefore locked in described implant), but along with pH declines and becomes more and more solvable.In another embodiment, described implant has been improved the release of the medicine of the dissolubility under low pH with rising.In another embodiment, described implant has been improved the release of the medicine with acid pKa.In another embodiment, the time dependence of described increase discharges to have improved compound is released into the ability in systemic circulation.

In another embodiment, the medicine that has a pH dependent solubility is haloperidol.In another embodiment, described pH dependent drug is risperidone.In another embodiment, any other medicine with pH dependent solubility that described pH dependent drug is known in the art.Various probabilities represent another embodiment of the present invention.

In another embodiment, pH declines along with degraded and improves described polymer degradation rate in time.In another embodiment, pH declines along with degraded and has caused the self-catalysis degraded of described polymer.Various probabilities represent independently embodiment of the present invention.

In another embodiment, implant of the present invention shows the advantage that pH declines along with degraded, and this advantage for example, is not observed in less dosage form (microgranule).

In another embodiment, the polymer for method and composition of the present invention comprises PLA and does not contain PGA.In another embodiment, described polymer comprises PLA and PGA.In another embodiment, described polymer is only comprised of PLA.In another embodiment, described polymer is comprised of PLA and PGA.Various probabilities represent independently embodiment of the present invention.

In another embodiment, the drug loading of the implant of method and composition of the present invention is 30-60%.(embodiment 7) as herein provided, result of the present invention has proved the usefulness of the biodegradable implant within the scope of specific medicine carrying.In one embodiment, " drug loading " refers to the amount of the mass percent of medicine in described implant.In another embodiment, " drug loading " refers to the percentage by weight of described medicine.In another embodiment, if for example also there is other materials except described curative drug and described polymer in described implant, described other materials is not considered in the calculating of described drug loading.Various probabilities represent independently embodiment of the present invention.

In another embodiment, described drug loading is about 40-50%.In another embodiment, described drug loading is 1-5%.In another embodiment, described drug loading is 2-5%.In another embodiment, described drug loading is 5-10%.In another embodiment, described drug loading is 10-15%.In another embodiment, described drug loading is 15-20%.In another embodiment, described drug loading is 20-25%.In another embodiment, described drug loading is 25-30%.In another embodiment, described drug loading is 30-35%.In another embodiment, described drug loading is 35-40%.In another embodiment, described drug loading is 40-45%.In another embodiment, described drug loading is 45-50%.In another embodiment, described drug loading is 50-55%.In another embodiment, described drug loading is 55-60%.In another embodiment, described drug loading is 60-65%.In another embodiment, described drug loading is 65-70%.In another embodiment, described drug loading is 70-75%.In another embodiment, described drug loading is 75-80%.In another embodiment, described drug loading is 80-85%.In another embodiment, described drug loading is 85-90%.In another embodiment, described drug loading is 90-95%.In another embodiment, described drug loading is 95-99%.In another embodiment, described drug loading is 5-15%.In another embodiment, described drug loading is 10-20%.In another embodiment, described drug loading is 15-25%.In another embodiment, described drug loading is 20-30%.In another embodiment, described drug loading is 25-35%.In another embodiment, described drug loading is 30-40%.In another embodiment, described drug loading is 35-45%.In another embodiment, described drug loading is 45-55%.In another embodiment, described drug loading is 50-60%.In another embodiment, described drug loading is 55-65%.In another embodiment, described drug loading is 60-70%.In another embodiment, described drug loading is 70-80%.In another embodiment, described drug loading is 80-90%.In another embodiment, described drug loading is 90-99%.In another embodiment, described drug loading is 5-20%.In another embodiment, described drug loading is 10-25%.In another embodiment, described drug loading is 15-30%.In another embodiment, described drug loading is 20-35%.In another embodiment, described drug loading is 25-40%.In another embodiment, described drug loading is 30-45%.In another embodiment, described drug loading is 35-50%.In another embodiment, described drug loading is 40-55%.In another embodiment, described drug loading is 45-60%.In another embodiment, described drug loading is 50-65%.In another embodiment, described drug loading is 55-70%.In another embodiment, described drug loading is 5-25%.In another embodiment, described drug loading is 10-30%.In another embodiment, described drug loading is 15-35%.In another embodiment, described drug loading is 20-40%.In another embodiment, described drug loading is 25-45%.In another embodiment, described drug loading is 30-50%.In another embodiment, described drug loading is 35-55%.In another embodiment, described drug loading is 40-60%.In another embodiment, described drug loading is 45-65%.In another embodiment, described drug loading is 50-70%.

In another embodiment, described drug loading is 2%.In another embodiment, described drug loading is 3%.In another embodiment, described drug loading is 5%.In another embodiment, described drug loading is 6%.In another embodiment, described drug loading is 8%.In another embodiment, described drug loading is 10%.In another embodiment, described drug loading is 12%.In another embodiment, described drug loading is 14%.In another embodiment, described drug loading is 16%.In another embodiment, described drug loading is 18%.In another embodiment, described drug loading is 20%.In another embodiment, described drug loading is 22%.In another embodiment, described drug loading is 24%.In another embodiment, described drug loading is 26%.In another embodiment, described drug loading is 28%.In another embodiment, described drug loading is 30%.In another embodiment, described drug loading is 32%.In another embodiment, described drug loading is 34%.In another embodiment, described drug loading is 36%.In another embodiment, described drug loading is 38%.In another embodiment, described drug loading is 40%.In another embodiment, described drug loading is 42%.In another embodiment, described drug loading is 44%.In another embodiment, described drug loading is 46%.In another embodiment, described drug loading is 48%.In another embodiment, described drug loading is 50%.In another embodiment, described drug loading is 52%.In another embodiment, described drug loading is 54%.In another embodiment, described drug loading is 56%.In another embodiment, described drug loading is 58%.In another embodiment, described drug loading is 60%.In another embodiment, described drug loading is 65%.In another embodiment, described drug loading is 70%.Various drug loading represent independently embodiment of the present invention.

For describing numeral and other scopes of method and composition of the present invention, be understood to comprise boundary value.Each value in described scope or the combination of a plurality of values represent independent embodiment of the present invention.

In one embodiment, " curative drug " is when to individual administration, to show the therapeutic effect of any type or any medicine or the compound of beneficial effect.In another embodiment, the contained curative drug of the implant of method and composition of the present invention is risperidone.In another embodiment, described curative drug is 9-OH-risperidone.In another embodiment, described curative drug is tiotixene.In another embodiment, described curative drug is haloperidol.In another embodiment, described curative drug is hydrochlorothiazide (HCTZ).In another embodiment, described curative drug is corticosterone.In another embodiment, described curative drug is ibuprofen.In another embodiment, described curative drug is aspirin.In another embodiment, described curative drug is pimozide.In another embodiment, described curative drug is Aripiprazole.In another embodiment, described curative drug is olanzapine.In another embodiment, described curative drug is donepezil.In another embodiment, any other curative drug that described curative drug is known in the art.

In one embodiment, the advantage that PLA polymer and PLA:PGA polymer show is that medicine needn't carry out chemical modification before being impregnated in wherein; On the contrary, only they mechanical mixture need to be entered in described polymeric matrix.Therefore, can mix multiple therapeutic agent.

In other embodiments, described curative drug is dopaminergic.In one embodiment, described dopaminergic is agonist.In one embodiment, described dopaminergic is antagonist.In one embodiment, described dopaminergic is partial agonist.In one embodiment, described dopaminergic is monoamine reuptake inhibitors.In one embodiment, described dopaminergic is monoamine uptake promoter.

In other embodiments, described curative drug one of is following medicine or belongs to one of following kind: antihypertensive, antidepressants, antianxiety drugs, anticoagulation (anticlotting agent), anticonvulsant, blood sugar lowering, Decongestant, antihistaminic, cough medicine, anti-inflammatory agent, psychosis, cognition enhancer, pravastatin, appetrol, autoimmune disease medicine, anti-sexual impotence medicine, antimicrobial drug and antifungal agent, sleeping pill, antiparkinsonism drug, antibiotic, antiviral agents, antineoplastic agent, barbiturate (barbituate), tranquilizer, nutrient, beta blocker, emetic, Bendectin, diuretic, anticoagulant, cardiac tonic, androgens, adrenocortical hormones, anabolic agent, growth hormone cinogenic agent, anti-infective, Coronary Vasodilators, carbonic anhydrase inhibitors, antiprotozoal, gastrointestinal tract medicine, 5-hydroxytryptamine antagonist, anesthetics, blood sugar lowering, anti-Alzheimer disease medicine, antiulcerative, platelet suppressant drug, glycogen phosphorylase inhibitors and phosphodiesterase inhibitor.

In other embodiments, described curative drug one of is following medicine: chlorpropamide, fluconazol, Atorvastatin calcium, hydroxyzine hydrochloride, doxepin hydrochloride, Amlodipine Besylate Tablet, piroxicam, celecoxib (celicoxib), valdecoxib (valdicoxib), carindacillin sodium, bacampicillin hydrochloride, triacetyloleandomycin and doxycycline hydrochloride.

In other embodiments, described curative drug one of is following medicine or belongs to one of following kind: platinum compounds (spiroplatin for example, cisplatin and carboplatin), methotrexate, fluorouracil, amycin, mitomycin, peace silk mycin, bleomycin, cytosine arabinoside, arabinosyladenine, sulfydryl polylysine, vincristine, busulfan, chlorambucil, melphalan (PAM for example, L-PAM or melphalan), mercaptopurine, mitotane, procarbazine hydrochloride, dactinomycin (actinomycin D), daunorubicin hydrochloride, doxorubicin hydrochloride, paclitaxel and other taxaneses (taxenes), rapamycin, Manumycin A, TNP-470, plicamycin (mithramycin), aminoglutethimide, estramustine phosphate sodium, flutamide, leuprorelin acetate, megestrol acetate, Tamoxifen Citrate, testolactone, trilostane, amsacrine (m-AMSA), asparaginase (L-ASP), erwinia asparaginase, Intederon Alpha-2a, Interferon Alpha-2b, teniposide (VM-26), vinblastine sulfate (VLB), vincristine sulfate, Bleomycin Sulphate, hydroxyurea, procarbazine and dacarbazine, mitotic inhibitor, for example etoposide, colchicine and vinca alkaloids, radiopharmaceutical, for example radioiodine and phosphorus product, hormones, for example progestogens, estrogens and anti-estrogens, vermifuge, antimalarial and antitubercular agent, biological product, for example immune serum, antitoxin and venom, rabies prophylaxis goods, bacterial vaccine, viral vaccine, respiratory product, for example xanthine derivative theophylline and aminophylline, thyroid drug, for example iodine goods and antithyroid drug, cardiovascular goods, comprise chelating agen and mercurial diuretic and cardiac glycoside, glucagon, blood products, for example parenteral ferrum, chlorhematin, blood porphyrin and derivant thereof, biological response modifier, for example subunit (for example mycobacteria, corynebacterium) of muramyldipeptide, muramyl-tripeptide, microorganism wall composition, lymphokine (for example antibacterial endomycin is as lipopolysaccharide, macrophage activating factor), antibacterial, synthetic dipeptides N-acetyl group-muramyl-L-alanyl-D-isoglutamic acid, antifungal agent, for example ketoconazole, nystatin, griseofulvin, flucytosine (5-fc), miconazole, amphotericin B, ricin, cyclosporine and beta-Lactam antibiotic (for example sulfanilamide amide rhzomorph), hormones, growth hormone for example, melanotropin, estradiol, beclometasone, betamethasone, betamethasone acetate and betamethasone sodium phosphate, Vetamethasone disodium hydrogen phosphate, Vetamethasone sodium phosphate, cortisone acetate, dexamethasone, dexamethasone acetate, dexamethasone sodium phosphate, flunisolide, hydrocortisone, hydrocortisone acetate, hydrocortisone cipionate, hydrocortisone sodium phosphate, hydrocortisone sodium succinate, methylprednisolone, methylprednisolone acetate, Methylprednisolone Sodium Succinate, paramethasone acetate, prednisolone, prednisolone acetate, prednisolone phosphate ester sodium, special cloth acid prednisolone, prednisone, triamcinolone, triamcinolone acetonide, triamcinolone diacetate, triamcinolone hexacetonide, fludrocortisone acetate, oxytocin, vassopressin and derivant thereof, vitamins, for example chlorine cobalt ammonium neinoic acid, retinoid and derivant, for example vitamin A palmitate and alpha-tocopherol, peptide class, for example Mn-superoxide dismutase, enzyme, for example alkali phosphatase, antiallergic agent, for example amelexanox, anticoagulant, for example phenprocoumon and heparin, blood circulation medicine, for example Propranolol, metabolism reinforcing agent, for example glutathione, antitubercular agent, for example para-aminosalicylic acid, isoniazid, capreomycin sulfate Capastat sulfate, cycloserine, ebutol, ethionamide, pyrazinamide, rifampicin and streptomycin sulfate, antiviral agents, for example amantadine, azidothymidine AZT (AZT, DDI, FOSCARNET or zidovudine), ribavirin and a hydration vidarabine (vidarabine, ara-A), anti-anginal drug, for example diltiazem, nifedipine, verapamil, erythrityl tetranitrate, sorbide nitrate, nitroglycerin (glyceryl trinitrate) and pentaerithrityl tetranitrate, anticoagulant, for example phenprocoumon, heparin, antibiotic, for example dapsone, chloromycetin, neomycin, cefaclor, cefadroxil, cefalexin, cefradine, erythromycin, clindamycin, lincomycin, amoxicillin, ampicillin, bacampicillin, carbenicillin, dicloxacillin, cyclacillin, picloxacillin, hetacillin, methicillin, nafcillin, oxazacillin, penicillin comprise benzylpenicillin and penicillin V, ticarcillin, rifampicin and tetracycline, anti-inflammatory agent, for example diflunisal, ibuprofen, indomethacin, Meclofenamate, mefenamic acid, naproxen, oxyphenbutazone, Phenylbutazone, piroxicam, sulindac, tolmetin, aspirin and Salicylate, antiprotozoal, for example chloroquine, oxychloroquine, metronidazole, quinine and protostib (meglumine antimonate), antirheumatic, for example penicillamine, anesthetics, for example paregoric, opiates, for example codeine, heroin, methadone, morphine and opium, cardiac glycoside, for example deslanoside, Digitoxin, digoxin, digitalin and digitalis, neuromuscular blocking agent, for example atracurium methanesulfonates, gallamine triethiodide, hexafluronium bromide, sulphur Metocurine, pancuronium bromide, Choline Chloride Succinate (Choline Chloride Succinate), tubocurarine chloride and vecuronium bromide, tranquilizer (sleeping pill), for example amobarbital, amobarbital sodium, allopropylbarbital, butabarbital sodium, chloral hydrate, ethchlorvynol, ethinamate, flurazepam hydrochloride, glutethimide, levomepromazine hydrochloride, methyprylon, midazolam hydrochloride, Paraldehyde, pentobarbital, pentobarbital sodium, sodium phenobarbital, barbose, talbumal (talbutal), temazepam and triazolam, local anaesthetics, for example bupivacaine hydrochloride, chloroprocaine hydrochloride, etidocaine hydrochloride, lidocaine hydrochloride, Mepivacaine Hydrochloride, procaine hydrochloride and tetracaine hydrochloride, GENERAL ANESTHETICS, for example droperidol, etomidate, Fentanyl Citrate and Droperidol, ketalar, methohexital sodium and penthiobarbital, and radioactive particle or ion, for example strontium, iodate rhenium (iodide rhenium) and yttrium.

In another embodiment, the metabolite that described curative drug is risperidone.In another embodiment, the metabolite that described curative drug one of is said medicine.In one embodiment, described metabolite is active metabolite.

In another embodiment, the medicine that described curative drug is life-time service.

In another embodiment, described curative drug is high-effect medicine.In one embodiment, " high-effect medicine " refers to the medicine that needs low serum-concentration can bring into play treatment effect.In another embodiment, " high-effect medicine " refers to the medicine that needs low tissue concentration can bring into play treatment effect.In one embodiment, " high-effect medicine " refers to the medicine that needs low systemic concentrations can bring into play treatment effect.Various probabilities represent independently embodiment of the present invention.

In one embodiment, the required concentration of high-effect medicine performance treatment effect is 0.01mg/kg.In another embodiment, described concentration is 0.02mg/kg.In another embodiment, described concentration is 0.03mg/kg.In another embodiment, described concentration is 0.04mg/kg.In another embodiment, described concentration is 0.05mg/kg.In another embodiment, described concentration is 0.06mg/kg.In another embodiment, described concentration is 0.07mg/kg.In another embodiment, described concentration is 0.08mg/kg.In another embodiment, described concentration is 0.09mg/kg.In another embodiment, described concentration is 0.10mg/kg.In another embodiment, described concentration is 0.12mg/kg.The various definition of " high-effect medicine " represent independently embodiment of the present invention.

In one embodiment, the required concentration of high-effect medicine performance treatment effect is 1 nanogram (ng)/ml.In another embodiment, described concentration is 1.5ng/ml.In another embodiment, described concentration is 2ng/ml.In another embodiment, described concentration is 3ng/ml.In another embodiment, described concentration is 4ng/ml.In another embodiment, described concentration is 5ng/ml.In another embodiment, described concentration is 6ng/ml.In another embodiment, described concentration is 7ng/ml.In another embodiment, described concentration is 8ng/ml.In another embodiment, described concentration is 9ng/ml.In another embodiment, described concentration is 10ng/ml.In another embodiment, described concentration is 12ng/ml.In another embodiment, described concentration is 15ng/ml.In another embodiment, described concentration is 20ng/ml.The various definition of " high-effect medicine " represent independently embodiment of the present invention.

Various curative drugs represent independent embodiment of the present invention.

In another embodiment, the combination that the implant of method and composition of the present invention comprises curative drug.In one embodiment, described implant comprises two kinds of curative drugs.In another embodiment, described implant comprises three kinds of curative drugs.In another embodiment, described implant comprises four kinds of curative drugs.In another embodiment, described implant comprises and surpasses four kinds of curative drugs.In another embodiment, the combination that described implant comprises one of said medicine and other medicine.In another embodiment, the combination that described implant comprises two or more unlisted medicines above.In another embodiment, the drug regimen comprising in described implant has cooperative effect.In another embodiment, the drug regimen comprising in described implant has additive effect.Various probabilities represent independently embodiment of the present invention.

As mentioned above, multiple medicine can be mixed in PLA polymer and PLA:PGA polymer.Before mixing, can prepare described medicine (or " active component ") by any method known in the art.By for example mixing, granulation or the preparation of the tabletting process pharmaceutical composition that comprises active component is well known in the art.In one embodiment, by described active treatment composition and pharmacy is acceptable and the mixed with excipients compatible with described active component.In another embodiment, one of derivant (as: salt, ester, N-oxide etc.) of described active component or its physiology tolerance is mixed with the usual additive (as: carrier, stabilizing agent or inert diluent) for this object.

In another embodiment, active component is prepared in described compositions as the form of the acceptable salt of pharmacy of neutralization.The acceptable salt of pharmacy comprises acid-addition salts (forming with the free amine group of polypeptide or antibody molecule), itself and mineral acid example hydrochloric acid or phosphoric acid, or form with organic acid such as acetic acid, oxalic acid, tartaric acid, mandelic acid.The salt forming with free carboxy also can be derived from inorganic base as sodium hydroxide, potassium hydroxide, ammonium hydroxide, calcium hydroxide or hydrated ferric oxide., or derived from organic base as 2-aminopropane., trimethylamine, 2-ethylaminoethanol, histidine, procaine etc.

Above-mentioned various additive, excipient, dosage form and medication represent independently embodiment of the present invention.

In another embodiment, the PLA:PGA molar ratio of the polymer of method and composition of the present invention is about 75:25 to 100:0.In another embodiment, described ratio is 85:15 to 100:0.In another embodiment, described ratio is 50:50 to 100:0.In another embodiment, described ratio is 50:50 to 55:45.In another embodiment, described ratio is 55:15 to 60:40.In another embodiment, described ratio is 60:40 to 65:35.In another embodiment, described ratio is 65:35 to 70:30.In another embodiment, described ratio is 70:30 to 75:25.In another embodiment, described ratio is 75:25 to 80:20.In another embodiment, described ratio is 80:20 to 85:15.In another embodiment, described ratio is 85:15 to 90:10.In another embodiment, described ratio is 90:10 to 95:5.In another embodiment, described ratio is 95:5 to 100:0.In another embodiment, described ratio is 96:4 to 100:0.In another embodiment, described ratio is 97:3 to 100:0.In another embodiment, described ratio is 98:2 to 100:0.In another embodiment, described ratio is 99:1 to 100:0.In another embodiment, described ratio is 50:50 to 60:40.In another embodiment, described ratio is 55:45 to 65:35.In another embodiment, described ratio is 60:40 to 70:30.In another embodiment, described ratio is 65:35 to 75:25.In another embodiment, described ratio is 70:30 to 80:20.In another embodiment, described ratio is 75:25 to 85:15.In another embodiment, described ratio is 80:20 to 90:10.In another embodiment, described ratio is 85:15 to 95:5.In another embodiment, described ratio is 90:10 to 100:0.In another embodiment, described ratio is 50:50 to 65:35.In another embodiment, described ratio is 55:45 to 70:30.In another embodiment, described ratio is 60:40 to 75:25.In another embodiment, described ratio is 65:35 to 80:20.In another embodiment, described ratio is 70:30 to 85:15.In another embodiment, described ratio is 75:25 to 90:10.In another embodiment, described ratio is 80:20 to 95:5.In another embodiment, described ratio is 85:15 to 100:0.In another embodiment, described ratio is 50:50 to 70:30.In another embodiment, described ratio is 55:45 to 75:25.In another embodiment, described ratio is 60:40 to 80:20.In another embodiment, described ratio is 65:35 to 85:15.In another embodiment, described ratio is 70:30 to 90:10.In another embodiment, described ratio is 75:25 to 95:05.In another embodiment, described ratio is 80:20 to 100:0.In another embodiment, described ratio is 50:50 to 75:25.In another embodiment, described ratio is 55:45 to 80:20.In another embodiment, described ratio is 60:40 to 85:15.In another embodiment, described ratio is 65:35 to 90:10.In another embodiment, described ratio is 70:30 to 95:5.In another embodiment, described ratio is 75:25 to 100:0.

In another embodiment, described ratio is 50:50.In another embodiment, described ratio is 52:48.In another embodiment, described ratio is 54:46.In another embodiment, described ratio is 56:44.In another embodiment, described ratio is 58:42.In another embodiment, described ratio is 60:40.In another embodiment, described ratio is 62:38.In another embodiment, described ratio is 64:36.In another embodiment, described ratio is 66:34.In another embodiment, described ratio is 68:32.In another embodiment, described ratio is 70:30.In another embodiment, described ratio is 72:28.In another embodiment, described ratio is 74:26.In another embodiment, described ratio is 76:24.In another embodiment, described ratio is 78:22.In another embodiment, described ratio is 80:20.In another embodiment, described ratio is 82:18.In another embodiment, described ratio is 84:16.In another embodiment, described ratio is 86:14.In another embodiment, described ratio is 88:12.In another embodiment, described ratio is 90:10.In another embodiment, described ratio is 92:8.In another embodiment, described ratio is 94:6.In another embodiment, described ratio is 96:4.In another embodiment, described ratio is 97:3.In another embodiment, described ratio is 98:2.In another embodiment, described ratio is 99:1.In another embodiment, described ratio is 100:0 (for example: be substantially less than 1%PGA).

(embodiment 5) as herein provided, result of the present invention has proved the usefulness of the certain drug PLA:PGA ratio of biodegradable implant.In one embodiment, described PLA:PGA ratio is molar ratio.In another embodiment, described PLA:PGA ratio is quality ratio.In another embodiment, described PLA:PGA ratio is weight rate.In another embodiment, described PLA:PGA ratio is volume ratio.Above-mentioned various PLA:PGA ratio represents independently embodiment of the present invention.

In another embodiment, the polymer of method and composition of the present invention shows the intrinsic viscosity of about 0.2-0.9dl/g in chloroform.In another embodiment, described intrinsic viscosity is 0.6-0.85dl/g.In another embodiment, described intrinsic viscosity is 0.2-0.3dl/g.In another embodiment, described intrinsic viscosity is 0.25-0.35dl/g.In another embodiment, described intrinsic viscosity is 0.3-0.4dl/g.In another embodiment, described intrinsic viscosity is 0.35-0.45dl/g.In another embodiment, described intrinsic viscosity is 0.4-0.5dl/g.In another embodiment, described intrinsic viscosity is 0.45-0.55dl/g.In another embodiment, described intrinsic viscosity is 0.5-0.6dl/g.In another embodiment, described intrinsic viscosity is 0.55-0.65dl/g.In another embodiment, described intrinsic viscosity is 0.6-0.7dl/g.In another embodiment, described intrinsic viscosity is 0.65-0.75dl/g.In another embodiment, described intrinsic viscosity is 0.7-0.8dl/g.In another embodiment, described intrinsic viscosity is 0.75-0.85dl/g.In another embodiment, described intrinsic viscosity is 0.8-0.9dl/g.In another embodiment, described intrinsic viscosity is 0.85-0.95dl/g.In another embodiment, described intrinsic viscosity is 0.2-0.35dl/g.In another embodiment, described intrinsic viscosity is 0.25-0.40dl/g.In another embodiment, described intrinsic viscosity is 0.3-0.45dl/g.In another embodiment, described intrinsic viscosity is 0.35-0.5dl/g.In another embodiment, described intrinsic viscosity is 0.4-0.55dl/g.In another embodiment, described intrinsic viscosity is 0.45-0.6dl/g.In another embodiment, described intrinsic viscosity is 0.5-0.65dl/g.In another embodiment, described intrinsic viscosity is 0.55-0.70dl/g.In another embodiment, described intrinsic viscosity is 0.6-0.75dl/g.In another embodiment, described intrinsic viscosity is 0.65-0.80dl/g.In another embodiment, described intrinsic viscosity is 0.7-0.85dl/g.In another embodiment, described intrinsic viscosity is 0.75-0.9dl/g.In another embodiment, described intrinsic viscosity is 0.8-0.95dl/g.In another embodiment, described intrinsic viscosity is 0.2-0.40dl/g.In another embodiment, described intrinsic viscosity is 0.25-0.45dl/g.In another embodiment, described intrinsic viscosity is 0.3-0.5dl/g.In another embodiment, described intrinsic viscosity is 0.35-0.55dl/g.In another embodiment, described intrinsic viscosity is 0.4-0.6dl/g.In another embodiment, described intrinsic viscosity is 0.45-0.65dl/g.In another embodiment, described intrinsic viscosity is 0.5-0.7dl/g.In another embodiment, described intrinsic viscosity is 0.55-0.75dl/g.In another embodiment, described intrinsic viscosity is 0.6-0.8dl/g.In another embodiment, described intrinsic viscosity is 0.65-0.85dl/g.In another embodiment, described intrinsic viscosity is 0.7-0.9dl/g.In another embodiment, described intrinsic viscosity is 0.75-0.95dl/g.In another embodiment, described intrinsic viscosity is 0.2-0.45dl/g.In another embodiment, described intrinsic viscosity is 0.25-0.5dl/g.In another embodiment, described intrinsic viscosity is 0.3-0.55dl/g.In another embodiment, described intrinsic viscosity is 0.35-0.6dl/g.In another embodiment, described intrinsic viscosity is 0.4-0.65dl/g.In another embodiment, described intrinsic viscosity is 0.45-0.7dl/g.In another embodiment, described intrinsic viscosity is 0.5-0.75dl/g.In another embodiment, described intrinsic viscosity is 0.55-0.80dl/g.In another embodiment, described intrinsic viscosity is 0.6-0.85dl/g.In another embodiment, described intrinsic viscosity is 0.65-0.9dl/g.In another embodiment, described intrinsic viscosity is 0.7-0.95dl/g.

In another embodiment, described intrinsic viscosity is 0.2dl/g.In another embodiment, described intrinsic viscosity is 0.25dl/g.In another embodiment, described intrinsic viscosity is 0.3dl/g.In another embodiment, described intrinsic viscosity is 0.35dl/g.In another embodiment, described intrinsic viscosity is 0.4dl/g.In another embodiment, described intrinsic viscosity is 0.45dl/g.In another embodiment, described intrinsic viscosity is 0.5dl/g.In another embodiment, described intrinsic viscosity is 0.55dl/g.In another embodiment, described intrinsic viscosity is 0.6dl/g.In another embodiment, described intrinsic viscosity is 0.65dl/g.In another embodiment, described intrinsic viscosity is 0.7dl/g.In another embodiment, described intrinsic viscosity is 0.75dl/g.In another embodiment, described intrinsic viscosity is 0.8dl/g.In another embodiment, described intrinsic viscosity is 0.85dl/g.In another embodiment, described intrinsic viscosity is 0.9dl/g.In another embodiment, described intrinsic viscosity is 0.95dl/g.

Above-mentioned various intrinsic viscosity represents independently embodiment of the present invention.

In one embodiment, " intrinsic viscosity " refers to the measuring of ability of the viscosity of solution described in the enhancing by polymer in solution.In another embodiment, intrinsic viscosity, along with polymer molecular weight increases and increases, is the function of polymerizing condition, and can be independent of the PLA:PGA rate of change of described polymer.In another embodiment, intrinsic viscosity is defined as to the ultimate value of the specific viscosity/concentration rate when zero-dose.Therefore, at variable concentrations, determine viscosity, be then extrapolated to zero-dose.In another embodiment, " intrinsic viscosity " is the synonym of " intrinsic viscosity ".The various definition of " intrinsic viscosity " represent independently embodiment of the present invention.

For measuring the method for intrinsic viscosity, be well known in the art, be described in such as people (J Biomed Mater Res A68 (1): 43-51 such as Meek MF, 2004) and the people (J Control Release71 (2): 165-73,2001) such as Deng X.In another embodiment, according to the intrinsic viscosity of measuring of embodiment 1 description of the present disclosure.In another embodiment, in chloroform, measure intrinsic viscosity.In another embodiment, in hexafluoroisopropanol solution, measure intrinsic viscosity.In another embodiment, in any other suitable solvent known in the art, measure intrinsic viscosity.In another embodiment, described solvent is FDA III level solvent (hypotoxicity, the minimum that needs of removing residual solvent).The whole bag of tricks represents independently embodiment of the present invention.

In another embodiment, the implant of method and composition of the present invention has approximately 1 to 3 (millimeter [mm])/mm ³surface area to volume (SA:V) ratio.In another embodiment, described ratio is 0.5-1mm ²/ mm ³.In another embodiment, described ratio is 0.7-1.2mm ²/ mm ³.In another embodiment, described ratio is 0.9-1.4mm ²/ mm ³.In another embodiment, described ratio is 1.1-1.6mm ²/ mm ³.In another embodiment, described ratio is 1.3-1.8mm ²/ mm ³.In another embodiment, described ratio is 1.5-2mm ²/ mm ³.In another embodiment, described ratio is 2-2.5mm ²/ mm ³.In another embodiment, described ratio is 2.5-3mm ²/ mm ³.In another embodiment, described ratio is 3-3.5mm ²/ mm ³.In another embodiment, described ratio is 3.5-4mm ²/ mm ³.In another embodiment, described ratio is 4-4.5mm ²/ mm ³.In another embodiment, described ratio is 4.5-5mm ²/ mm ³.In another embodiment, described ratio is 5-5.5mm ²/ mm ³.In another embodiment, described ratio is 5.5-6mm ²/ mm ³.In another embodiment, described ratio is 0.5-1.5mm ²/ mm ³.In another embodiment, described ratio is 1-2mm ²/ mm ³.In another embodiment, described ratio is 1.5-2.5mm ²/ mm ³.In another embodiment, described ratio is 2-3mm ²/ mm ³.In another embodiment, described ratio is 2.5-3.5mm ²/ mm ³.In another embodiment, described ratio is 3-4mm ²/ mm ³.In another embodiment, described ratio is 3.5-4.5mm ²/ mm ³.In another embodiment, described ratio is 4-5mm ²/ mm ³.In another embodiment, described ratio is 4.5-5.5mm ²/ mm ³.In another embodiment, described ratio is 5-6mm ²/ mm ³.In another embodiment, described ratio is 5.5-6.5mm ²/ mm ³.In another embodiment, described ratio is 6-7mm ²/ mm ³.In another embodiment, described ratio is 6.5-7.5mm ²/ mm ³.In another embodiment, described ratio is 7-8mm ²/ mm ³.In another embodiment, described ratio is 0.5-2mm ²/ mm ³.In another embodiment, described ratio is 1-2.5mm ²/ mm ³.In another embodiment, described ratio is 1.5-3mm ²/ mm ³.In another embodiment, described ratio is 2-3.5mm ²/ mm ³.In another embodiment, described ratio is 2.5-4mm ²/ mm ³.In another embodiment, described ratio is 3-4.5mm ²/ mm ³.In another embodiment, described ratio is 3.5-5mm ²/ mm ³.In another embodiment, described ratio is 4-5.5mm ²/ mm ³.In another embodiment, described ratio is 4.5-6mm ²/ mm ³.In another embodiment, described ratio is 5-6.5mm ²/ mm ³.In another embodiment, described ratio is 5.5-7mm ²/ mm ³.In another embodiment, described ratio is 6-7.5mm ²/ mm ³.In another embodiment, described ratio is 6.5-8mm ²/ mm ³.In another embodiment, described ratio is 0.5-2.5mm ²/ mm ³.In another embodiment, described ratio is 1-3mm ²/ mm ³.In another embodiment, described ratio is 1.5-3.5mm ²/ mm ³.In another embodiment, described ratio is 2-4mm ²/ mm ³.In another embodiment, described ratio is 2.5-4.5mm ²/ mm ³.In another embodiment, described ratio is 3-5mm ²/ mm ³.In another embodiment, described ratio is 3.5-5.5mm ²/ mm ³.In another embodiment, described ratio is 4-6mm ²/ mm ³.In another embodiment, described ratio is 4.5-6.5mm ²/ mm ³.In another embodiment, described ratio is 5-7mm ²/ mm ³.In another embodiment, described ratio is 5.5-7.5mm ²/ mm ³.In another embodiment, described ratio is 6-8mm ²/ mm ³.In another embodiment, described ratio is 0.5-3.5mm ²/ mm ³.In another embodiment, described ratio is 1-4mm ²/ mm ³.In another embodiment, described ratio is 1.5-4.5mm ²/ mm ³.In another embodiment, described ratio is 2-5mm ²/ mm ³.In another embodiment, described ratio is 2.5-5.5mm ²/ mm ³.In another embodiment, described ratio is 3-6mm ²/ mm ³.In another embodiment, described ratio is 3.5-6.5mm ²/ mm ³.In another embodiment, described ratio is 4-7mm ²/ mm ³.In another embodiment, described ratio is 4.5-7.5mm ²/ mm ³.In another embodiment, described ratio is 6-8mm ²/ mm ³.In another embodiment, described ratio is 0.5-4.5mm ²/ mm ³.In another embodiment, described ratio is 1-5mm ²/ mm ³.In another embodiment, described ratio is 1.5-5.5mm ²/ mm ³.In another embodiment, described ratio is 2-6mm ²/ mm ³.In another embodiment, described ratio is 2.5-6.5mm ²/ mm ³.In another embodiment, described ratio is 3-7mm ²/ mm ³.In another embodiment, described ratio is 3.5-7.5mm ²/ mm ³.In another embodiment, described ratio is 4-8mm ²/ mm ³.In another embodiment, described ratio is 4.5-8.5mm ²/ mm ³.

In another embodiment, described ratio is 0.5mm ²/ mm ³.In another embodiment, described ratio is 0.6mm ²/ mm ³.In another embodiment, described ratio is 0.7mm ²/ mm ³.In another embodiment, described ratio is 0.8mm ²/ mm ³.In another embodiment, described ratio is 1.0mm ²/ mm ³.In another embodiment, described ratio is 1.5mm ²/ mm ³.In another embodiment, described ratio is 2mm ²/ mm ³.In another embodiment, described ratio is 2.5mm ²/ mm ³.In another embodiment, described ratio is 3mm ²/ mm ³.In another embodiment, described ratio is 3.5mm ²/ mm ³.In another embodiment, described ratio is 4mm ²/ mm ³.In another embodiment, described ratio is 4.5mm ²/ mm ³.In another embodiment, described ratio is 5mm ²/ mm ³.In another embodiment, described ratio is 5.5mm ²/ mm ³.In another embodiment, described ratio is 6mm ²/ mm ³.In another embodiment, described ratio is 6.5mm ²/ mm ³.In another embodiment, described ratio is 7mm ²/ mm ³.Above-mentioned various SA:V ratio represents independently embodiment of the present invention.

(embodiment 6) as herein provided, result of the present invention has proved the usefulness of the biodegradable implant of specific SA:V ratio ranges.For measuring the method for SA:V ratio, be well known in the art.In one embodiment, by the measurement from described shape (for example, for regular shape), calculate surface area and volume, measure SA:V ratio.(for example, for irregularly shaped) in another embodiment, is used BET (Brunauer, Emmett and Teller) apparatus measures surface area (J de Kanel and J W Morse, J Phys E:Sci Instrum12:272-273,1979).In another embodiment, use any other commercial measurement surface area known in the art.In another embodiment, by water or one other fluid, replace coming measurement volumes.In another embodiment, use any other commercial measurement volume known in the art.Various probabilities represent independently embodiment of the present invention.

In another embodiment, the implant of method and composition of the present invention has the length of about 1-5mm.In one embodiment, " length " refers to the longest dimension of described implant.In another embodiment, " length " refers to the length of linear side dimension (for example, the in the situation that of cylindrical implant).In another embodiment, " linear side dimension " refers to needn't be completely straight, and slight bending for example.Various probabilities represent independently embodiment of the present invention.

In another embodiment, the length of described implant is 1-2mm.In another embodiment, described length is 0.5-1.0mm.In another embodiment, described length is 1.5-2mm.In another embodiment, described length is 2-2.5mm.In another embodiment, described length is 2.5-3mm.In another embodiment, described length is 3-3.5mm.In another embodiment, described length is 3.5-4mm.In another embodiment, described length is 4-4.5mm.In another embodiment, described length is 4.5-5mm.In another embodiment, described length is 5-5.5mm.In another embodiment, described length is 0.5-1.5mm.In another embodiment, described length is 1.5-2.5mm.In another embodiment, described length is 2-3mm.In another embodiment, described length is 2.5-3.5mm.In another embodiment, described length is 3-4mm.In another embodiment, described length is 3.5-4.5mm.In another embodiment, described length is 4-5mm.In another embodiment, described length is 4.5-5.5mm.In another embodiment, described length is 5-6mm.In another embodiment, described length is 0.5-2mm.In another embodiment, described length is 1-2.5mm.In another embodiment, described length is 1.5-3mm.In another embodiment, described length is 2-3.5mm.In another embodiment, described length is 2.5-4mm.In another embodiment, described length is 3-4.5mm.In another embodiment, described length is 3.5-5mm.In another embodiment, described length is 4-5.5mm.In another embodiment, described length is 4.5-6mm.In another embodiment, described length is 0.5-2.5mm.In another embodiment, described length is 1-3mm.In another embodiment, described length is 1.5-3.5mm.In another embodiment, described length is 2-4mm.In another embodiment, described length is 2.5-4.5mm.In another embodiment, described length is 3-5mm.In another embodiment, described length is 3.5-5.5mm.In another embodiment, described length is 4-6mm.In another embodiment, described length is 4.5-6.5mm.In another embodiment, described length is 5-7mm.In another embodiment, described length is 0.5-3.5mm.In another embodiment, described length is 1-4mm.In another embodiment, described length is 2-5mm.In another embodiment, described length is 3-6mm.In another embodiment, described length is 4-7mm.In another embodiment, described length is 5-8mm.In another embodiment, described length is 0.5-4.5mm.In another embodiment, described length is 1-5mm.In another embodiment, described length is 2-6mm.In another embodiment, described length is 3-7mm.

In another embodiment, described length is 0.5mm.In another embodiment, described length is 0.6mm.In another embodiment, described length is 0.7mm.In another embodiment, described length is 0.8mm.In another embodiment, described length is 0.9mm.In another embodiment, described length is 1.0mm.In another embodiment, described length is 1.2mm.In another embodiment, described length is 1.4mm.In another embodiment, described length is 1.6mm.In another embodiment, described length is 1.8mm.In another embodiment, described length is 2.0mm.In another embodiment, described length is 2.2mm.In another embodiment, described length is 2.4mm.In another embodiment, described length is 2.6mm.In another embodiment, described length is 2.8mm.In another embodiment, described length is 3.0mm.In another embodiment, described length is 3.5mm.In another embodiment, described length is 4mm.In another embodiment, described length is 4.5mm.In another embodiment, described length is 5mm.In another embodiment, described length is 5.5mm.In another embodiment, described length is 6mm.In another embodiment, described length is 7mm.In another embodiment, described length is 8mm.Above-mentioned all lengths represents independently embodiment of the present invention.

In another embodiment, the implant of method and composition of the present invention has the diameter of about 2-4mm.In one embodiment, " diameter " refers to the distance across the area of section of described implant.In another embodiment, for example, the in the situation that of disc implant, the described distance across area of section can be longer than above-mentioned length.In another embodiment, for example, the in the situation that of clavate implant, the described distance across area of section is shorter than described length.In another embodiment, described area of section refers to not be necessary for circle, but can be ellipse, square, rectangle etc., as mentioned above.Therefore, in another embodiment, described diameter is the longest of described area of section and the geometrical mean of short diameter.In another embodiment, described diameter is its longest and arithmetic mean of instantaneous value of the shortest diameter.In another embodiment, described diameter is the greatest length of its various diameters.In another embodiment, described diameter is the cornerwise distance across described area of section, for example, the in the situation that of square or rectangular.In another embodiment, described diameter is the distance across described maximum cross-section area, for example in the situation that described diameter along with the length variations of implant.In another embodiment, described diameter is the average distance across described maximum cross-section area.Various probabilities represent independently embodiment of the present invention.

In another embodiment, described diameter is about 2-4mm.In another embodiment, described diameter is 0.5-1mm.In another embodiment, described diameter is 1-1.5mm.In another embodiment, described diameter is 1.5-2mm.In another embodiment, described diameter is 2-2.5mm.In another embodiment, described diameter is 2.5-3mm.In another embodiment, described diameter is 3-3.5mm.In another embodiment, described diameter is 3.5-4mm.In another embodiment, described diameter is 4-4.5mm.In another embodiment, described diameter is 4.5-5mm.In another embodiment, described diameter is 5-5.5mm.In another embodiment, described diameter is 5.5-6mm.In another embodiment, described diameter is 0.5-1.5mm.In another embodiment, described diameter is 1-2mm.In another embodiment, described diameter is 1.5-2.5mm.In another embodiment, described diameter is 2-3mm.In another embodiment, described diameter is 2.5-3.5mm.In another embodiment, described diameter is 3-4mm.In another embodiment, described diameter is 3.5-4.5mm.In another embodiment, described diameter is 4-5mm.In another embodiment, described diameter is 4.5-5.5mm.In another embodiment, described diameter is 5-6mm.In another embodiment, described diameter is 0.5-2mm.In another embodiment, described diameter is 1-2.5mm.In another embodiment, described diameter is 1.5-3mm.In another embodiment, described diameter is 2-3.5mm.In another embodiment, described diameter is 2.5-4mm.In another embodiment, described diameter is 3-4.5mm.In another embodiment, described diameter is 3.5-5mm.In another embodiment, described diameter is 4-5.5mm.In another embodiment, described diameter is 4.5-6mm.In another embodiment, described diameter is 1-3mm.In another embodiment, described diameter is 1.5-3.5mm.In another embodiment, described diameter is 2-4mm.In another embodiment, described diameter is 2.5-4.5mm.In another embodiment, described diameter is 3-5mm.In another embodiment, described diameter is 3.5-5.5mm.In another embodiment, described diameter is 4-6mm.In another embodiment, described diameter is 1-4mm.In another embodiment, described diameter is 2-5mm.In another embodiment, described diameter is 3-6mm.In another embodiment, described diameter is 4-7mm.

In another embodiment, described diameter is 0.5mm.In another embodiment, described diameter is 0.6mm.In another embodiment, described diameter is 0.7mm.In another embodiment, described diameter is 0.8mm.In another embodiment, described diameter is 0.9mm.In another embodiment, described diameter is 1.0mm.In another embodiment, described diameter is 1.2mm.In another embodiment, described diameter is 1.4mm.In another embodiment, described diameter is 1.6mm.In another embodiment, described diameter is 1.8mm.In another embodiment, described diameter is 2.0mm.In another embodiment, described diameter is 2.2mm.In another embodiment, described diameter is 2.4mm.In another embodiment, described diameter is 2.6mm.In another embodiment, described diameter is 2.8mm.In another embodiment, described diameter is 3.0mm.In another embodiment, described diameter is 3.2mm.In another embodiment, described diameter is 3.4mm.In another embodiment, described diameter is 3.6mm.In another embodiment, described diameter is 3.8mm.In another embodiment, described diameter is 4.0mm.In another embodiment, described diameter is 4.2mm.In another embodiment, described diameter is 5mm.In another embodiment, described diameter is 5.5mm.In another embodiment, described diameter is 6mm.Above-mentioned various diameter represents independently embodiment of the present invention.

In another embodiment, the implant of method and composition of the present invention has approximately 0.75 gram (g) or less quality.As herein provided, the present invention proof utilizes about 0.75g or less implant to send the feasibility (embodiment 14) of risperidone of the effective dose of 6 months for the mankind.In another embodiment, the present invention proof utilizes about 1.5g or less implant to send the feasibility of risperidone of the effective dose of a year.In another embodiment, described implant has about 0.1g or less quality.In another embodiment, described quality is 0.2g or less.In another embodiment, described quality is 0.3g or less.In another embodiment, described quality is 0.4g or less.In another embodiment, described quality is 0.5g or less.In another embodiment, described quality is 0.6g or less.In another embodiment, described quality is 0.7g or less.In another embodiment, described quality is 0.8g or less.In another embodiment, described quality is 0.9g or less.In another embodiment, described quality is 1g or less.In another embodiment, described quality is 1.1g or less.In another embodiment, described quality is 1.2g or less.In another embodiment, described quality is 1.3g or less.In another embodiment, described quality is 1.4g or less.In another embodiment, described quality is 1.5g or less.In another embodiment, described quality is 1.6g or less.In another embodiment, described quality is 1.7g or less.In another embodiment, described quality is 1.8g or less.In another embodiment, described quality is 1.9g or less.In another embodiment, described quality is 2g or less.In another embodiment, described quality is 2.2g or less.In another embodiment, described quality is 2.4g or less.In another embodiment, described quality is 2.6g or less.In another embodiment, described quality is 2.8g or less.In another embodiment, described quality is 3g or less.

In another embodiment, described quality is 0.1g.In another embodiment, described quality is 0.2g.In another embodiment, described quality is 0.3g.In another embodiment, described quality is 0.4g.In another embodiment, described quality is 0.5g.In another embodiment, described quality is 0.6g.In another embodiment, described quality is 0.7g.In another embodiment, described quality is 0.8g.In another embodiment, described quality is 0.9g.In another embodiment, described quality is 1g.In another embodiment, described quality is 1.1g.In another embodiment, described quality is 1.2g.In another embodiment, described quality is 1.3g.In another embodiment, described quality is 1.4g.In another embodiment, described quality is 1.5g.In another embodiment, described quality is 1.6g.In another embodiment, described quality is 1.7g.In another embodiment, described quality is 1.8g.In another embodiment, described quality is 1.9g.In another embodiment, described quality is 2g.In another embodiment, described quality is 2.2g.In another embodiment, described quality is 2.4g.In another embodiment, described quality is 2.6g.In another embodiment, described quality is 2.8g.In another embodiment, described quality is 3g.

In another embodiment, described quality is about 0.1-0.3g.In another embodiment, described quality is 0.2-0.4g.In another embodiment, described quality is 0.3-0.5g.In another embodiment, described quality is 0.4-0.6g.In another embodiment, described quality is 0.5-0.7g.In another embodiment, described quality is 0.6-0.8g.In another embodiment, described quality is 0.7-0.9g.In another embodiment, described quality is 0.8-1.0g.In another embodiment, described quality is 0.1-0.4g.In another embodiment, described quality is 0.2-0.5g.In another embodiment, described quality is 0.3-0.6g.In another embodiment, described quality is 0.4-0.7g.In another embodiment, described quality is 0.5-0.8g.In another embodiment, described quality is 0.6-0.9g.In another embodiment, described quality is 0.7-1.0g.In another embodiment, described quality is 0.1-0.5g.In another embodiment, described quality is 0.2-0.6g.In another embodiment, described quality is 0.3-0.7g.In another embodiment, described quality is 0.4-0.8g.In another embodiment, described quality is 0.5-0.9g.In another embodiment, described quality is 0.6-1.0g.In another embodiment, described quality is 0.8-1.2g.In another embodiment, described quality is 1.0-1.4g.In another embodiment, described quality is 1.2-1.6g.In another embodiment, described quality is 1.4-1.8g.In another embodiment, described quality is 1.6-2g.In another embodiment, described quality is 1.8-2.2g.In another embodiment, described quality is 2-2.4g.In another embodiment, described quality is 2.5-2.9g.In another embodiment, described quality is 0.1-0.6g.In another embodiment, described quality is 0.2-0.7g.In another embodiment, described quality is 0.3-0.8g.In another embodiment, described quality is 0.4-0.9g.In another embodiment, described quality is 0.5-1.0g.In another embodiment, described quality is 0.6-1.1g.In another embodiment, described quality is 0.8-1.3g.In another embodiment, described quality is 1.0-1.5g.In another embodiment, described quality is 1.2-1.7g.In another embodiment, described quality is 1.4-1.9g.In another embodiment, described quality is 1.6-2.1g.In another embodiment, described quality is 1.8-2.3g.In another embodiment, described quality is 2-2.5g.In another embodiment, described quality is 2.5-3g.In another embodiment, described quality is 0.1-0.8g.In another embodiment, described quality is 0.2-0.9g.In another embodiment, described quality is 0.3-1.1g.In another embodiment, described quality is 0.5-1.2g.In another embodiment, described quality is 0.6-1.3g.In another embodiment, described quality is 0.8-1.5g.In another embodiment, described quality is 1.0-1.7g.In another embodiment, described quality is 1.2-1.9g.In another embodiment, described quality is 1.6-2.1g.In another embodiment, described quality is 1.8-2.5g.In another embodiment, described quality is 2-2.7g.In another embodiment, described quality is 0.1-1.1g.In another embodiment, described quality is 0.2-1.2g.In another embodiment, described quality is 0.3-1.3g.In another embodiment, described quality is 0.5-1.5g.In another embodiment, described quality is 0.6-1.6g.In another embodiment, described quality is 0.8-1.8g.In another embodiment, described quality is 1.0-2g.In another embodiment, described quality is 1.5-2.5g.In another embodiment, described quality is 2-3g.In another embodiment, described quality is 0.2-1.7g.In another embodiment, described quality is 0.3-1.8g.In another embodiment, described quality is 0.5-2g.In another embodiment, described quality is 0.8-2.3g.In another embodiment, described quality is 1.0-2.5g.In another embodiment, described quality is 1.5-3g.In another embodiment, described quality is 0.2-2.2g.In another embodiment, described quality is 0.3-2.3g.In another embodiment, described quality is 0.5-2.5g.In another embodiment, described quality is 0.8-2.8g.In another embodiment, described quality is 1-3g.

Above-mentioned various quality representation independently embodiment of the present invention.

In another embodiment, by comprising that the method for solvent cast prepares the implant of method and composition of the present invention.In another embodiment, by comprising that the method for mold prepares described implant.In another embodiment, by comprising that the method for melting mixing prepares described implant.In another embodiment, by comprising that the method for melting mixing extrusion molding prepares described implant, described melting mixing extrusion molding is without using surfactant.In another embodiment, by comprising that the method for melting mixing extrusion molding prepares described implant, described melting mixing extrusion molding is without using emulsion.In another embodiment, by comprising that the method for melting mixing extrusion molding prepares described implant, described extrusion by melting is without using surfactant or emulsion.In another embodiment, by comprising that the method for extrusion molding prepares described implant.In one embodiment, described extrusion molding is high-pressure extrusion molding.In one embodiment, the implant of preparing by extrusion molding shows the density increasing.In another embodiment, the implant of preparing by extrusion molding shows the uniformity of improving.In another embodiment, can prepare more various implant shape by extrusion molding.In another embodiment, by extruding preparation implant in the situation that, in manufacture process, lose less material.Various probabilities represent independently embodiment of the present invention.

In another embodiment, implant of the present invention shows that Billy has advantages of larger possible drug loading by the technology of emulsification method.In another embodiment, implant of the present invention for example shows, owing to using the method (solvent cast) without cleaning agent to have advantages of larger possible drug loading.Various probabilities represent independently embodiment of the present invention.

In another embodiment, the invention provides the method that is used for the treatment of the relevant disease of the individual probability with not complying with.Described method comprises the goal treatment medicine in long-term delivery system to individual administration, and described long-term delivery system comprises implantable clavate structure and described goal treatment medicine.

In another embodiment, the invention provides implant of the present invention or implant group for the preparation of the purposes of the pharmaceutical composition of the relevant disease of the individual probability with not complying with for the treatment of.

In another embodiment, the invention provides the Drug therapy level in individuality is maintained by a definite date to the method at least about 1 month, the method comprises to one group of biodegradable implant of described individual administration, this is organized biodegradable implant and is comprised of the one or more independent biodegradable implants with following component: (a) with respect to the quality of described implant, by mass, the curative drug existing with the amount of 10%-60%; (b) with respect to the quality of described implant, by mass, the polymer existing with the amount of 40%-90%, described polymer comprises PLA and optional PGA, wherein PLA:PGA molar ratio is 50:50 to 100:0, if and wherein described independent biodegradable implant outnumber one, they substantially do not have each other difference on their PLA:PGA molar ratio, thereby the Drug therapy level in individuality is maintained by a definite date at least about 1 month.

In another embodiment, the invention provides the Drug therapy level in individuality is maintained by a definite date to the method at least about 2 months, the method comprises to one group of biodegradable implant of described individual administration, this is organized biodegradable implant and is comprised of the one or more independent biodegradable implants with following component: (a) with respect to the quality of described implant, by mass, the curative drug existing with the amount of 10%-60%; (b) with respect to the quality of described implant, by mass, the polymer existing with the amount of 40%-90%, described polymer comprises PLA and optional PGA, wherein PLA:PGA molar ratio is 50:50 to 100:0, if and wherein described independent biodegradable implant outnumber one, they substantially do not have each other difference on their PLA:PGA molar ratio, thereby the Drug therapy level in individuality is maintained by a definite date at least about 2 months.

In another embodiment, the invention provides the Drug therapy level in individuality is maintained by a definite date to the method at least about 3 months, the method comprises to one group of biodegradable implant of described individual administration, this is organized biodegradable implant and is comprised of the one or more independent biodegradable implants with following component: (a) with respect to the quality of described implant, by mass, the curative drug existing with the amount of 10%-60%; (b) with respect to the quality of described implant, by mass, the polymer existing with the amount of 40%-90%, described polymer comprises PLA and optional PGA, wherein PLA:PGA molar ratio is 50:50 to 100:0, if and wherein described independent biodegradable implant outnumber one, they substantially do not have each other difference on their PLA:PGA molar ratio, thereby the Drug therapy level in individuality is maintained by a definite date at least about 3 months.

In another embodiment, the invention provides the Drug therapy level in individuality is maintained by a definite date to the method at least about 4 months, the method comprises to one group of biodegradable implant of described individual administration, this is organized biodegradable implant and is comprised of the one or more independent biodegradable implants with following component: (a) with respect to the quality of described implant, by mass, the curative drug existing with the amount of 10%-60%; (b) with respect to the quality of described implant, by mass, the polymer existing with the amount of 40%-90%, described polymer comprises PLA and optional PGA, wherein PLA:PGA molar ratio is 50:50 to 100:0, if and wherein described independent biodegradable implant outnumber one, they substantially do not have each other difference on their PLA:PGA molar ratio, thereby the Drug therapy level in individuality is maintained by a definite date at least about 4 months.

In another embodiment, the invention provides the Drug therapy level in individuality is maintained to the method that surpasses 4 months that schedules to last, the method comprises to one group of biodegradable implant of described individual administration, this is organized biodegradable implant and is comprised of the one or more independent biodegradable implants with following component: (a) with respect to the quality of described implant, by mass, the curative drug existing with the amount of 10%-60%; (b) with respect to the quality of described implant, by mass, the polymer existing with the amount of 40%-90%, described polymer comprises PLA and optional PGA, wherein PLA:PGA molar ratio is 50:50 to 100:0, if and wherein described independent biodegradable implant outnumber one, they substantially do not have each other difference on their PLA:PGA molar ratio, thereby the Drug therapy level in individuality is maintained and scheduled to last over 4 months.

In another embodiment, the invention provides implant of the present invention or implant group for the preparation of the purposes of the pharmaceutical composition one of the Drug therapy level in individuality being maintained in the above-mentioned time period.

In another embodiment, except their PLA:PGA molar ratio, another parameter of described independent implant is equal to each other, for example the intrinsic viscosity of their drug loading, quality, SA:V ratio, length, diameter or described polymer.In another embodiment, the PLA:PGA ratio of described independent implant is equal to each other, but other parameters are unequal.In another embodiment, except their PLA:PGA ratio, two kinds in other parameters of these of described independent implant are equal to each other.In another embodiment, except their PLA:PGA ratio, three kinds in other parameters of these of described independent implant are equal to each other.In another embodiment, except their PLA:PGA ratio, four kinds in other parameters of these of described independent implant are equal to each other.In another embodiment, except their PLA:PGA ratio, five kinds in other parameters of these of described independent implant are equal to each other.In another embodiment, except their PLA:PGA ratio, other parameters of all these of described independent implant are equal to each other.Various probabilities represent independently embodiment of the present invention.

In another embodiment, described independent implant is on their drug loading but not be equal to each other on their PLA:PGA ratio.In another embodiment, described independent implant is equal to each other on their the PLA:PGA ratio qualitatively but not at them.In another embodiment, described independent implant is on their SA:V ratio but not be equal to each other on their PLA:PGA ratio.In another embodiment, described independent implant is in their length but not be equal to each other on their PLA:PGA ratio.In another embodiment, described independent implant is on their diameter but not be equal to each other on their PLA:PGA ratio.In another embodiment, described independent implant is in their polymer intrinsic viscosity but not be equal to each other on their PLA:PGA ratio.In another embodiment, in these parameters 2 of described independent implant, be equal to each other.In another embodiment, in these parameters 3 of described independent implant, be equal to each other.In another embodiment, in these parameters 4 of described independent implant, be equal to each other.In another embodiment, described independent implant is equal to each other in all these parameters.Various probabilities represent independently embodiment of the present invention.

In another embodiment, the PLA:PGA ratio in described independent implant is substantially constant, for example: described independent implant is not that each part freely with different PLA:PGA ratios forms.In another embodiment, this is applicable to the drug loading of described independent implant.In another embodiment, this is applicable to the quality of described independent implant.In another embodiment, this is applicable to the SA:V ratio of described independent implant.In another embodiment, this is applicable to the length of described independent implant.In another embodiment, this is applicable to the diameter of described independent implant.In another embodiment, this is applicable to the intrinsic viscosity of the polymer in described independent implant.Various probabilities represent independently embodiment of the present invention.

As provided herein, the present invention for example proves, by single polymers system (the implant group of homology) and can reach long term maintenance curative drug level.In addition, the single polymers implant system in rabbit (Fig. 3 B) proves that each polymer approaches symmetrical serum-concentration figure.And as shown in Figure 3 B, the Trendline of the data with 0.86 correlation coefficient (R2) of description showed maximum release value in the time of about 6 months.

In another embodiment, the invention provides the Drug therapy level in individuality is maintained by a definite date to the method at least about 3 months, it comprises: (1) is to the one or more biodegradable implant of described individual administration initial set, wherein said initial set is comprised of the one or more independent biodegradable implants with following component: (a) with respect to the quality of described implant, by mass, the curative drug existing with the amount of 10%-60%; (b) with respect to the quality of described implant, by mass, the polymer existing with the amount of 40%-90%, described polymer comprises PLA and optional PGA, and wherein PLA:PGA molar ratio is 50:50 to 100:0; (2) when approaching the peak point of release of biodegradable implant of described initial set, to described individual administration, maintain the one or more biodegradable implant of group, the wherein said biodegradable implant that maintains group is comprised of other independent biodegradable implant, and the described independent biodegradable implant in the described other PLA:PGA molar ratio of independent biodegradable implant and the biodegradable implant of described initial set equates.In the method, if the independent biodegradable implant of described initial set outnumbers one, they substantially do not have each other difference on their PLA:PGA molar ratio, thereby the Drug therapy level maintaining in individuality scheduled to last at least about 3 months.

In another embodiment, the invention provides the Drug therapy level in individuality is maintained by a definite date to the method at least about a year, it comprises: (1) is to the one or more biodegradable implant of described individual administration initial set, wherein said initial set is comprised of the one or more independent biodegradable implants with following component: (a) with respect to the quality of described implant, by mass, the curative drug existing with the amount of 10%-60%; (b) with respect to the quality of described implant, by mass, the polymer existing with the amount of 40%-90%, described polymer comprises PLA and optional PGA, and wherein PLA:PGA molar ratio is 50:50 to 100:0; (2) when approaching the peak point of release of biodegradable implant of described initial set, to described individual administration, maintain the one or more biodegradable implant of group, the wherein said biodegradable implant that maintains group is comprised of other independent biodegradable implant, and the PLA:PGA molar ratio of the described independent biodegradable implant in the described other PLA:PGA molar ratio of independent biodegradable implant and the biodegradable implant of described initial set equates.In the method, if the independent biodegradable implant of described initial set outnumber one, they substantially do not have each other difference on their PLA:PGA molar ratio, thereby the Drug therapy level maintaining in individuality scheduled to last at least about 1 year.

In another embodiment, " peak point of release " refers to the maximum point discharging.In another embodiment, this term refers to the research based on before implant described in administration, the average peak point of release in human individual.Various probabilities represent another embodiment of the present invention.

In another embodiment, " approach " peak point of release and refer to administration in 1 week of described peak point of release.In another embodiment, this term refers to administration in 10 days of described peak point of release.In another embodiment, this term refers to administration in 2 weeks of described peak point of release.In another embodiment, this term refers to administration in 3 weeks of described peak point of release.In another embodiment, this term refers to administration in 4 weeks of described peak point of release.In another embodiment, this term refers to administration in 5 weeks of described peak point of release.In another embodiment, this term refers to administration in 6 weeks of described peak point of release.In another embodiment, this term refers to administration in 2 months of described peak point of release.

In another embodiment, this term refer to described rate of release maximum horizontal 10% in some administration.In another embodiment, this term refer to described rate of release maximum horizontal 5% in point.In another embodiment, this term refer to described rate of release maximum horizontal 15% in point.In another embodiment, this term refer to described rate of release maximum horizontal 20% in point.In another embodiment, this term refer to described rate of release maximum horizontal 25% in point.In another embodiment, this term refer to described rate of release maximum horizontal 30% in point.In another embodiment, this term refer to described rate of release maximum horizontal 35% in point.In another embodiment, this term refer to described rate of release maximum horizontal 40% in point.In another embodiment, this term refer to described rate of release maximum horizontal 50% in point.Various probabilities represent another embodiment of the present invention.

In another embodiment, the invention provides the method that the Drug therapy level in individuality is maintained to the time period of prolongation, it comprises: (1) is to the one or more biodegradable implant of described individual administration initial set, wherein said initial set is comprised of the one or more independent biodegradable implants with following component: (a) with respect to the quality of described implant, by mass, the curative drug existing with the amount of 10%-60%; (b) with respect to the quality of described implant, by mass, the polymer existing with the amount of 40%-90%, described polymer comprises PLA and optional PGA, and wherein PLA:PGA molar ratio is 50:50 to 100:0; (2) when approaching the peak point of release of biodegradable implant of described initial set, to described individual administration, maintain the one or more biodegradable implant of group, the wherein said biodegradable implant that maintains group is comprised of other independent biodegradable implant, the described other PLA:PGA molar ratio of independent biodegradable implant equates with the described biodegradable implant separately in the biodegradable implant of described initial set, thereby the Drug therapy level in individuality maintained to the time period of prolongation.In the method, if the independent biodegradable implant of described initial set outnumber one, they substantially do not have each other difference on their PLA:PGA molar ratio.

In another embodiment, " time period of prolongation " refer to by a definite date at least about 6 months.In another embodiment, this term refers to by a definite date at least about 4 months.In another embodiment, this term refers to by a definite date at least about 5 months.In another embodiment, this term refers to by a definite date at least about 7 months.In another embodiment, this term refers to by a definite date at least about 8 months.In another embodiment, this term refers to by a definite date at least about 9 months.In another embodiment, this term refers to by a definite date at least about 10 months.In another embodiment, this term refers to by a definite date at least about 12 months.In another embodiment, this term refers to by a definite date at least about 14 months.In another embodiment, this term refers to by a definite date at least about 16 months.In another embodiment, this term refers to by a definite date at least about 18 months.In another embodiment, this term refers to by a definite date at least about 21 months.In another embodiment, this term refers to by a definite date at least about 24 months.In another embodiment, this term refers to and schedules to last over 24 months.Various probabilities represent independently embodiment of the present invention.

In another embodiment, if described in maintain group independent biodegradable implant outnumber one, they substantially do not have each other difference on their PLA:PGA molar ratio.In another embodiment, described initial set and the described independent biodegradable implant that maintains group on their PLA:PGA molar ratio in group and all substantially there is no each other difference between group.Various probabilities represent independently embodiment of the present invention.

In another embodiment, where necessary repeating step (b) the Drug therapy level in described individuality is maintained to the time period of expectation.

When in another embodiment, the release of group implant starts to decline before approaching, described in administration, maintain group.

In another embodiment, the invention provides the biodegradable implant of (a) initial set of the present invention; And (b) the biodegradable implant that maintains group of the present invention for the preparation of for the Drug therapy level in individuality being maintained to the purposes of the pharmaceutical composition of one of above-mentioned time period.

In one embodiment, described within approximately every 6 months, being administered once, maintain group.In another embodiment, after scheduling to last approximately 5 months, described in administration, maintain group.In another embodiment, this time period is approximately 4 months.In another embodiment, this time period is approximately 3 months.In another embodiment, this time period is approximately 2 months.In another embodiment, this time period is approximately 6 weeks.In another embodiment, this time period is approximately 1 month.In another embodiment, this time period is approximately 7 months.In another embodiment, this time period is approximately 8 months.In another embodiment, this time period is approximately 9 months.In another embodiment, this time period is approximately 10 months.In another embodiment, this time period is approximately 11 months.In another embodiment, this time period is approximately 12 months.In another embodiment, this time period is approximately 14 months.In another embodiment, this time period is approximately 16 months.In another embodiment, this time period is approximately 18 months.In another embodiment, this time period is approximately 20 months.In another embodiment, this time period is approximately 22 months.In another embodiment, this time period is approximately 24 months.In another embodiment, this time period is approximately 30 months.In another embodiment, this time period is approximately 36 months.Various probabilities represent independently embodiment of the present invention.

In another embodiment, except their PLA:PGA molar ratio, the described independent implant that maintains group equates in another parameter with the independent implant in described initial set, for example: the intrinsic viscosity of their drug loading, quality, SA:V ratio, length, diameter or described polymer.In another embodiment, described in maintain group independent implant equate in one of these parameters with the independent implant in described initial set, but not equate on their PLA:PGA molar ratio.In another embodiment, from the described independent implant that maintains group, equate on PLA:PGA ratio with the independent implant in described initial set, but unequal in other parameters.In another embodiment, except their PLA:PGA molar ratio, from the described independent implant of group that maintains, equate on two kinds in these other parameters with independent implant in described initial set.In another embodiment, except their PLA:PGA molar ratio, from the described independent implant of group that maintains, equate on three kinds in these other parameters with independent implant in described initial set.In another embodiment, except their PLA:PGA molar ratio, from the described independent implant of group that maintains, equate on four kinds in these other parameters with independent implant in described initial set.In another embodiment, except their PLA:PGA molar ratio, from the described independent implant of group that maintains, equate on five kinds in these other parameters with independent implant in described initial set.In another embodiment, except their PLA:PGA molar ratio, from the described independent implant of group that maintains, equate in all these other parameters with the independent implant in described initial set.In another embodiment, from the described independent implant of group that maintains, equate on two kinds in these other parameters with independent implant in described initial set, but their PLA:PGA molar ratio is unequal.In another embodiment, from the described independent implant of group that maintains, equate on three kinds in these other parameters with independent implant in described initial set, but their PLA:PGA molar ratio is unequal.In another embodiment, from the described independent implant of group that maintains, equate on four kinds in these other parameters with independent implant in described initial set, but their PLA:PGA molar ratio is unequal.In another embodiment, from the described independent implant of group that maintains, equate on five kinds in these other parameters with independent implant in described initial set, but their PLA:PGA molar ratio is unequal.Various probabilities represent independently embodiment of the present invention.

In other embodiments, the independent implant that maintains group described in has any above-mentioned feature of the independent implant of described initial set.Various character representations independently embodiment of the present invention.

As the present invention's proof, the near symmetrical of the release profiles of single polymers group provides to utilize for about every 6 months and has repeated medicine is passed in (overlapping) implantation probability (Figure 13) to maintain for a long time.In one embodiment, this method has been offset the stable decline of one group of implant with the progressively release (onset) of subsequent group.

The time period that Drug therapy level can be maintained by method of the present invention in another embodiment, is one month.In another embodiment, the described time period is 1.5 months.In another embodiment, the described time period is 2 months.In another embodiment, the described time period is 2.5 months.In another embodiment, the described time period is 3 months.In another embodiment, the described time period is 3.5 months.In another embodiment, the described time period is 4 months.In another embodiment, the described time period is 5 months.In another embodiment, the described time period is 6 months.In another embodiment, the described time period is 7 months.In another embodiment, the described time period is 8 months.In another embodiment, the described time period is 9 months.In another embodiment, the described time period is 10 months.In another embodiment, the described time period is 11 months.In another embodiment, the described time period is 12 months.In another embodiment, the described time period is 13 months.In another embodiment, the described time period is 14 months.In another embodiment, the described time period is 15 months.In another embodiment, the described time period is 16 months.In another embodiment, the described time period is 17 months.In another embodiment, the described time period is 18 months.

In another embodiment, the described time period starts after the step 1 of the biodegradable implant of initial set described in administration month.In another embodiment, the described time period starts after 1 week in described initial administration.In another embodiment, 2 weeks after described initial administration described time period started.In another embodiment, 3 weeks after described initial administration described time period started.In another embodiment, 5 weeks after described initial administration described time period started.In another embodiment, 6 weeks after described initial administration described time period started.In another embodiment, 2 months after described initial administration described time period started.In another embodiment, 2.5 months after described initial administration described time period started.In another embodiment, 3 months after described initial administration described time period started.

The above-mentioned various time period represents independently embodiment of the present invention.

In another embodiment, method of the present invention also comprises the one or more different biodegradable implant to described individual administration starting group, the implant of wherein said starting group is different on PLA:PGA ratio from described initial set implant, and described starting group implant reaches stable state release level quickly than described initial set implant thus.In another embodiment, described starting group implant is different on their drug loading from described initial set implant.In another embodiment, described starting group implant is different on their SA:V ratio from described initial set implant.In another embodiment, described starting group implant is different qualitatively theirs from described initial set implant.In another embodiment, described starting group implant is different in their length from described initial set implant.In another embodiment, described starting group implant is different on their diameter from described initial set implant.In another embodiment, described starting group implant is different in their polymer intrinsic viscosity from described initial set implant.In another embodiment, described starting group implant is different on 2 kinds in these features from described initial set implant.In another embodiment, described starting group implant is different on 3 kinds in these features from described initial set implant.In another embodiment, described starting group implant is different on 4 kinds in these features from described initial set implant.In another embodiment, described starting group implant is all different in all these features from described initial set implant.Various probabilities represent independently embodiment of the present invention.

In another embodiment, described starting group implant does not substantially have each other difference in their PLA:PGA ratio, drug loading, length, diameter, SA:V ratio and intrinsic viscosity.In another embodiment, on a kind of in these parameters of described starting group implant, substantially differ from one another.In another embodiment, described starting group implant surpasses on a kind of substantially different each other in these parameters.In another embodiment, described starting group implant has the release profiles differing from one another.Various probabilities represent independently embodiment of the present invention.

In other embodiments, described starting group implant has any above-mentioned feature of the independent implant of described initial set.Various character representations independently embodiment of the present invention.

In another embodiment, comprising initial set implant and maintaining in the method for the present invention of equal implant of group, by described starting group implant and described initial set implant co-administered.In one embodiment, " jointly " refer to one or more implants of other groups in administration on the same day.In another embodiment, " jointly " refer to administration during single operation or program process.In another embodiment, this term refers to administration in other group implants one day of administration.In another embodiment, this term refers to administration in other group implants 2 days of administration.In another embodiment, this term refers to administration in other group implants 3 days of administration.In another embodiment, this term refers to administration in other group implants 4 days of administration.In another embodiment, this term refers to administration in other group implants 1 week of administration.In another embodiment, this term refers to administration in other group implants 2 weeks of administration.In another embodiment, this term refers to administration in other group implants 3 weeks of administration.In another embodiment, this term refers to administration in other group implants 1 month of administration.In another embodiment, this term refers to administration in other group implants 2 months of administration.Various probabilities represent independently embodiment of the present invention.

In another embodiment, described starting group implant makes it possible to earlier reach Drug therapy level, as provided herein (embodiment 16).In another embodiment, existence due to described starting group implant, reduced the required implant number of described initial set implant (with respect to the described group implant that maintains), because described starting group implant contribution non-existent levels of drugs when maintaining group implant described in administration.

By the release profiles that relatively single polymers design and multiple polymer design, the present invention has proved the ability that starting group can discharge sooner.With described multiple polymer, design time point in early days and observe higher serum levels (Fig. 1 and 3A).

In another embodiment, replace carrying out administration starting group implant with initial implantation, increase the number (with respect to the described group implant that maintains) of implant more promptly to reach treatment level.

In another embodiment, described in administration, the step of initial set implant is reversible.In another embodiment, described in administration, the step of starting group implant is reversible.In one embodiment, " reversible " refers to the ability of removing residue implant group by operation or other modes.In one embodiment, " reversible " refers to the ability of removing remaining one or more implants.In another embodiment, " reversible " refers to the ability of the implant group of removing most of surplus.In another embodiment, " reversible " refers to the ability of one or more implants of removing most of surplus.Various probabilities represent independently embodiment of the present invention.

In one embodiment, the individuality of method of the present invention is the mankind.In another embodiment, described individuality is primates.In another embodiment, described individuality is mammal.In another embodiment, described individuality is rodent.In another embodiment, described individuality is laboratory animal.In another embodiment, described individuality is domestic animal.In another embodiment, described individuality is male.In another embodiment, described individuality is female.The individuality of any other type that in another embodiment, described individuality is known in the art.Various probabilities represent independently embodiment of the present invention.

In other embodiments, the independent implant of above-mentioned any group has the random length of implant of the present invention.In other embodiments, described independent implant has the total length equating with the random length of implant of the present invention.

In another embodiment, the step of the independent implant of above-mentioned any group of administration is reversible.In another embodiment, the step of above-mentioned any group of administration is reversible.In one embodiment, " reversible " refers to one of implication provided above.Various probabilities represent independently embodiment of the present invention.

In other embodiments, the independent implant of above-mentioned any group has the arbitrary diameter of implant of the present invention.In other embodiments, described independent implant has the total length of the arbitrary diameter that equals implant of the present invention.

In other embodiments, the independent implant of above-mentioned any group has any SA:V ratio of implant of the present invention.In other embodiments, described independent implant has total SA:V ratio of any SA:V ratio that equals implant of the present invention.

In other embodiments, the independent implant of above-mentioned any group has any quality of implant of the present invention.In other embodiments, described independent implant has the gross mass of any quality that equals implant of the present invention.

In another embodiment, the independent implant of above-mentioned any group is incorporated in single structure (such as clavate structure, bundle etc.).In another embodiment, described structure has the random length of implant of the present invention.In another embodiment, described structure has the arbitrary diameter of implant of the present invention.In another embodiment, described structure has any SA:V ratio of implant of the present invention.In another embodiment, described structure has any quality of implant of the present invention.In another embodiment, described structure can reduce the number of implant infrastructure.Various probabilities represent independently embodiment of the present invention.

In other embodiments, the biodegradable implant of the individuality of above-mentioned any group has the arbitrary characteristics of implant of the present invention.Various character representations independently embodiment of the present invention.

In another embodiment, method of the present invention also comprises by different approaches, jointly carries out the administration of described curative drug, to reach and to maintain curative drug level, until the rate of release of described implant is enough with the initial administration of implant.The different pharmaceutical with described initial set implant co-administered in another embodiment, with similar treatment effect.Can use any route of administration known in the art.Various approach represent independently embodiment of the present invention.

In another embodiment, the speed the invention provides with substantial linear is discharged into curative drug the method in individual bodily tissue in scheduling to last some months, it comprises to described individual administration implant of the present invention or implant group, thereby curative drug is discharged in individual bodily tissue in scheduling to last some months with the speed of substantial linear.

In another embodiment, the speed the invention provides with substantial linear is discharged into tiotixene the method in individual bodily tissue in scheduling to last some months, it comprises the implant of the present invention containing tiotixene to described individual administration, thereby in scheduling to last some months, discharges tiotixene with the speed of substantial linear.

In another embodiment, the speed the invention provides with substantial linear is discharged into haloperidol the method in individual bodily tissue in scheduling to last some months, it comprises the implant of the present invention containing haloperidol to described individual administration, thereby in scheduling to last some months, discharges haloperidol with the speed of substantial linear.

In another embodiment, the speed the invention provides with substantial linear is discharged into HCTZ the method in individual bodily tissue in scheduling to last some months, it comprises the implant of the present invention containing HCTZ to described individual administration, thereby in scheduling to last some months, discharges HCTZ with the speed of substantial linear.

In another embodiment, the speed the invention provides with substantial linear is discharged into ibuprofen the method in individual bodily tissue in scheduling to last some months, it comprises the implant of the present invention containing ibuprofen to described individual administration, thereby in scheduling to last some months, discharges ibuprofen with the speed of substantial linear.

In another embodiment, the speed the invention provides with substantial linear is discharged into aspirin the method in individual bodily tissue in scheduling to last some months, it comprises the implant of the present invention containing aspirin to described individual administration, thereby in scheduling to last some months, discharges aspirin with the speed of substantial linear.

In another embodiment, the speed the invention provides with substantial linear is discharged into corticosterone the method in individual bodily tissue in scheduling to last some months, it comprises the implant of the present invention that comprises corticosterone to described individual administration, thereby in scheduling to last some months, discharges corticosterone with the speed of substantial linear.

In different embodiments, " some months " refers to any time section of the present invention.The various time periods represent independently embodiment of the present invention.

In another embodiment, the invention provides with the speed of substantial linear and in several weeks, curative drug is discharged into the method in individual bodily tissue scheduling to last, it comprises to described individual administration implant of the present invention or implant group, thereby curative drug is discharged in individual bodily tissue scheduling to last in several weeks with the speed of substantial linear.

In different embodiments, described curative drug is any curative drug of the present invention.Various curative drugs represent independently embodiment of the present invention.

In one embodiment, the speed of the substantial linear of method and composition of the present invention be described implant in steady state release the rate of release in the stage.In one embodiment, " stable state " refers to the wherein time period of the rate of release of implant demonstration substantial linear, as illustrative in this paper embodiment 10.

In one embodiment, the speed of described substantial linear is 0.1mg/ days.In another embodiment, described speed is 0.2mg/ days.In another embodiment, described speed is 0.3mg/ days.In another embodiment, described speed is 0.4mg/ days.In another embodiment, described speed is 0.5mg/ days.In another embodiment, described speed is 0.6mg/ days.In another embodiment, described speed is 0.8mg/ days.In another embodiment, described speed is 1mg/ days.In another embodiment, described speed is 1.2mg/ days.In another embodiment, described speed is 1.5mg/ days.In another embodiment, described speed is 1.8mg/ days.In another embodiment, described speed is 2.0mg/ days.In another embodiment, described speed is 2.5mg/ days.In another embodiment, described speed is 3mg/ days.In another embodiment, described speed is 3.5mg/ days.In another embodiment, described speed is 4mg/ days.In another embodiment, described speed is 5mg/ days.In another embodiment, described speed is 6mg/ days.In another embodiment, described speed is 7mg/ days.In another embodiment, described speed is 8mg/ days.In another embodiment, described speed is 10mg/ days.Various rate representation independently embodiment of the present invention.

In another embodiment, described speed is about 0.1-0.3mg/ days.In another embodiment, described speed is 0.2-0.4mg/ days.In another embodiment, described speed is 0.3-0.5mg/ days.In another embodiment, described speed is 0.4-0.6mg/ days.In another embodiment, described speed is 0.5-0.7mg/ days.In another embodiment, described speed is 0.6-0.8mg/ days.In another embodiment, described speed is 0.7-0.9mg/ days.In another embodiment, described speed is 0.8-1.0mg/ days.In another embodiment, described speed is 0.1-0.4mg/ days.In another embodiment, described speed is 0.2-0.5mg/ days.In another embodiment, described speed is 0.3-0.6mg/ days.In another embodiment, described speed is 0.4-0.7mg/ days.In another embodiment, described speed is 0.5-0.8mg/ days.In another embodiment, described speed is 0.6-0.9mg/ days.In another embodiment, described speed is 0.8-1.1mg/ days.In another embodiment, described speed is 1.0-1.3mg/ days.In another embodiment, described speed is 1.5-1.8mg/ days.In another embodiment, described speed is 0.1-0.5mg/ days.In another embodiment, described speed is 0.2-0.6mg/ days.In another embodiment, described speed is 0.3-0.7mg/ days.In another embodiment, described speed is 0.4-0.8mg/ days.In another embodiment, described speed is 0.5-0.9mg/ days.In another embodiment, described speed is 0.6-1.0mg/ days.In another embodiment, described speed is 0.8-1.2mg/ days.In another embodiment, described speed is 1.0-1.4mg/ days.In another embodiment, described speed is 1.5-1.9mg/ days.In another embodiment, described speed is 2-2.4mg/ days.In another embodiment, described speed is 0.1-0.6mg/ days.In another embodiment, described speed is 0.2-0.7mg/ days.In another embodiment, described speed is 0.3-0.8mg/ days.In another embodiment, described speed is 0.5-1.0mg/ days.In another embodiment, described speed is 0.6-1.1mg/ days.In another embodiment, described speed is 0.8-1.3mg/ days.In another embodiment, described speed is 1.0-1.5mg/ days.In another embodiment, described speed is 1.5-2mg/ days.In another embodiment, described speed is 2-2.5mg/ days.In another embodiment, described speed is 2.5-3mg/ days.In another embodiment, described speed is 3-3.5mg/ days.In another embodiment, described speed is 3.5-4mg/ days.In another embodiment, described speed is 4-4.5mg/ days.In another embodiment, described speed is 0.3-1.3mg/ days.In another embodiment, described speed is 0.5-1.5mg/ days.In another embodiment, described speed is 0.8-1.8mg/ days.In another embodiment, described speed is 1.0-2mg/ days.In another embodiment, described speed is 1.5-2.5mg/ days.In another embodiment, described speed is 2-3mg/ days.In another embodiment, described speed is 2.5-3.5mg/ days.In another embodiment, described speed is 3-4mg/ days.In another embodiment, described speed is 3.5-4.5mg/ days.In another embodiment, described speed is 4-5mg/ days.In another embodiment, described speed is 0.5-2mg/ days.In another embodiment, described speed is 1.0-2.5mg/ days.In another embodiment, described speed is 1.5-3mg/ days.In another embodiment, described speed is 2-3.5mg/ days.In another embodiment, described speed is 2.5-4mg/ days.In another embodiment, described speed is 3-4.5mg/ days.In another embodiment, described speed is 3.5-5mg/ days.In another embodiment, described speed is 0.5-2.5mg/ days.In another embodiment, described speed is 1-3mg/ days.In another embodiment, described speed is 1.5-3.5mg/ days.In another embodiment, described speed is 2-4mg/ days.In another embodiment, described speed is 2.5-4.5mg/ days.In another embodiment, described speed is 3-5mg/ days.In another embodiment, described speed is 1-4mg/ days.In another embodiment, described speed is 1.5-4.5mg/ days.In another embodiment, described speed is 2-5mg/ days.In another embodiment, described speed is 3-6mg/ days.

Above-mentioned various rate representation independently embodiment of the present invention.

In another embodiment, the speed the invention provides with substantial linear is discharged into risperidone the method in individual bodily tissue in scheduling to last at least 1 month, it comprises implant of the present invention or the implant group containing risperidone to described individual administration, thereby risperidone is discharged in individual bodily tissue in scheduling to last at least 1 month with the speed of substantial linear.

In another embodiment, the speed the invention provides with substantial linear is discharged into risperidone the method in individual bodily tissue in scheduling to last at least 2 months, it comprises implant of the present invention or the implant group containing risperidone to described individual administration, thereby risperidone is discharged in individual bodily tissue in scheduling to last at least 2 months with the speed of substantial linear.

In another embodiment, the speed the invention provides with substantial linear is discharged into risperidone the method in individual bodily tissue in scheduling to last at least 3 months, it comprises implant of the present invention or the implant group containing risperidone to described individual administration, thereby risperidone is discharged in individual bodily tissue in scheduling to last at least 3 months with the speed of substantial linear.

In another embodiment, the speed the invention provides with substantial linear is discharged into risperidone the method in individual bodily tissue in scheduling to last at least 4 months, it comprises implant of the present invention or the implant group containing risperidone to described individual administration, thereby risperidone is discharged in individual bodily tissue in scheduling to last at least 4 months with the speed of substantial linear.

In another embodiment, the speed the invention provides with substantial linear is discharged into risperidone the method in individual bodily tissue in scheduling to last at least 5 months, it comprises implant of the present invention or the implant group containing risperidone to described individual administration, thereby risperidone is discharged in individual bodily tissue in scheduling to last at least 5 months with the speed of substantial linear.

In another embodiment, the speed the invention provides with substantial linear is discharged into risperidone the method in individual bodily tissue in scheduling to last at least 6 months, it comprises implant of the present invention or the implant group containing risperidone to described individual administration, thereby risperidone is discharged in individual bodily tissue in scheduling to last at least 6 months with the speed of substantial linear.

In another embodiment, the speed the invention provides with substantial linear is discharged into risperidone the method in individual bodily tissue in scheduling to last at least 7 months, it comprises implant of the present invention or the implant group containing risperidone to described individual administration, thereby risperidone is discharged in individual bodily tissue in scheduling to last at least 7 months with the speed of substantial linear.

In another embodiment, the speed the invention provides with substantial linear is discharged into risperidone the method in individual bodily tissue in scheduling to last at least 8 months, it comprises implant of the present invention or the implant group containing risperidone to described individual administration, thereby risperidone is discharged in individual bodily tissue in scheduling to last at least 8 months with the speed of substantial linear.

In another embodiment, the speed the invention provides with substantial linear is discharged into risperidone the method in individual bodily tissue in scheduling to last at least 9 months, it comprises implant of the present invention or the implant group containing risperidone to described individual administration, thereby risperidone is discharged in individual bodily tissue in scheduling to last at least 9 months with the speed of substantial linear.

In another embodiment, the speed the invention provides with substantial linear is discharged into risperidone the method in individual bodily tissue in scheduling to last at least 10 months, it comprises implant of the present invention or the implant group containing risperidone to described individual administration, thereby risperidone is discharged in individual bodily tissue in scheduling to last at least 10 months with the speed of substantial linear.

In another embodiment, the speed the invention provides with substantial linear is discharged into risperidone the method in individual bodily tissue in scheduling to last at least 11 months, it comprises implant of the present invention or the implant group containing risperidone to described individual administration, thereby risperidone is discharged in individual bodily tissue in scheduling to last at least 11 months with the speed of substantial linear.

In another embodiment, the speed the invention provides with substantial linear is discharged into risperidone the method in individual bodily tissue in scheduling to last at least 12 months, it comprises implant of the present invention or the implant group containing risperidone to described individual administration, thereby risperidone is discharged in individual bodily tissue in scheduling to last at least 12 months with the speed of substantial linear.

In another embodiment, the speed the invention provides with substantial linear is discharged into risperidone the method in individual bodily tissue in scheduling to last at least 14 months, it comprises implant of the present invention or the implant group containing risperidone to described individual administration, thereby risperidone is discharged in individual bodily tissue in scheduling to last at least 14 months with the speed of substantial linear.

In another embodiment, the speed the invention provides with substantial linear is discharged into risperidone the method in individual bodily tissue in scheduling to last at least 16 months, it comprises implant of the present invention or the implant group containing risperidone to described individual administration, thereby risperidone is discharged in individual bodily tissue in scheduling to last at least 16 months with the speed of substantial linear.

In another embodiment, the speed the invention provides with substantial linear is discharged into risperidone the method in individual bodily tissue in scheduling to last at least 18 months, it comprises implant of the present invention or the implant group containing risperidone to described individual administration, thereby risperidone is discharged in individual bodily tissue in scheduling to last at least 18 months with the speed of substantial linear.

In another embodiment, the invention provides the schizoid method in the treatment mankind, it comprises to described mankind's administration implant of the present invention or implant group, thus the schizophrenia in the treatment mankind.

In one embodiment, described schizophrenia is catatonic schizophrenia.In another embodiment, described schizophrenia is paranoid schizophrenia.In another embodiment, described schizophrenia is disorganized schizophrenia.In another embodiment, described schizophrenia is undifferentiated schizophrenia.In another embodiment, described schizophrenia is residual schizophrenia.In another embodiment, described schizophrenia is feminine gender or Deficit Schizophrenia.In another embodiment, described schizophrenia is psychosis.In another embodiment, described schizophrenia is the schizophrenia of any other type known in the art.Various probabilities represent independently embodiment of the present invention.

As provided herein, method of the present invention is effectively (embodiment 8-9) aspect schizophrenia sending for a long time risperidone and treatment.For major part, discharge interval, in the target zone of the interior risperidone serum-concentration of body in 2-15ng/ml (Foster RH and Goa KL (1998) Pharmacoeconomics14:97-133) (Fig. 1 and 3).

In another embodiment, the invention provides the method for the bipolar disorder in the treatment mankind, it comprises to described mankind's administration implant of the present invention or implant group, thus the bipolar disorder in the treatment mankind.

In another embodiment, the invention provides the dull-witted method in the treatment mankind, it comprises to described mankind's administration implant of the present invention or implant group, thus the dementia in the treatment mankind.

In another embodiment, the invention provides the method for the delirium in the treatment mankind, it comprises to described mankind's administration implant of the present invention or implant group, thus the delirium in the treatment mankind.

In another embodiment, the invention provides the method for the anxiety (agitation) in the treatment mankind, it comprises to described mankind's administration implant of the present invention or implant group, thus the anxiety in the treatment mankind.

In another embodiment, the invention provides the method for the impulse control disorder in the treatment mankind, it comprises to described mankind's administration implant of the present invention or implant group, thus the impulse control disorder in the treatment mankind.

In another embodiment, the invention provides the method for the psychotic depression in the treatment mankind, it comprises to described mankind's administration implant of the present invention or implant group, thus the psychotic depression in the treatment mankind.

In another embodiment, the invention provides the schizoid method for the treatment of in the mankind, it comprises and carrying out for maintaining one of the said method of the Drug therapy level of individuality, thus the schizophrenia in the treatment mankind.

In another embodiment, the invention provides the method for the bipolar disorder for the treatment of in the mankind, it comprises and carrying out for maintaining one of the said method of the Drug therapy level of individuality, thus the bipolar disorder in the treatment mankind.

In another embodiment, the invention provides the dull-witted method for the treatment of in the mankind, it comprises and carrying out for maintaining one of the said method of the Drug therapy level of individuality, thus the dementia in the treatment mankind.

In another embodiment, the invention provides the method for the delirium for the treatment of in the mankind, it comprises and carrying out for maintaining one of the said method of the Drug therapy level of individuality, thus the delirium in the treatment mankind.

In another embodiment, the invention provides the method for the anxiety for the treatment of in the mankind, it comprises and carrying out for maintaining one of the said method of the Drug therapy level of individuality, thus the anxiety in the treatment mankind.

In another embodiment, the invention provides the method for the impulse control disorder for the treatment of in the mankind, it comprises and carrying out for maintaining one of the said method of the Drug therapy level of individuality, thus the impulse control disorder in the treatment mankind.

In another embodiment, the invention provides the method for the psychotic depression for the treatment of in the mankind, it comprises and carrying out for maintaining one of the said method of the Drug therapy level of individuality, thus the psychotic depression in the treatment mankind.

In another embodiment, the invention provides implant of the present invention or implant group for the preparation of the purposes of the schizoid pharmaceutical composition for the treatment of.In another embodiment, the invention provides and be used for the treatment of the schizoid compositions that comprises implant of the present invention or implant group.

In another embodiment, the invention provides implant of the present invention or implant group for the preparation of the purposes of the pharmaceutical composition for the treatment of bipolar disorder.In another embodiment, the invention provides and be used for the treatment of comprising of bipolar disorder of the implant of the present invention or compositions of implant group.

In another embodiment, the invention provides implant of the present invention or implant group for the preparation of the purposes of the dull-witted pharmaceutical composition for the treatment of.In another embodiment, the invention provides and be used for the treatment of the dull-witted compositions that comprises implant of the present invention or implant group.

In another embodiment, the invention provides implant of the present invention or implant group for the preparation of the purposes of the pharmaceutical composition for the treatment of delirium.In another embodiment, the invention provides and be used for the treatment of comprising of delirium of the implant of the present invention or compositions of implant group.

In another embodiment, the invention provides implant of the present invention or implant group for the preparation of the purposes of the pharmaceutical composition for the treatment of anxiety.In another embodiment, the invention provides and be used for the treatment of comprising of anxiety of the implant of the present invention or compositions of implant group.

In another embodiment, the invention provides implant of the present invention or implant group for the preparation of the purposes of the pharmaceutical composition for the treatment of impulse control disorder.In another embodiment, the invention provides and be used for the treatment of comprising of impulse control disorder of the implant of the present invention or compositions of implant group.

In another embodiment, the invention provides implant of the present invention or implant group for the preparation of the purposes of the pharmaceutical composition for the treatment of psychotic depression.In another embodiment, the invention provides and be used for the treatment of comprising of psychotic depression of the implant of the present invention or compositions of implant group.

The treatment phase of any above-mentioned disease that method of the present invention provides can be any time section of the present invention.Each time period represents independently embodiment of the present invention.

In one embodiment, " treatment " refer to therapeutic intervention.In another embodiment, this term refers to Primary preventive intervention.In another embodiment, this term refers to improve the symptom of disease or disease.In another embodiment, this term refers to improve and is secondary to the disease that is just being treated or symptom, disease or the disease of disease.In another embodiment, " treatment " refer to slow down disease process.Various probabilities represent independently embodiment of the present invention.

For the method for diagnosing and evaluate the seriousness of above-mentioned disease, be well known in the art, be described in for example by the American Psychiatric Association, among the Diagnostic and Statistical Manual of Mental Disorders (DSM) that Washington D.C. publishes.The whole bag of tricks represents independently embodiment of the present invention.In another embodiment, by evaluating method diagnosis schizophrenia or the above-mentioned another kind of disease described in the description of method of risperidone treatment effect above.

Evaluating risperidone treatment is well known in the art in the method for the effect of animal and human's apoplexy due to endogenous wind.In animal, can evaluate by for example PPI (following) motor behavior, bull stick (rotarod) and catalepsy assessment method the effect of risperidone treatment.In one embodiment, in " rearging cage (home cage) " active monitoring system (MedAssociates, St.Albans, VT), measure motor behavior.This system is placed on the clean rearging cage of standard in the light beam frame (photobeam frame) with two horizon sensors, and described sensor arrangement becomes to have the 8-bundle array bar at 1.25 inches of intervals.Computer detection system monitoring is about the interruption of the light beam of the parameter of walking about.The number that the light beam that causes when cage moves by animal is interrupted is determined and is always walked about.At Med Associates personal computer design software identifying recording layer and at each movement monitoring, in the phase, for example, with 5 minutes intervals, monitor 30 minutes altogether.Rat is conventionally accustomed to several days to instrument and task before they are exposed to amfetamine first.

In another embodiment, use bull stick to evaluate the usefulness of risperidone treatment.In one embodiment, use the bull stick pedal instrument (Stoelting Co., Wood Dale, EL) accelerating to determine motor function.In order to adapt to this instrument, rat is placed on static rod.Then by Speed Setting for to rise to gradually 20rpm from 2rpm.Keeping the maximum score of balance and posture is (for example 5 minutes that fix; Lelas S, the people such as Wong H, J Pharmacol Exp Ther309:293-302,2004).After this time period or when animal falls from rod, stop test.

In another embodiment, by catalepsy assessment method, evaluate the effect of risperidone treatment.For example, in animal (rat), test catalepsy is to evaluate the exercise effect of risperidone implant.Rat foreleg is positioned to cage side, and record recovers the required time quantum of normal posture.Recovering whole four lower limbs is positioned to raise entopic incubation period at the bottom of cage and is interpreted as the athletic injury of indicating risperidone to cause.

In another embodiment, with audition, startle and respond the effect of evaluating risperidone treatment.Audition startle response be after loud auditory stimulus can be quantitative reflex movement.Due to the not stronger stimulus to the sense organ of preexist, so there is prepulse inhibition (PPI) (Hoffman HS, Searle JL (1965) J Comp Physiol Psychol60:53-58) when the response that startles reduces.By administration dopamine (DA) agonist, can weaken PPI as apomorphine (APO) and amfetamine (AMPH); this effect reverses (Mansbach RS, Geyer MA (1989) .Neuropsychopharmacol2:299-308 by dopamine-receptor antagonist as haloperidol and risperidone; The people such as Swerdlow NR, (1991) .J Pharmacol Exp Ther256:530-536; The people such as Swerdlow NR, Neuropsychopharmacol18:50-56).Like this, by DA receptor stimulating agent, weakening PPI is effective animal model (Braff DL, Geyer MA (1990) Arch Gen Psychiatry47:181-188) of the defect in the sensory gating process of observing in schizophrenia.

For recording the method for auditory evoked potential, be well known in the art.In one embodiment, by solid, locate implantation three utmost point electrode assemblies and record auditory evoked potential.In another embodiment, these assemblies are used for without anesthetic record auditory evoked potential.These methods are well known in the art, are described in such as (people such as Connolly, 2003; The people such as Connolly, 2004; The people such as Maxwell, 2004; The people such as Siegel, 2005) in.

For evaluating risperidone, in the other method of the usefulness of animal, be behavior observation, the method is well known in the art, be described in for example Elmer GI, in the people (Cocaine cross-sensitization to dopamine uptake inhibitors:unique effects of GBR12909.Pharmacol Biochem Behav53:911-918,1996) such as Brockington A.For example, in every 5 minutes intervals, observe and record the existence of following behavior or do not exist: peace and quiet; Smell news; Lick; Sting; Reason hair; Mobile (whole four lower limbs move); Back leg stand (two forelegs all leave cage at the bottom of); Handstand (head down) (animal nose is lower than flatly standing, walk or run over 5 seconds); Wave (animal head or health rhythmically oscillating motion over 3 seconds); Turn-take (pitch of the laps is walked or run over 5 seconds continuously).

In another embodiment, by quantitative dopamine D ₂and/or 5-hydroxy tryptamine 5HT _1Az _2AZa _cthe usefulness of risperidone treatment is evaluated in for example, expression in brain sample (: cortex, Hippocampus, striatum and/or cerebellum) of receptor.Risperidone increases dopamine D ₂expression of receptor also reduces 5-hydroxy tryptamine 5HT _iAz _2A/ _2Cexpression of receptor.5-hydroxytryptamine receptor Western blotting can utilize polyclonal antibody AB5406 (Chemicon, Temecula, CA), PC176L (Calbiochem, CA) or and AB5655 (Chemicon).D ₂receptor protein trace can utilize polyclonal antibody WR-3526 (Research and Diagnostic Antibodies, Berkeley, CA).Various probabilities represent independently embodiment of the present invention.

For evaluating risperidone, in the method for the mankind's therapeutic efficiency, be described in (the Biol Psychiatry200557 (6): 577-85), the people such as Moller HJ (Int Clin Psychopharmacol.200520 (3): 121-30) and people (the Am J Psychiatry.2004161 (6): 1057-65) such as Hirschfeld RM such as people such as Heresco-Levy U.In another embodiment, use DSM-IV, by evaluating the seriousness of the disease of risperidone treatment, described the therapeutic efficiency of risperidone in human body.For evaluating risperidone, at the above-mentioned the whole bag of tricks of the therapeutic efficiency of animal body, all can be used for people, vice versa.

For evaluating the above-mentioned the whole bag of tricks of risperidone effect, represent independently embodiment of the present invention.

In another embodiment, the invention provides that to comprise drug loading be by mass the curative drug of about 20-30% (comprising end value) and be the implant of the polymer of 70%-80% (comprising end value) by mass, described polymer comprises PLA and optional PGA, wherein PLA:PGA ratio is by mass for 80:20 to 100:0 (comprising end value), and described implant has the R establishing an equation under meeting ₀radius:

(\frac{{dM}_{d}}{dt}) = : 4 {πR}_{0}^{2} {(1 - \frac{C_{w} \sqrt{D}}{{2 R}_{0} \sqrt{k}} t)}^{2} \frac{C_{w} \sqrt{D} \erf [\sqrt{kt}]}{2 \sqrt{k}}

Wherein:

" erf (x) " refers to

DM _d/ dt is the expectation steady state release rates of curative drug when time t, and D is the diffusion coefficient that water enters substrate, and k is reaction rate, C _wconcentration C for the water in implant described in when the time t _w;

Wherein k is by formula

determine, wherein S is the dissolubility of curative drug in water; The constant that wherein k is about 0.05-0.33.

In one embodiment, the curative drug containing in above-mentioned implant is risperidone.In another embodiment, described curative drug is haloperidol, and D is 1.7 * 10 in this case ^Λ-10 and k be 0.07 (embodiment 10).In another embodiment, described curative drug is tiotixene, and D is 9 * 10 in this case ^Λ-10 and k be 0.06.In another embodiment, described curative drug is HCTZ, and D is 2.1 * 10 in this case ^Λ-6 and k be 0.26.In another embodiment, described curative drug is corticosterone, and D is 2.5 * 10 in this case ^Λ-7 and k be 0.33.In another embodiment, described curative drug is ibuprofen, and D is 7.0 * 10 in this case ^Λ-6 and k be 0.16.In another embodiment, described curative drug is aspirin, and D is 8.0 * 10 in this case ^Λ-2 and k be 0.06.In another embodiment, any other curative drug that described curative drug is known in the art.Various probabilities represent independently embodiment of the present invention.

In another embodiment, degradation reaction velocity coefficient k depends on the pharmaceutical properties (embodiment 11) that the combination by the existence of drug solubility and OH group provides.For having identical water miscible medicine, the speed of polymer hydrolysis increases along with the density of OH group, and for the medicine with identical OH groups density, k is along with dissolubility declines.

In another embodiment, k is definite by rule of thumb, as described in Example 10.

In another embodiment, the existence of described medicine can affect depolymerization speed.In one embodiment, the diffusion that described medicine enters described polymeric matrix by affecting water affects depolymerization speed.In another embodiment, described medicine affects depolymerization speed by affecting the speed of degradation reaction.In another embodiment, described medicine is by the combined effect depolymerization speed of above-mentioned mechanism.Various probabilities represent independently embodiment of the present invention.

In another embodiment, for example the invention provides, by utilizing equation of the present invention (equation 4,5a or 5b), design implant is to send the method for the curative drug of targeted release rates.

In another embodiment, the invention provides that (for

example equation

8,9 or 10 by utilizing equation of the present invention; Embodiment 12), design implant is to send the method for the curative drug of targeted rate serum-concentration.

In another embodiment, the invention provides and when time t, obtain rate of releasing drug dM _dthe method of/dt, it comprises that its radius of administration used the definite implant of equation of the present invention (for example equation 4,5a or 5b).

In another embodiment, the invention provides the method that reaches serum-concentration x when time t, it comprises that its radius of administration used the definite implant of equation of the present invention (for

example equation

8,9 or 10).

Any method of the present invention can adopt any implant of the present invention.The various combinations of the inventive method and implant of the present invention represent independently embodiment of the present invention.

In another embodiment, the invention provides and be included in the test kit that carries out the reagent that uses in the inventive method.In another embodiment, the invention provides the test kit that comprises implant of the present invention.

experimental detail part

embodiment 1: in monkey, from PLGA implant, discharge for a long time haloperidol

material and experimental technique

Experimenter

Use two monkeys (machin, Rangos Research Facility), accept 6 implants that comprise copolymer p LGA (poly-(d, l-lactic acid-ethanol)) for every.For experimental monkey groups, this implant comprises 40% haloperidol by mass, and one of other 60% PLGA polymer by below table 2 description form.The implant that comprises the PLGA polymer that 100% table 2 describes to contrast monkey administration.PLGA polymer by

alkermes (Cincinnati, OH) provides.The mean dose of haloperidol in 12 months be 1mg/kg/ days to obtain the serum-concentration of 2-10ng/ml.

Table 2: at the implant for primates experiment, the polylactic acid of PLGA polymer: molar ratio and the intrinsic viscosity of polyglycolic acid (PLA:PGA).The dl/g that intrinsic viscosity in table be take in chloroform is unit representation, uses No. 25 Cannon-Fenske glass capillary tube viscometers at 30 ℃, and 0.5dl/g measures.

Implant number	PLA:PGA molar ratio	Intrinsic viscosity (IV)
			1	75:25	0.66-0.80
2	85:15	0.66-0.80
			3	90:10	High (0.87)
4	90:10	Low (0.68)
			5	95:5	0.66-0.80
6	100:0	0.66-0.80

Preparation implant

Polymer and haloperidol (Sigma, St.Louis, MO) are mixed with 60/40 mass ratio and by acetone (Fisher Scientific, Pittsburgh, PA) solvent cast.Gained film extrusion die is moulded to disc implant, and the diameter of this implant is 20mm, has the average thickness of 1.22 ± 0.0mm, and quality is that 493 ± 2mg and density are 1.28 ± 0.0g/cc.

Determine pharmacokinetics

Monthly extract blood twice.By centrifugal blood serum is freezing until analyze at-80 ℃.To every animal, duplicate at each time point, determine serum risperidone and 9-OH risperidone concentration.By centrifugalize sample and by high pressure lipuid chromatography (HPLC) (HPLC), measure haloperidol level, follow ultraviolet (UV) to detect (Fig. 1).The levels of drugs of the mensuration gained of control animal is zero.

result

In whole embodiment, implant is by well tolerable and do not observe bad dermoreaction.As shown in Figure 1, through altogether within 443 days, measuring haloperidol, discharge.At initial 224 days, except a value (the 40th day 27.1ng/ml), average serum concentration was 10.5 ± 1.5ng/ml.In subsequently 176 days, Fluoride in Serum piperidine alcohols horizontal dimension be held in 4.0 ± 0.4ng/ml compared with harmonic(-)mean concentration.Level decline (average serum concentration is 1.2 ± 0.3ng/ml) in the end 45 days research process.

Therefore the haloperidol that, uses biodegradable implant to reach 14 months in monkey body discharges.

embodiment 2: in rabbit, from PLGA implant, discharge for a long time haloperidol

material and experimental technique

Experimental design

Test two kinds of implant systems, the first contains five different single polymers implants (being similar to embodiment 1), and the second contains five implants that are comprised of single polymers.The target of single polymers model is to reduce initial spike, release is maintained to 1 year simultaneously.

Experimenter

Rabbit (N=12, Covance, Denver, PA) weight range is 4.0kg to 5.7kg.Five implants (wherein the haloperidol carrying capacity of the total pastille of 418 ± 7mg/kg is 40%) that animals received is comprised of single polymers, 100%PLA, continue the dosage that obtains 1.13 ± 0.02mg/kg/ days of sending for 365 days of expecting.Other five animals received comprise the implant of polymer system of the combination of 75:25,85:15, the high IV of 90:10, the low IV of 90:10 and 100:0PLGA.The mean dose of this group is 473 ± 4mg/kg, and expectation is sent 365 days, obtains the mean dose of 1.29 ± 0.03mg/kg/ days.The implant that two rabbits are accepted pastille not in contrast.A contrast is accepted 100%PLA implant with simulation single polymers condition, the polymer system that the implant that another accepts to be comprised of 75:25,85:15, the high IV of 90:10, the low IV of 90:10 and 100:0PLGA combines with simulation.

Preparation implant

The operation of using embodiment 1 to describe makes implant, and average quality is 536 ± 2mg in this case, and density is 1.24 ± 0.00g/cc.Fasten implant to help implant position, location when the necropsy.

Determine pharmacokinetics

Use Waters20-postion SPE vacuum manifold and Waters Oasis MCX SPE cartridge case (3ml/60 μ g cartridge case) to carry out Solid-Phase Extraction (SPE).With first alcohol and water, adjust cartridge case, load the sample that comprises 2% phosphoric acid, be then used in 5% methanol in 0.1N hydrochloric acid, then with 100% acetonitrile, wash cartridge case, then be used in the 5%NH in 100% acetonitrile ₄the eluting of OH.Sample is dry in 80 ℃ of water-baths under nitrogen, reprovision in 100 μ l mobile phases, vortex, more centrifugal 5 minutes.The reprovision sample of 75 μ l is packed in automatic sampler and inject 50 μ l.Use Waters XTerra RP185um, 4.6 * 150mm post carries out HPLC, flow velocity 1.0ml/min, running time 30min.Mobile phase and sample buffer are by 55%H ₂o, 35% acetonitrile and 10%100mM ammonium bicarbonate form, pH10.In 280nm wavelength place detected peaks.The standard solution of preparing risperidone and 9-OH risperidone in normal rat serum (scope 1.25-50ng/ml), extraction, and be included in each run so that standard curve and the retention time of each compound to be provided.The retention time of risperidone and 9-OH risperidone is respectively 8.6 and 5.9min.

Histopathology

After nine months, five rabbits are put to death to obtain pathological analysis in mid-term, after four months, put to death remaining seven rabbits.In accepting all animals of implant, find remaining implant still by bolt in original place (Fig. 2).

After removing, in implantation, latter 282 days is its initial mass to the remaining implant of average residual 17%, is 5% of its initial mass at 423 days afterwards.HPLC/UV and NMR spectrum have confirmed to exist haloperidol and PLGA catabolite in remaining implant.HPLC content of dispersion analysis in remaining implant shows that the implant of removing at the 282nd day is for average 10% risperidone by weight, and those that removed at the 423rd day are average 9% risperidone by weight.At 25 ℃, on Varian Unity Inova300Mhz instrument, carry out NMR, use Vnmr6.1b software analysis collection of illustrative plates (Varian, Inc., Palo Alto.CA) (figure C3).At DMSO and chloroform (CDCl ₃) in the control sample of operation PLA (the high IV of Alkermes100DL) and haloperidol to define the important peak (being respectively Fig. 3 D-E) of each compound.From rabbit, remove implant, be originally dissolved in DMSO-d6, then by removing by filter residual solid, and be dissolved in chloroform.In DMSO, there is the haloperidol peak of all expectations.The small peak of 5.2-5.4ppm is in PLA-indication at CH peak because under low copolymer concentration, PLA corresponding-CH3 summit is fuzzy by haloperidol peak.CDCl ₃sample 8.1 and the feature haloperidol peak intensity that contains of 7.4ppm place lower than DMSO sample, infer because most of haloperidol are extracted in DMSO.Chloroform fraction contains at 0.9,1.2,3.9 and 4.5 peak, consistent with the catabolite lactic acid of PLA.

Implant does not cause that capsule forms, and this causes the process of simply removing.HPLC/UV and NMR spectrum has confirmed to exist in remaining implant haloperidol and PLGA catabolite.Histologic analysis shows in all rabbits that all tracts are all in normal limit.

result

In rabbit, carry out similar experiment, in this case by five different single polymers systems (being similar to embodiment 1) and five implant comparisons that formed by single polymers.The rabbit of administration multiple polymer system has the haloperidol level of 4.0 ± 0.6ng/ml in 360 days.In initial 198 days, there is the higher concentration (average serum level is 6.1 ± 0.7ng/ml) (Fig. 3 A) of initial period.Then through 320 days, be down to gradually the level of average out to 1.1 ± 0.3ng/ml, at the 360th day, fall below detection level.B) rabbit of administration single polymers system shows more symmetrical release profiles and has the average serum concentration of 2.5 ± 0.4ng/ml, falls below detection level, as (Fig. 3 B) that observe in multiple polymer system at the 360th day.

Therefore, by the experimental result that rabbit obtains, confirmed the experimental result in monkey, proved that the haloperidol that uses biodegradable implant can reach 12 months discharges.These results also show at least in some cases, by single polymers system, can obtain the release profiles more symmetrical than multiple polymer system.

embodiment 3: the impact of implant geometry on rate of release

material and experimental technique

The implant of preparing the 50:50PLGA polymer that comprises 40% haloperidol and 60% by solvent cast.At 100 ℃, material extrusion die is moulded to dish or is slowly pressed into rod with high pressure piston extruder (DACA Instruments, Goleta, CA).The weight-matched of rod and dish.The surface area of these geometries and volume (SA:V) ratio is, dish is 1.92 (3mm radius, 1.6mm thickness), and rod is 1.56 (1.8mm radius, 4.5mm length).

In order to measure release profiles, implant is placed in to 500 milliliters of (ml) phosphate buffered saline (PBS)s (PBS), pH7.0,37 ℃, 40rpm, in the dark.

result

Checked the impact that implant geometry (rod is on dish) discharges haloperidol.Two kinds of geometry release profiles almost identical (Fig. 4), prove that rod has the release profiles closely similar with dish.Therefore, in individuality, can use clavate implant to send the medicine that maintains treatment level within the time period extending.

embodiment 4: the stability of risperidone in physiological water solution

In order to evaluate the long-time stability of risperidone in physiological solution, 10mg risperidone is dissolved in 100 μ l acetonitriles, be dissolved in subsequently 1,000ml PBS (0.9%NaCl, 0.01M NaOH, 0.01M NaH ₂pO ₄, pH7.0) in to obtain the final solution of 10000 nanograms (ng)/ml.At 37 ℃, in lucifuge ampoule bottle with 40 revs/min of these solution of jolting.By UV spectrographic method (Amersham Biosciences, Buckinghamshire, UK), measure on every Wendesdays time the drug level of 1ml sample.Drug level only shows that slight variation (was 1.4%, is equivalent to 0.004%/sky in 343 days; Linear trend: y=-0.0004x+9.777).Use UV spectrophotography and HPLC to repeat research (Fig. 5).Correlation coefficient between HPLC and UV spectrophotography is 0.99, shows that UV spectrophotography is the exact method for external risperidone concentration analysis.

Therefore, risperidone time period through extending in physiology's solution is stable.

the impact that embodiment 5:PLA:PGA ratio discharges risperidone

Evaluation discharges from comprising the risperidone of the different polymer of 50:50,65:35 and 75:25PLGA, the impact external risperidone being discharged to assess PLA:PGA ratio.The implant that makes by embodiment 1 description, comprises 20% risperidone (RBI, Flanders, NJ) and 80%PLGA (Alkermes) in this case.Every kind of implant type is placed in to the independent light-shading bottle of 500ml PBS in triplicate and at 37 ℃, 40rpm jolting.From each bottle, take out weekly 1ml aliquot for 3 times and by UV spectrophotometric analysis, add again afterwards 1ml buffer to maintain constant volume.75:25 polymer shows the slowest release profiles (Fig. 6 A).

In other research, determine the concordance of effect between mice.The risperidone implant that comprises 75:25PLA:PGA, 20% drug loading to eight mice administrations, at 42 days post-evaluation risperidones and 9-OH risperidone serum-concentration.Table 1 shows result, and by the risperidone weight in implant is calculated to obtain to mg/kg/ days rates of release divided by the release natural law (120) of estimating again divided by mice weight.

Table 1: eight implants that mice administration comprises risperidone to top, five mice administrations do not contain the contrast implant of risperidone to bottom.

embodiment 6: the impact that surface area discharges risperidone volume ratio

material and experimental technique

It is 4 rods of 2.75 and 6.17 to the ratio of volume (SA:V) that research utilizes surface area under every kind of condition, and both all utilize 30% risperidone drug loading, 75:25%PLGA.Rod is placed in to the independent PBS bottle of 37 ℃ of 40rpm.The 0.3ml sample gathering for 3 times is weekly analyzed by HPLC and UV spectrophotography (Bio-teck Instruments, Winooski, VT).

result

For the impact of determining that SA:V ratio discharges risperidone, by thering is same composition but the rod of different SA:V ratios measure risperidone and discharge.The release profiles that these 2 kinds of SA:V ratios discharged in initial 44 days is different, and wherein the rod of small radii (larger SA:V) shows release (Fig. 6 B) faster.Therefore the larger-diameter rod that, has a less SA:V ratio provides with the rod of small diameter compares sending of longer-term.

From the release of biodegradable implant, be the function of SA:V ratio, these results confirm and have strengthened the result of embodiment 3, as equation (8) below further describes.Therefore, rod and dish can be used in the long-term release that obtains biodegradable implant.

embodiment 7: determine the best risperidone drug loading in implant

For determining the best risperidone concentration of implant, use single polymers (85:15PLGA) to be combined with the risperidone of 10%, 20%, 30%, 40%, 50% or 60% drug weight ratio and prepare implant (Fig. 7).Therefore implant has the quality of about 50mg separately, and contained drug quality is respectively 5,10,15,20,25 and 30mg.The total drug loading of major part of 10% and 60% drug loading implant discharged in initial 30 days, and the implant of 20%, 30%, 40% and 50% drug loading discharges their risperidone more lentamente.By 40% and 50% risperidone carrying capacity implant, obtain the most linear release profiles, they have similar slope in whole test period.

embodiment 8: risperidone implant improves PPI and P20 amplitude resistance for the 14th day and 21 days after implantation the N40-of stagnant amfetamine induction brings out the interruption of current potential

material and experimental technique

Risperidone implant obtains the serum risperidone concentration of 7.3 ± 0.68ng/ml (meansigma methods ± SEM) and the serum 9-OH risperidone of 8.1 ± 0.95ng/ml on the 42nd day after implantation.The brain level of risperidone and 9-OH risperidone is respectively 6.2 ± 1.45 and 4.6 ± 0.52ng/gm.By 85:15PLGA, 0.66-0.80IV and 20% risperidone drug loading, make disc implant (SA:V ratio is 2.34).Mice (C57BL/6J) is accepted or contains risperidone (n=8) or only containing the implant of polymer (n=8), then three utmost point electrode assemblie (PlasticsOne Inc. are implanted in three-dimensional location, Roanoke, VA) for non-narcotic auditory evoked potential (people such as Connolly, 2003 of recording; The people such as Connolly, 2004; The people such as Maxwell, 2004; The people such as Siegel, 2005).After implantation the 14th to 21 days, that by people such as (, Sensorimotor gating deficits in transgenic mice expressing a constitutively active form of Gs alpha.Neuropsychopharmacol29:494-501) Gould TJ, describes carries out the startle research of startling of response and prepulse inhibition (PPI) of audition.After implant electrode, the 28th day record brings out current potential.At lumbar injection amfetamine 2mg/kg, after six minutes, start to record drug exposure test, and in earlier stage compare with the amfetamine phase of recording.By Micro1401 hardware and Spike5 software (CED, Cambridge, England), produce and stimulate and transmit by being connected to the speaker on cage top.With 500ms, be partitioned into and provide over the ground a string 50 white noise clicks (10ms persistent period), between each pair, interval is 9 seconds, with respect to the background of 70db, is 85db.Between 1 to 500Hz, filter waveform, check baseline when stimulating beginning, the twice standard exclusion based on RMS amplitude moves each scanning of illusion.From stimulating, 50ms is to stimulating rear 200ms to produce mean wave.Within 15 minutes, adapt to faraday cup to before stimulation starts mice.

result

Mice (C57BL/6J) is accepted to contain risperidone (n=8) or only containing the implant of polymer, then uses the non-narcotic brainstem auditory evoked that records of three utmost point electrode assemblies of implanting.Although risperidone implant does not change the amplitude that startles (Fig. 8 A), they have improved PPI (Fig. 8 B) with respect to contrast really.In addition, risperidone implant has improved the P20 amplitude in control animal (mankind P50 analog) (Fig. 9 A), and has weakened the minimizing (Fig. 9 B) of N40 (the mankind N100 analog) amplitude of amfetamine induction.The abnormal response of P50 and N100 component relate to the abnormal neuronal structure that acoustic response produces and regulate, and point out neurological damage more general in schizophrenia (Adler LE, the people such as Olincy A, Schizophr Bull24:189-202,1998; Freedman R, the people such as Adler LE, Harv Rev Psychiatry2:179-192,1994).

embodiment 9: the time point of risperidone implant after improves PPI and P20 amplitude and block amfetamine the N40-of induction brings out the interruption of current potential

After implantation after time point, the risperidone implant of testing to determine embodiment 8 on startling, the impact of PPI, N20 and N40.In this case, in the animal of accepting risperidone implant, observed the appreciable impact on all these parameters, the larger rate of release that this obtains with time point after and thereby higher plasma concentration consistent, as shown in embodiment 5-7.

embodiment 10: can the degradation rate based on drug solubility and implant determine hydrolyzable can be biological the rate of release of the implant of degraded

material and experimental technique

Medicine

Checked six kinds of medicines:

1). tiotixene: N, N-dimethyl-9-[3-(4-methylpiperazine-1-yl) propylidene] thioxanthene-2-sulfonamide.

2). haloperidol: 4-[4-(4-chlorphenyl)-4-hydroxyl-piperidino]-1-(4-fluorophenyl)-Ding-1-ketone.

3). hydrochlorothiazide (HCTZ): 9-is chloro-5,5-dioxo-5 λ ⁶-sulfo--2,4-diazabicylo [4.4.0] last of the ten Heavenly stems-6,8,10-triolefin-8-sulfonamide.

4). corticosterone: 11-hydroxyl-17-(2-hydroxyacetyl)-10,13-dimethyl-1,2,6,7,8,9,10,11,12,13,14,15,16,17-, ten tetrahydro cyclopentyls [a] phenanthrene-3-ketone.

5). ibuprofen: 2-[4-(2-methyl-propyl) phenyl] propanoic acid.

6). aspirin: Aspirin.

Table 3 is listed the character of medicine.All medicines are all available from Sigma-Aldrich, Inc..

Table 3: the character of medicine used in the present embodiment

* after 14 days, measure as described below.

The unit of * k is 1/ day, D dimensionless.By the data fitting that Figure 10 is drawn, to equation (4), obtain, as Figure 11 represents.

Ultraviolet (UV) scanning

Medicine dissolution, at PBS, in pH7.4, is reached to the dissolution in vitro degree of expectation.The blank cuvette that use contains saline solution, as reference, carries out absorbance scanning to drug solution in the scope of 200nm to 400nm.For each medicine produces feature UV footmark, in external test subsequently, use the wavelength that produces relevant maximum peak.Make the standard curve of each medicine in PBS, thereby can use Lambert-Bear law that absorbance is converted into concentration.

Polymer/drug bead is manufactured

Solvent cast 400mg50:50PLGA and 100mg medicine are to obtain 20% drug loading by mass.Polymer and medicine are dissolved in 45 milliliters of (mL) acetone (Fisher Scientific, Inc.) and vortex, then pour in evaporating dish and under vacuum (3 inches of Hg) and put into 40 ℃ of vacuum drying ovens with trace air-flow.After seven days, from baking oven, take out evaporating dish.Evaporation residue is the film mixture of polymer and medicine, has uniform outward appearance.The careful thin film that weighs to be to confirm completely except desolventizing, and at 25 (kip) klb and 60 ℃, uses

the pellet press of-coating is pressed into four uniform dish type beads with 1mm thickness and 1.2mm diameter.Bead is carefully weighed and measure to determine density.Use 500mg polymer and without medicine, manufacture in an identical manner the negative control bead of 0% drug loading.

The dissolubility of medicine in water

The various medicament mixed of the incremental change from 0.5 to 200mg scope, in the glass jar with cover (Wheaton, Inc.) that contains 10 to 50mL distilled water, and are mixed 14 days 21 ℃ of appropriateness.With regular time interval take out 1mL aliquot and by UV analysis of spectral method to determine maximum saturation concentration.

Vitro drug release is measured

Use three groups (every group of four identical beads) to measure in triplicate.Each bead is added in the brown glass glass jar with cover (Wheaton, Inc.) that comprises 500mL PBS solution, 37 ℃ of in the dark appropriate joltings.Interval is by UV analysis of spectral method 1mL aliquot at a fixed time.Positive control cylinder comprises PBS and 10mg medicine (the maximum release of expection of 20% medicine carrying bead of 50mg quality), also uses positive control to determine each medicine stability along with experimentation in saline solution.

result

Checked the release of six kinds of medicines from the PLGA substrate.In Figure 10, the release umber f by described medicine from described bead is depicted as the function of time t.All drug releases and f ≈ 1 in long-time section.Before this discharges limit completely, be the quite constant region of rate of release wherein, as what proved by described release umber (Δ f) and the linear relationship between the time (Δ t).

These results show can obtain linear drug release with the biodegradable polymer of single type.

Above-mentioned release measurement shows two other feature: first, some medicines (for example tiotixene) just discharge when experiment starts, and other drug (for example haloperidol) has induction period, in induction period, do not discharge can measuring amount medicine.In addition,, in steady state release process (stable Δ f/ Δ t), different medicines shows different rates of release.Result is, in steady state release phase of drug release and total time section, all observes variation.Vision is observed the bead that proof comprises different pharmaceutical and is dissolved with different speed, and the naked eyes that become after the different time periods are invisible, and this time period is during corresponding to f ≈ 1 by UV spectroscopy measurements.Therefore, can characterize by two global parameters the rate of releasing drug of described polymer: period of delay (reaching the required time of steady state release rates) and steady state release rates.

In above-mentioned various substrate, use identical polymer.Therefore, the period of delay of substrate and steady state release rates is not both the drug component due to substrate.Difference in the rate of release of drug matrices is attributable to different diffusion rates and the leaching rate of medicine in polymeric matrix, and/or owing to different depolymerization speed.The depolymerization speed of the substrate adopting in this experiment is different, as different bead rate of disappearances, proves.Therefore, the existence of described medicine affects depolymerization speed.

For understanding the impact on depolymerization of the medicine mix, the following model of deriving degradation process based on data of the present invention: compare with depolymerization speed, the movement (diffusion) of medicine in polymeric matrix is perhaps insignificant.Therefore, release mainly occurs by depolymerization.Polymer P LGA is degraded into lactic acid and glycolic by reacting with water:

(C ₃H ₄O ₂) _x(C ₂H ₂O ₂) _y+2H ₂O→CH ₃CHOHCOOH+HCHOHCOOH。

Therefore, degradation rate depends on the availability of hydrone.Water enters in the downtrod system of diffusion of described bead therein, this indication surface corrosion.Water enters the diffusibility of described polymer when very high therein, and this causes bulk erosion.

This degradation reaction is similar to the first order reaction between polymer and water, therefore proportional with the local concentration of two kinds of materials.Yet, because polymer forms the major part of described bead, so its concentration is fixed throughout.Therefore, the local concentration of degradation reaction and water (function of diffusion coefficient) multiplication by constants is proportional.The diffusion coefficient that water is entered to described polymer globules is defined as D, and the diffusion/reaction equation of water is write to (1):

\frac{{&PartialD; c}_{w}}{&PartialD; t} = D {&dtri;}^{2} c_{w} - {kc}_{w} - - - (1)

Wherein reaction rate k is constant, and it comprises local polymer concentration.Suitable boundary condition is water in the concentration at particle edge by solution value c _w ⁰determine, and the initial concentration of (when t=0) water in described particle is zero.

Equation (1) indicates D therein to approach in 0 system, does not diffuse into polymer particle, the c in bead _wbe zero, and institute respond and all occur in described polymer/solution interface place.Diffusion rate is greater than in the system of reaction rate therein, and water reduces whole particle volume by infiltration and by bulk erosion.By supposing that described bead is the concentration curve that semi-infinite medium solves water.When the diffusion length of water is less than bead size, this hypothesis is suitable for starting stage and the steady-state process of degraded.

By the distance definition of polymer/solution interface, be x, find:

\frac{c_{w}}{c_{w}} = e^{- kt} (1 - \erf [\frac{x}{\sqrt{Dt}}]) + k {&Integral;}_{0}^{t} e^{- {kt}^{'}} (1 - \erf [\frac{x}{\sqrt{{Dt}^{'}}}]) {dt}^{'} - - - (2)

At any given position (x), locate, then by obtain the amount of polymers that reacts and degrade with water through time integral:

{dM}_{p} (x, t) = k {&Integral;}_{0}^{t} c_{w} (x, t^{'}) {dt}^{'} - - - (3 . a)

DM wherein _p(x, t) is the variation that polymer globules quality is ordered at x.Therefore, the gross mass of degradation polymer is described as:

{ΔM}_{p} = {&Integral;}_{x = 0}^{\infty} {dM}_{p} (x, t) dx = k {&Integral;}_{x = 0}^{\infty} {&Integral;}_{0}^{t} c_{w} (x, t^{'}) {dt}^{'} dx - - - (3 . b)

Release amount M _d(ignoring drug diffusion) is:

M_{d} (t) = φ {dM}_{p} = φk {&Integral;}_{0}^{\infty} {&Integral;}_{0}^{t} c_{w} (x, t^{'}) {dt}^{'} dx - - - (4)

Wherein Φ is the parts by weight of medicine in particle.At first, when t is very little, by M _dbe described as:

M_{d} \approx \frac{2 φ c_{w}^{0} D^{1 / 2} t^{3 / 2}}{3 π^{1 / 2}} ~ t^{3 / 2} - - - (5 . a)

And time point after, rate of release is provided by following formula:

M_{d} \approx \frac{φ c_{w}^{0} D^{1 / 2} t}{{2 k}^{1 / 2}} ~ t - - - (5 . b)

Therefore determine, initial release amount is along with the time rises with (3/2) power, and its rate of release (slope) only depends on water diffusion coefficient D.Along with the time increases, release quantitative change must be linear with the time.In this scheme, system reaches " stable state " when degradation rate and release amount are constant in time.Therefore, rate of release changes along with the ratio between diffusion and reaction constant.

For whole six kinds of testing drugs, the release data shown in the good fit Figure 10 of model being described by equation (4), table 2 is listed the value (curve description of haloperidol and aspirin is in Figure 11) of D and k.This is noticeable, because tested medicine is different; For example haloperidol and aspirin are very different.The difference that time point is below seen is from the finite size of bead.

Therefore, can be by only comprising the rate of releasing drug of the biodegradable substrate of specification of a model that two kinds of fitting parameters are D and k.

embodiment 11: can determine parameter D and the k discharging in equation by drug solubility and hydroxy density thereof

Degradation reaction coefficient (parameter k) variation of observing all medicines is less than an order of magnitude (0.05-0.33); On the contrary, diffusion coefficient D changes over 8 orders of magnitude (table 2).

Molecular diffusion constant in solid polymer medium is by D ₀e sup[-δ ε] description, wherein D ₀be proportionality coefficient, ε is activation energy or interaction energy, and δ is the thermodynamic equilibrium constant that depends on system temperature etc.In the case, polymeric matrix is identical, and temperature is also like this; Therefore, the D of all polymer/drug beads ₀with δ be identical.Therefore yet activation energy ε is responsive to the concrete interaction between diffusate and substrate, can change along with drug type and carrying capacity (mass fraction).The dissolubility (suppose ideal mixture) of described medicine in water can also be described as term ε: dissolubility S equals S _oe-sup[-δ ε], S wherein ₀be proportionality coefficient, σ is thermodynamic equilibrium constant.Relation in conjunction with D and S causes following relationship:

D = (D_{0} S_{0}^{- δ / σ}) S^{δ / σ} - - - (6)

Wherein the term in round parentheses is here system constants.

As Figure 12 describes, dissolubility data meets equation (6).By power law, describe the dependence of D to dissolubility, wherein coefficient is about 5.3.

In a word, between the steady state period of the PLGA implant containing 20% drug loading, the model that equation (4) is described can be for prediction rate of releasing drug.5.3 powers of D and dissolubility are proportional, and k is the numeral within the scope of about 0.05-0.33.

embodiment 12: determine as the function of time and implant character from PLGA polymeric implant drug release and the serum drug level obtaining

Because the focus of embodiment 10-11 is to check the impact of drug/polymer/water mutual effect on degraded and rate of release, so initial model employing has extremely large-sized implant.The present embodiment is described the time dependence concentration of drug disposition.For this reason, model is above modified to the limited implant size of explanation (1) and (2) drug absorption and removing (metabolic rate).Long-pending (SA) is proportional for the rate of releasing drug of implant and implant surface.Proofread and correct implant quality, the SA of implant, the variation of A can be described to equation 7, wherein R (t) is the implant radius as the function of time t, R ₀for initial radium, D is the diffusion coefficient that water enters substrate, and k is reaction rate and C _wconcentration for water.

A = 4 π R^{2} (t) = 4 π R_{0}^{2} {(1 - \frac{C_{w} \sqrt{D}}{{2 R}_{0} \sqrt{k}} t)}^{2} - - - (7)

Therefore the rate of releasing drug of unit interval can calculate as equation 8.

(\frac{{dM}_{d}}{dt}) = A (t) \frac{C_{w} \sqrt{D} \erf [\sqrt{kt}]}{2 \sqrt{k}} = 4 {πR}_{0}^{2} {(1 - \frac{C_{w} \sqrt{D}}{{2 R}_{0} \sqrt{k}} t)}^{2} \frac{C_{w} \sqrt{D} \erf [\sqrt{kt}]}{2 \sqrt{k}} - - - (8)

Wherein " erf (x) " refers to

Medicine exponential decay in the metabolic rate writing blood of risperidone (can be had to feature rate of disintegration τ, it is as the function of medicine and metabolic rate), obtain the complex function for active drug concentration shown in equation 9 (complex function).This function can be asymmetric, and its asymmetric degree is set by the typical metabolism time τ-value of given medicine.High τ-value is indicated slow metabolic rate, and therefore this function is more symmetrical.Low τ-value indicates fast metabolism and function along with peak approaches t=0 and becomes absolutely wrong title.

Drug level is complex function as the function of time.Error function is about erf (x)～1-e ^-7x/4, obtain the equation 10 of drug level.A ₁for equaling the constant of the total content of dispersion of implant, variable a ₂the constant that equals metabolic rate, variable a ₃reflection medicine is from diffusion and the variable a of implant ₄the total interval that discharges of reflection depolymerization impact.Matching rabbit haloperidol data, we obtain coefficient τ ≈ 0.027, and in indication rabbit, the serum half-life of haloperidol is approximately 130 minutes, with disclosed data consistent (Wurzburger RJ, the people such as Miller RL, J Pharmacol Exp Ther217:757-763).This equation meets data in previous rabbit body, correlation coefficient (R ²) be 0.87.

\frac{{dM}_{d}}{dt} ~ a_{1} (1 - e^{{- a}_{2} t}) (1 + e^{a_{3} \sqrt{t}}) {(1 - a_{4} t)}^{2} - - - (10)

embodiment 13: determine that polymer forms and the contribution of intrinsic viscosity to the release of PLGA polymeric implant

As the change polymer of describing in embodiment 1-7 forms and intrinsic viscosity, to determine the other contribution of these variablees to the release of PLGA polymeric implant.Produced the other equation of having introduced these variablees.

embodiment 14: human experimenter is amplified to risperidone implant in proportion

There is significant interspecific difference in the metabolism of risperidone, for obtaining equal plasma concentration, rabbit and monkey all need to exceed than the mankind dosage (Bacopoulos NG, the people such as Redmond DE, the J Pharmacol Exp Ther212:1-5 of about 15 to 30 times; Jibiki I, the people such as Kubota T, Jpn J Psychiatry Neurol47:627-629; Klintenberg R, Gunne L, Andren PE (2002) Mov Disord17:360-365).Therefore,, although body weight is variant, for the absolute dosages of above-mentioned zooscopy, approach the dose of necessary for human.Due to when as durative action preparation administration, the risperidone of the about 1mg/kg/ month of human needs (being generally about 1.8mg/ days), so the implant system that contains 600mg provides the patient for body weight 50kg the treatment of a year.Therefore,, for the risperidone of a year, for the implant design of zooscopy, must need to have approximately 1.5 grams of materials of 40% drug loading.Under the density of 1.2g/cc and the diameter of 3.6mm, this needs the implant rod of about 6.5cm.

By the risperidone implant in following parameters to mankind's administration:

Drug loading is about 30%-60%, comprises end value;

PLA:PGA molar ratio is about 50:50 to 100:0, comprises end value.

Clavate.

SA:V ratio is 1.5 to 2.

For example: length is that about 3-5mm (comprising end value) and diameter are the clavate implant display-object SA:V ratio of 2 to 3.6mm (comprising end value).By the one or more implants of administration, obtain the concentration curve of substantial symmetry, as seen in embodiment 2, in the time of about 6 months, reach peak level and after implantation, between 2 to 8 months, obtain risperidone treatment level (Figure 13 A).

embodiment 15: circulation administration or risperidone implant obtain the long-term treatment level of risperidone

By approximately within every 6 months, introducing the implant of new a group, with the symmetrical release profiles of describing in embodiment 14, provide long-term treatment levels of drugs (Figure 13 B).For example: every 6 months administration 3.2cm length also have two rods of 100%PLA.As described, the implant of each subsequent group improves levels of drugs with the identical speed of speed declining with front group of implant contribution, thereby makes total rate of release maintain approximately constant (Figure 13 C).

embodiment 16: by comprising that initial implantation the polymer discharging sooner improves initial drug level

The limitation of single polymers system is to postpone to reach treatment level after initial implantation.Therefore, will provide the other implant that arrives sooner the peak concentration time to comprise in initial implantation.Comprise one or more implants of describing in table 4.By changing parameter a1 and the a4 relevant with depolymerization (PLGA ratio and intrinsic viscosity) with content of dispersion (accumulated dose), by equation 8-10, obtained the rate of release of rapid release implant and the serum-concentration of generation of table 4.

Table 4: the initial other polymeric implant using of implanting.Implant comprises 40-60% risperidone carrying capacity (comprising end value), and shows that the target of 0.15mg/ days sends.Each rod has 3.6mm diameter, and the density of 1.2 grams/cc (g/cc) obtains having the rod of about 125mg/cm implant.

For example: Figure 14 A has illustrated respectively the release that has about 2,4,8 and 12 week half-life and discharge four kinds of rapid release implants at interval for about 4,8,16 and 24 weeks completely.For example: it is 0.8cm that one group of implant of half that contains first 6 months medicines comprises average length, 4 implants that are comprised of 50:50,65:35,75:25 and 85:15PLGA respectively.By this group and the implant combination more slowly discharging, provide second half medicine.When initial implantation during the combination of this implant of administration, obtain curative drug level implanting in several days, and by implanting with 6 months intervals the implant more slowly discharging, greatly maintaining this curative drug level (Figure 14 B) thereafter.

embodiment 17: aseptic, biodegradable PLGA-risperidone implant provides long-term risperidone to release put

Measure the release in vitro curve of aseptic risperidone implant.As described in Figure 17, this implant discharged medicine from 0-58 days, no longer discharged thereafter medicine.Therefore, aseptic PLGA-risperidone implant provides the release profiles that is suitable for the inventive method.

For further characterizing the character that aseptic implant is compared with non-sterile implant, the method for using embodiment 5 to describe is implanted aseptic or non-sterile PLGA-risperidone implant to mice.At 14,27,56 or 83 days, remove implant, put to death mice and evaluate serum risperidone concentration.In initial 3 groups of putting to death for the 56th day, serum levels rises to the 27th and the 15-20ng/ml of 56 days from the 7-10ng/ml of the 14th day.When within the 83rd day, removing implant, in serum, there is no detectable medicine (Figure 18), consistent with release in vitro pattern (above-described embodiment) and residual risperidone content (embodiment below).

In a word, aseptic and non-sterile implant continues to pass medicine 56 days, and until within the 83rd day, still maintained adhesive force and removability.Like this, aseptic and non-sterile implant does not show marked difference.Therefore, the character of all implants of above-described embodiment proof is all applicable to aseptic and non-sterile implant.

embodiment 18: the residual risperidone content after removing in implant

After removing, evaluate residual risperidone content the mice from previous embodiment.As described in Figure 19, drug loading percentage ratio in time from its initial value 30% decline (that is: medicine with than depolymerization faster speed discharge).Therefore, implant maintains well adhesive force and can removing after drug release process, and this shows that implant of the present invention can remove in whole expectation delivery interval.Yet, because they are biodegradable, so without removing this implant.

embodiment 19: the vitro stability of risperidone under low pH

For determining that whether low pH environment can affect the stability of risperidone, pH4.4 to 7.4 storage 172 days, finds its complete stability (Figure 20) by risperidone.PH value 2.0 and 3.0, arrives similar results through the laboratory observations of 68 days.Therefore, risperidone is all stable in neutral pH and low pH.

Claims

1. an implantable long-term delivery system that improves drug compliance for the relevant disease of the probability with not complying with, it comprises: the curative drug in implantable clavate structure, wherein said clavate structure also comprises polymer, described polymer comprises polylactic acid (PLA) and polyglycolic acid (PGA), wherein PLA:PGA molar ratio is 50:50 to 100:0, wherein said curative drug exists with the amount of the 10%-60% of the quality of described implant, and described polymer exists with the amount of the 40%-90% of the quality of described implant, and wherein said curative drug is risperidone, 9-OH-risperidone or their active metabolite.

2. the implantable long-term delivery system of claim 1, wherein said clavate structure is removable in the phase at the whole medicine of passing.

3. the implantable long-term delivery system of claim 1, wherein said curative drug exists with the amount of the 30%-60% of the quality of described implant.

4. the implantable long-term delivery system of claim 1, wherein said curative drug shows the dissolubility increasing in the pH environment reducing.

5. the implantable long-term delivery system of claim 1, wherein said PLA:PGA molar ratio is 75:25 to 100:0.

6. the implantable long-term delivery system of claim 1, wherein said curative drug is antidepressants.

7. the implantable long-term delivery system of claim 1, wherein said curative drug is antianxiety drugs.

8. the implantable long-term delivery system of claim 1, wherein said curative drug is psychosis.

9. the implantable long-term delivery system of claim 1, wherein said implant has 1 to 4 (millimeter [mm]) ²/ mm ³surface area to volume ratio.

10. the implantable long-term delivery system of claim 1, wherein said implant has the length of 1-3 centimetre.

The implantable long-term delivery system of 11. claim 1, wherein said implant has the diameter of 2-4 millimeter.