MX2008000573A

MX2008000573A - Drug-containing implants and methods of use thereof.

Info

Publication number: MX2008000573A
Application number: MX2008000573A
Authority: MX
Inventors: Steven Siegel; Karen Winey
Original assignee: Univ Pennsylvania
Priority date: 2005-07-18
Filing date: 2006-07-18
Publication date: 2008-03-14
Also published as: JP2014001246A; CN103637977A; JP5405825B2; AU2006269927A1; KR101283946B1; EP1909689A2; WO2007011955A3; JP2009501798A; MX362908B; WO2007011955A2; CA2614601A1; JP2015078233A; JP6153952B2; EP1909689A4; KR20080033991A; CA2614601C; AU2006269927B2

Abstract

The present invention provides implants comprising a therapeutic drug and a polymer containing polylactic acid (PLA) and optionally polyglycolic acid (PGA). The present invention also provides methods of maintaining a therapeutic level of a drug in a subject, releasing a therapeutic drug at a substantially linear rate, and treating schizophrenia and other diseases and disorders, utilizing implants of the present invention.

Description

IMPLANTS THAT CONTAIN DRUGS AND METHODS OF USE THEREOF Field of the Invention The present invention provides implants comprising a therapeutic drug and a polymer containing polylactic acid (PLA) and optionally polyglycolic acid (PGA). The present invention also provides methods for maintaining a therapeutic level of a drug in a subject, by releasing a therapeutic drug in a substantially linear range, and treating schizophrenia and other disorders and conditions, using implants of the present invention. Background of the Invention Non-compliance with medications is the major determinant of recidivism in schizophrenia. Therefore, a therapeutic method that helps patients stay with their medications for prolonged periods could substantially improve clinical outcomes. Methods of administering current anti-schizophrenia medications (eg, risperidone) provide dosing for one month or less. Therefore, methods to provide therapeutic levels of risperidone and other drugs are needed in the art. Brief Description of the Invention The present invention provides implants comprising a therapeutic drug and a polymer containing polylactic acid (PLA) and optionally polyglycolic acid (PGA). The present invention also provides methods for maintaining a therapeutic level of a drug in a subject, by releasing a therapeutic drug in a substantially linear range, and treating schizophrenia and other diseases and disorders, using implants of the present invention. In one embodiment, the present invention provides a biodegradable implant comprising (a) a therapeutic drug that is in an amount of 10% -60% by mass, relative to the mass of the implant; and (b) a polymer that is in an amount of 40% -90% by mass, relative to the mass of the implant, the polymer PLA and optionally PGA comprising a molar ratio of PLA: PGA between 50:50 and 100. : 0 In another embodiment, the present invention provides a method for maintaining a therapeutic level of a drug in a subject for a period of at least 1 month, the method comprising administering to the subject a group of biodegradable implants, the group of biodegradable implants consisting of one or more individual biodegradable implants comprising (a) a therapeutic drug that is present in an amount of 10% -60% by mass, relative to the mass of the implant; and (b) a polymer that is in an amount of 40% -90% by mass, relative to the mass of the implant, the polymer PLA and optionally PGA comprising a molar ratio of PLA: PGA of between 50:50 and 100: 0 and wherein the individual biodegradable implants, if there are more than one in quantity, do not differ substantially from each other in their molar ratio PLA: PGA, thereby maintaining a therapeutic level of a drug in a subject during a period of less about 1 month In another embodiment, the present invention provides a method for maintaining a therapeutic level of a drug in a subject for a period of at least about 3 months, comprising (1) administering to the subject an initial group of biodegradable implants, wherein the initial group of biodegradable implants consists of one or more individual biodegradable implants having (a) a therapeutic drug that is present in an amount of 10% -60% by mass, relative to the mass of the implant; and (b) a polymer that is in an amount of 40% -90% by mass, relative to the mass of the implant, the polymer PLA and optionally PGA comprising a molar ratio of PLA: PGA of between 50:50 and 100: 0; and (2) administering to the subject a group of one or more biodegradable maintenance implants near the peak release point of the initial group of biodegradable implants, wherein the group of biodegradable maintenance implants consists of additional inhibitory biodegradable implants equivalent in molar portion PLA : PGA to the individual biodegradable implants in the initial group of biodegradable implants. The individual biodegradable implants of the initial groupif there are more than one in number, they do not differ substantially from each other in their molar ratio PLA: PGA, thereby maintaining a therapeutic level of a drug in a subject for a period of at least about 3 months. Brief Description of the Figures Figure 1: Longitudinal detection of haloperidol levels for 443 days in primates as a result of the implants.

Figure 2: A) Placement of implants during rabbit surgery. An implant tied with a strap (white arrow) is shown. The incision was lengthened to allow a photograph.

B) Necropsy in rabbits showing a degraded implant (black arrow) at the location of strapped between two hemostats. Fibrosis is not observed at the time of implant removal. Scale bar = 20 mm in both images. C) 1HRMN spectrum of PLA and 40% (w / w) of haloperidol mixture in DMSO-d6. Inserts-corresponds to the chemical structures of haloperidol and PLA. D) Rabbit sample in DMSO-d6 peaks that correspond to peaks observed for haloperidol in control spectra. E) Rabbit sample in chloroform, peaks in 0.9, 1.2, 3.9 and 4.5 are consistent with the degradation product of PLA, lactic acid. Figure 3. Concentration of haloperidol serum from polymer implants in rabbit. Each panel displays the mean ± SEM of 5 animals. A) Multiple polymer system. B) Simple polymer system. Each group of data is shown with a line indicative of evolution on a graph that illustrates the pattern of serum concentration over time. Figure 4: Cumulative in vitro concentration from disk-shaped implants and rod. Each point represents the average of 3 replicas of disks or rods. Figure 5. Stability of risperidone in physiological aqueous solution. A. Amount of risperidone remaining versus time. The y-intercept is 10.42 for HPLC and 10.23 mg for UV spectrophotometry. Similarly, the slope of the linear HPLC line of evolution is 0.01 and 0.00 for UV spectrophotometry. B) Values of the positive control solution in A, as well as samples in the volume surface area ratio study (Figure 6B) were analyzed and compared using HPLC and UV spectrophotometry. The correlation coefficient for these methods is 0.99 (182 samples), which shows that UV spectrophotometry is an accurate measure of the level of drug in an in vitro solution. Figure 6. Risperidone release in vitro varies with the polymer composition and SA: V: A ratio.) Polymer composition - Cumulative in vitro risperidone release of implants with 20% loading containing 50:50, 65:35 or 75:25 PLGA. The data is expressed as the percentage of total cumulative release over time. Each point represents the mean ± standard average error (SEM) of 3 implants. The complete release occurred in approximately 40, 80 and 120 days, respectively. B) SA ratio to volume - Rods with the smallest radii, and therefore a larger SA: V ratio (circles) exhibited faster in vitro release than rods with larger radii (triangles), as can be seen through a cumulative concentration greater between 28 and 44 days. The points represent the averages ± SEM of 4 rods. The data were analyzed with HPLC and UV spectrophotometry, which produced results identical to those of Figure 5. Figure 7. In vitro accumulative risperidone release of implants containing 85:15 PLGA with 10, 20, 30, 40, 50 or 60% drug load in weight. A) Cumulative mass of risperidone in the in vitro solution (mean ± SEM). B) The pattern of 40% risperidone implants is shown only for clarity. The line indicative of evolution, which has a correlation coefficient of 0.99, is included to illustrate the pattern. C) Cumulative mass released from risperidone implants at 30, 40, 50 and 60% is expressed as a percentage of the total drug to facilitate comparison of the release pattern as a function of drug loading. The average value of each type of implant is also illustrated. The indicative lines of evolution of each of these 4 implants had correlation coefficients (R2) of 0.99 and curves of 10% to 20% were issued to increase the visibility of the overlap lines. D) The 40% drug loading group is shown only for clarity. Figure 8. Risperidone implants increase PPI, but not in an outstanding way. Risperidone implants increased PPI (p = 0.052) without a significant change and stood out in 14 and 21 days after implantation. Figure 9. Risperidone implants increase the P20 and amphetamine-induced interruption of the block of N40 evoked potentials. A) Risperidone implants increased the amplitude P20 in C57BL / 6J mice (p = 0.03) and attenuated the amphetamine reduction of N40 (p = 0.02). Figure 10. The amount of drug released (normalized to the total amount) as a time function of different drugs. Although all the release profiles follow a similar S-shape, the ranges were very different, both in the initial release region, the slope of the constant release zone (where? F /? T is constant) and the characteristic time for total release (f = 1). Figure 11. Adjustment of data of haloperidol (A) and ibuprofen (B) of the model presented in equation 4, using the adjustment parameters D and k: For (A), k is approximately 0.1 (1 / days) and D is 0.045 . For (B) k is approximately 0.164 (1 / days) and D is 0.051.

Figure 12. Relationship between maximum drug solubility in water after 14 days (in mg / mL) and D, the water diffusion coefficient in the polymer / drug complex, as calculated from the adjustment of the data in Figure 10 to equation 4. D is to provide the solubility of the power of 5.3. Figure 13: Continuous supply model of biodegradable implants: A) Serum concentration pattern that results from one or more simple polymer implants. The indicative lines of evolution represent the pattern of drug release. B) Super-imposed profiles of every 4 implants of the polymer implant system alone. The re-implant of this polymer-drug combination is carried out every 6 months. C) The total serum concentration that results from the individual overlap implants (dotted lines) is shown with a solid line. The levels oscillate slightly, although they remain within a target range as long as implants occur near the time of the peak concentration of a given material. The arrows mark the implants in all the panels. Figure 14. Risperidone serum concentration resulting from a multiple polymer risperidone implant system. A) Serum concentration resulting from a group of 4 fast-release implants. B) Concentration of serum that results from a system of 5 polymers, where 4 polymers of rapid degradation ("start group") are combined with 1 long-lasting polymer that is reintroduced every 6 months as a maintenance group. The general drug concentration is represented by the solid line, and the release profiles of the individual polymers are represented by dotted lines. The target drug levels are achieved in approximately 1 week, with small oscillations around the subsequent target concentration. Figure 15. Insertion and removal of implants in the form of a rod. A) Insertion of a 1 cm rod-shaped implant through a 4 mm hole. The insert illustrates an implant of 1 cm before insertion. B) Implant insertion through a 4 mm hole using a trochador. C) Implant site after closure with a single stitch. D) Mouse 10 minutes later in a local cage without signs of distension. E) A mouse 2 weeks after implantation. The implant site is completely cured, with no signs of distension or observed adverse events. F) A subgroup of mice carrying implants removed 2 or 4 weeks before implantation to evaluate the reversion capability of the procedure. G) The implants were easily removed at both time points without signs of adhesions or local scars. Insert-implant removed. H) A mouse shown back to its local cage 10 minutes after the removal of the implant. The mice in these groups were subsequently sacrificed and levels of risperidone and risperidone 9-OH were obtained. The sterile risperidone implants produced serum risperidone levels of 7.3 in 2 weeks after implantation and 12.8 in 4 weeks after implantation. B) Implant shown in situ after closure with a single stitch. C) Mouse 10 minutes later in local cage without signs of distension. Figure 16. Representative cross-sectional shapes of rods, discs and implant cylinders of the present invention (a non-exhaustive list). Figure 17. In vitro risperidone concentration of implants, mean ± S.E.M, n = 4. Figure 18. Release profiles of sterile and non-sterile implants in mice. Sterile (S) or non-sterile (U) n = 4 each per time point. Figure 19. Content of risperidone in implants removed from mice, expressed as the percentage of implant mass. Figure 20. A. Stability of risperidone in solutions of pH 7.4, 6.4, 5.4 and 4.4. All samples remained stable, with a negligible daily change in drug mass with respect to the first 77 days of the tests (0.06% for pH 7.4, 0.04% for pH 6.4, 0.10% for pH 5.4 and 0.00% for pH 4.4). B. Stability of risperidone at pH 2.0- 7.4. Detailed Description of the Invention The present invention provides implants comprising a therapeutic drug and a polymer containing polylactic acid (PLA) and optionally polyglycolic acid (PGA). The present invention also provides methods for maintaining a therapeutic level of a drug in a subject, by releasing a therapeutic drug in a substantially linear range, and treating schizophrenia and other diseases and disorders, using implants of the present invention. In one embodiment, the present invention provides an implantable, long-term delivery system for improving medication adherence in disorders associated with a likelihood of non-compliance. The delivery system, in one embodiment, includes a therapeutic drug in a rod-shaped, implantable structure and improves medication adherence in subjects who have disorders associated with a likelihood of non-compliance.

The term "implantable" includes, in various embodiments, compositions that can be inserted into a subject, for example, subcutaneously, intramuscularly, etc. In a further embodiment, the implantable compositions are also removable. The term "long term" includes, in various modalities, periods of time greater than approximately three months, greater than approximately four months, greater than approximately five months, greater than approximately six months, greater than approximately seven months, greater than about eight months, greater than about nine months, greater than about ten months, greater than about eleven months, greater than about one year or more. The term "long-term administration system" includes, in one embodiment, systems which, once administered to the subject, gradually deliver the target therapeutic drug to the subject in an effective amount to treat a disorder associated with a likelihood of non-compliance . The drug can be administered, in other modalities, for a period greater than about three months, greater than about four months, greater than about five months, greater than about six months, greater than about seven months, greater than about approximately eight months, greater than about nine months, greater than about ten months, greater than about eleven months, greater than about one year or more. The language "medication adherence improvement" refers, in one modality, to increasing the percentage of time of subjects with a disorder associated with a probability of non-compliance being treated with respect to their condition with the therapeutic target drug. The language "condition associated with probability of non-compliance" includes, in one embodiment, psychotic disorders, such as schizophrenia, bipolar disorder, dementia, delirium, impulse control disorder, psychotic depression, drug addition, etc. The language "disorder associated with probability of non-compliance" refers, in one modality, to disorders that have a high range of non-compliance on the part of the subject. And it includes, in another modality, disorders in which the disorder affects the judgment or mental capacity of the subject. The language includes, in another modality, disorders with a low rank (for example, in several modalities, low of 90%, low of 80%, low of 70%, low of 60%, low of 50% , low of 40% and low of 30%) of compliance by the subject. The term "therapeutic drug" includes, in one embodiment, drugs used to treat disorders associated with a probability of non-compliance. In another embodiment, the therapeutic drug exhibits its improved solubility in a low pH environment. In another embodiment, a therapeutic drug is an anti-depressant. In another embodiment, the therapeutic drug is an anti-anxiety agent. In another embodiment, the therapeutic drug is an anti-psychotic agent. In another embodiment, the target therapeutic drug is the drug for birth control.

The term "improved solubility" refers, in another embodiment, to an increase of at least 10% with respect to solubility at a neutral pH. In another embodiment, the term refers to an increase of at least 20% with respect to solubility at a neutral pH. In another modality, the increase is at least 30%. In another modality, the increase is at least 40%. In another modality, the increase is at least 50%. In another modality, the increase is at least 60%. In another modality, the increase is at least 70%. In another modality, the increase is at least 80%. In another modality, the increase is at least 100% (2 times). In another modality, the increase is at least 3 times. In another modality, the increase is at least 4 times. In another modality, the increase is at least 5 times. In another modality, and increase is at least 6 times. In another modality, and increase is at least 8 times. In another modality, and increase is at least 3 times. In another modality, the increase is at least 10 times. In another modality, the increase is at least 15 times. In another modality, the increase is at least 20 times. In another modality, and increase is at least 30 times. In another modality, the increase is at least 40 times. In another modality, the increase is at least 50 times. In another modality, and increase is at least 70 times. In another modality, the increase is at least 100 times. In another modality, the increase is at least 150 times. In another modality, the increase is at least 200 times. In another modality, the increase is at least 300 times. In another modality, the increase is at least 500 times. In another modality, the increase is at least 1000 times. In another modality, the increase is at least or more than 1000 times. In another embodiment, the drug exhibits negligible solubility at a neutral pH. Each possibility represents a separate embodiment of the present invention. The term "reduced pH environment" refers, in another embodiment, to a pH below 5.0. In another embodiment, the term refers to a pH below 4.5. In another embodiment, the term refers to a pH below 4.0. In another embodiment, the term refers to a pH below 3.5. In another embodiment, the term refers to a pH below 3.0. In another embodiment, the term refers to a pH below 2.5. In another embodiment, the term refers to a pH below 2.0. In another embodiment, the term refers to a pH below 5.0. In another embodiment, the term refers to a pH of 4.5. In another embodiment, the term refers to a pH below 4.5. In another embodiment, the term refers to a pH of 4.0. In another embodiment, the term refers to a pH of 3.5. In another embodiment, the term refers to a pH of 3.0. In another embodiment, the term refers to a pH of 2.5. In another embodiment, the term refers to a pH of 2.0. Each possibility represents a separate embodiment of the present invention. In another embodiment, the present invention provides a biodegradable implant comprising (a) a therapeutic drug that is in an amount of 10% to 60% by mass, relative to the implant mass; and (b) a polymer that is in an amount of 40% to 90% by mass, relative to the implant mass, the polymer comprising PLA and optionally PGA in a molar ratio of PLA: PGA between 50:50 and 100: 0 In another embodiment, an implant of methods and compositions of the present invention is a sterile implant. In another modality, the implant does not need to be sterile. In another embodiment, the implant is substantially sterile. In another embodiment, the implant has been sterilized. In another embodiment, the implant is sterile, except for a minor contamination introduced between the removal of the sterile casing and the implant. Each possibility represents a separate embodiment of the present invention. The term "biodegradable", as used in the present invention, refers, in one embodiment, to a material that is degraded in a biological environment. In another embodiment, the term "biodegradable" refers to a material that has a finite half-life in a biological environment. In another embodiment, the term "biodegradable" refers to a material that has a measurable half-life in a biological environment. In another embodiment, the term "biodegradable" refers to a material that is degraded within a living organism. In another embodiment, the term "biodegradable" refers to a material that has a finite half-life within a living organism. In another embodiment, the term "biodegradable" refers to a material that has a measurable half-life within a living organism. In another form, the term "biodegradable" is equivalent to the term "bioerodible". In one modality, the half-life is 1 month or less. In another modality, the half-life is 2 months or less. In another fashion, the half-life is 3 months or less. In another fashion, the half-life is 4 months or less. In another fashion, the half-life is 5 months or less. In another fashion, the half-life is 6 months or less. In another fashion, the half-life is 8 months or less. In another fashion, the half-life is 10 months or less. In another fashion, the average life is one year or less. In a fashion, the average life is 1.5 years or less. In a fashion, the average life is 2 years or less. In a fashion, the average life is 3 years or less. In a fashion, the average life is 4 years or less. In a fashion, the average life is 5 years or less. In a fashion, the average life is 7 years or less. In a fashion, the average life is 10 years or less. Each possibility represents a separate modality of the present invention. The term "polymer" refers, in one embodiment, to a macromolecule composed of individual units or monomers. In another embodiment, the polymer is a branched polymer. In another embodiment, the polymer is a linear polymer. In another embodiment, the polymer is a crosslinked polymer. In another embodiment, the polymer is any other type of polymer known in the art. Each possibility represents a separate embodiment of the present invention. The PLA: PGA polymers contain PLA and PGA monomers, while the PLA polymers contain only PLA monomers. Methods for use and synthesis of PLA polymers and PLA: PGA polymers are well known in the art, and are described, for example, in the Fukushima K and associates publication (Macromol Biosci 5 (1): 21-9, 2005); Sajulnier B and associates (Macromol Biosci 15; 4 (3): 232-7, 2004); and Park SJ and associates (J Colloid Interface Sci 271 (2): 336-41, 2004). Each method represents a separate embodiment of the present invention. In one embodiment, an implant of the methods and compositions of the present invention is rod-shaped. As provided in the present invention, the results thereof show that rod-shaped implants, as well as disc-shaped implants, can be used to provide prolonged administration of risperidone and other drugs. In another embodiment, the implant is disc-shaped. In another modality, the implant is cylindrical. In another embodiment, the implant is a leaf. In another embodiment, the implant has any shape suitable for retention in a body tissue (e.g., subcutaneous tissue). In another embodiment, the implant has any suitable shape for structural stability in the subcutaneous space. In another embodiment, the implant has any suitable shape for the ability to tolerate in the subcutaneous space. In another embodiment, the implant has any shape in addition to that known in the art. The term "rod-shaped" refers, in one embodiment, to a shape whose cross-section is substantially round, and whose length is at least twice the diameter of the cross-section. In another embodiment, the cross-sectional shape is any other cross-sectional shape of the present invention. In another embodiment, the length is at least as large as the diameter of the cross section. In another embodiment, the length is at least 1.1 times the diameter of the cross section. In another embodiment, the length is at least 1.2 times the diameter. In another embodiment, the length is at least 1.3 times the diameter. In another embodiment, the length is at least 1.4 times the diameter. In another embodiment, the length is at least 1.5 times the diameter. In another embodiment, the length is at least 1.6 times the diameter. In another embodiment, the length is at least 1.7 times the diameter. In another embodiment, the length is at least 1.8 times the diameter. In another embodiment, the length is at least 1.9 times the diameter. In another embodiment, the length is at least 2.2 times the diameter. In another embodiment, the length is at least 2.5 times the diameter. In another embodiment, the length is at least 3 times the diameter. In another embodiment, the length is at least 4 times the diameter. Each possibility represents a separate embodiment of the present invention. The term "disk shape" refers, in one embodiment, to a flat, substantially round shape. In another form, the shape is oval, square, rectangular, etc. The thickness, in one modality, is less than the diameter of the circle, oval, etc. In another embodiment, the thickness is less than 0.9 times the diameter of the shape. In another embodiment, the thickness is less than 0.8 times the diameter. In another embodiment, the thickness is less than 0.7 times the diameter. In another embodiment, the thickness is less than 0.6 times the diameter. In another embodiment, the thickness is less than 0.5 times the diameter. In another embodiment, the thickness is less than 0.4 times the diameter. In another embodiment, the thickness is less than 0.3 times the diameter. In another embodiment, the thickness is less than 0.2 times the diameter. In another embodiment, the thickness is less than 0.1 times the diameter. Each possibility represents a separate embodiment of the present invention. In one embodiment, the rods, discs and cylinders referred to in the present invention have a substantially circular cross-sectional shape. In another embodiment, the cross sectional shape is ellipse. In another embodiment, the ellipse shape does not need to be rounded at the edges. In another embodiment, the cross-sectional shape has any shape from Figure 16. In another embodiment, the cross-sectional shape is any other form known in the art. Because the present invention has shown that the drug release range of an implant is proportional to its surface area, the shape of the implant can be modified, in one embodiment, to confer desirable characteristics therein without altering the range of release, as long as the surface area remains constant. The present invention has shown that the duration of drug release of an implant is proportional to its SA: V ratio; therefore, the shape of the implant can be modified, in one embodiment, to confer in it desirable characteristics without altering the duration of release, provided that the SA: V ratio remains constant. Each shape represents a separate embodiment of the present invention. The term "substantially circular" refers, in another embodiment, to a circle or circle type shape whose largest diameter in any given cross section is at least 150% of its shortest diameter. In another embodiment, the longest diameter in each cross section in each section is less than 145% of its shortest diameter. In another modality, the number is 140%. In another modality, the number is 135%. In another modality, the number is 130%. In another modality, the number is 125%. In another modality, the number is 120%. In another modality, the number is 115%. In another modality, the number is 110%. In another modality, the number is 105%. In another modality, the longest diameter is no greater than 150% of the shortest diameter. In another embodiment, the longest diameter is no greater than 145% of the shortest diameter. In another embodiment, the longest diameter is no greater than 140% of the shortest diameter. In another embodiment, the longest diameter is no greater than 135% of the shortest diameter. In another embodiment, the longest diameter is no greater than 130% of the shortest diameter. In another embodiment, the longest diameter is no greater than 125% of the shortest diameter. In another embodiment, the longest diameter is no greater than 120% of the shortest diameter. In another embodiment, the longest diameter is no greater than 115% of the shortest diameter. In another embodiment, the longest diameter is no greater than 110% of the shortest diameter. In another embodiment, the longest diameter is no greater than 105% of the shortest diameter. In another embodiment, the ratio of the longest to the shortest diameter is any other ratio that is consistent with a substantially circular shape. In another embodiment, the number is any other number that describes a substantially circular form. Each possibility represents another embodiment of the present invention. In another embodiment, the cross-sectional area is substantially constant in the length of the rods, discs and cylinders of the present invention. In another embodiment, the cross-sectional area is not constant. In another embodiment, the cross-sectional dimension is substantially constant with respect to the length of the rods, discs and cylinders of the present invention. In another embodiment, the cross-sectional dimensions are not constant. Each possibility represents a separate embodiment of the present invention. In another embodiment, an implant of the present invention has a rectangular cross-sectional shape. In another embodiment, the cross-sectional shape is a square. In another embodiment, the cross-sectional shape is any other form known in the art. In another embodiment, the implant is monolithic. In another embodiment, the implant is composed of several (10 or less) smaller components that fuse together. In another mode, the components are linked together. Each possibility represents a separate embodiment of the present invention. Each of the above general forms and cross-sectional shapes represents a separate embodiment of the present invention. Implant insertion methods are well known in the art. In one modality, the implants are inserted through the minimally invasive method, using a surgical instrument known as "trochador'J. In another modality, the implants are inserted using a procedure and a set of tools (trochador and obdurador) similar to those used for Norplant (Townsend S "Insertion and Removal of Norplant" Netw Fr 6: 8-9, 1991) In another embodiment, rod-shaped implants provide an advantage with respect to their ease of implantation and lack of subsequent discomfort (Fig. 15) In another embodiment, an advantage of rod-shaped implants is the small incisions referred to for insertion, for example, in various modalities, approximately 2 mm, 3 mm, 4 mm, 5 mm, 6 mm or 7 mm In another modality, implants provide an advantage due to their ability to be implanted in an external patient's base.The incision site is closed, in another modality, either with a single stitch or strip s sterilized (figure 15). In another embodiment, the implant is inserted through any other surgical method known in the art. Each method represents a separate embodiment of the present invention. In another embodiment, the implants of the present invention provide an advantage due to their lack of need for the subject to receive injections each week, thus increasing compliance to the patient. In another modality, the advantage of the implants is due to the increased autonomy of the resulting patient. In another modality, the advantage of the implants is due to their lack of irritation in the administration site. In another embodiment, an advantage of the implants of the present invention is due to their stability at body temperature during the delivery period. In another embodiment, the advantages of the implants are due to their ability to completely erode, thus exhibiting a lack of need to eliminate residual material. In one embodiment, erosion is mainly surface erosion. In another modality, erosion is mainly volume erosion. In another form, erosion is a combination of substantial amounts of surface erosion and volume erosion. Each possibility represents a separate embodiment of the present invention. In another embodiment, an implant of the methods and compositions of the present invention is strap-attached (Figure 2) to assist in locating it, and if necessary, eliminating it. As provided in the present invention, the elimination process has been successfully tested in mice and rats. In another modality, after palpating the implant, a small incision is made and recovered using forceps, the residual material of the implant. In another modality, the implant is removable. The term "removable" refers, in one embodiment, to the ability of the implant to be removed by surgery or other means. In another embodiment, the term "removable" refers to the ability of the implant remains to be removed. In another embodiment, the term "removable" refers to the ability to remove most of the remains of the implant. In one embodiment, the implant is removed due to an adverse reaction to the medicament of the present invention. In another modality, the implant is eliminated due to the decision by a specialist. In another modality, the implant is removed due to the decision by a patient. In another embodiment, the implant is removed due to overdosage of medication. In another embodiment, the implant is removed due to any other reason for which it is desired to have the treatment. As provided in the present invention (Figure 15), the implant of the present invention is easily removable and remains cohesive during the period of drug administration. In another embodiment, the implant is removable throughout the period of administration of the drug.

In another embodiment, the implant is removable throughout the period of administration of the detectable drug. In another embodiment, the implant is easily removable throughout the period of administration of the drug. In another embodiment, it is easily removable throughout the period of administration of the detectable drug. In another embodiment, the implant has cohesion properties throughout the period of administration of the drug. In another embodiment, the implant has cohesion properties throughout the period of detectable drug administration. Each possibility represents a separate embodiment of the present invention. The term "easily removable" refers, in another embodiment, to a capacity to be eliminated using forceps or a similar instrument. In another embodiment, the term refers to a capacity to be eliminated without the use of strong suction. In another embodiment, the term refers to a capacity to be eliminated without the need to remove surrounding tissue. Each possibility represents a separate embodiment of the present invention. In another embodiment, the implants of the present invention exhibit the advantage that the internal pH environment decreases as the polymer degrades to monomers. The decrease in pH at the time of degradation improves the time-dependent release, in another embodiment, of drugs and active agents that are insoluble at neutral pH (and therefore are secured in the implant), but become increasingly soluble as the pH decreases. In another embodiment, the implants improve the release of drugs with increased solubility at a low pH. In another embodiment, the implants improve the release of drugs with an acid pKa. In another embodiment, the increased time-dependent release increases the ability of the compound to be delivered in the systemic circulation. In another embodiment, the drug with a pH-dependent solubility is haloperidol. In another embodiment, the pH-dependent drug is risperidone. In another embodiment, the pH dependent drug is any other drug with a pH dependent solubility known in the art. Each possibility represents another embodiment of the present invention. In another embodiment, the decrease in pH at the time of degradation increases the degradation range of the polymer with respect to time. In another embodiment, the decrease in pH at the time of degradation results in self-catalysis of polymer degradation. Each possibility represents a separate embodiment of the present invention. In another embodiment, the implants of the present invention exhibit the advantage of a decrease in pH at the time of degradation, which is not observed with smaller dosage forms (e.g., microparticles). In another embodiment, the polymer used in the methods and compositions of the present invention comprises PLA but not PGA. In another embodiment, the polymer comprises PLA and PGA. In another embodiment, the polymer consists of PLA alone. In another embodiment, the polymer consists of PLA and PGA. Each possibility represents a separate embodiment of the present invention. In another embodiment, the drug loading of the implant of the methods and compositions of the present invention is between 30% and 60%. As provided in the present invention (example 7), the results thereof have demonstrated the efficacy of the drug loading ranges in particular of biodegradable implants. The term "drug loading" refers, in one embodiment, to the amount of drug in the implant as a percentage by mass. In another embodiment, the term "drug loading" refers to the weight percentage of the drug. In another embodiment, for example, if other materials are found in the implant in addition to the drug and the therapeutic polymer, the drug loading is calculated without regard to the other materials. Each possibility represents a separate embodiment of the present invention. In another modality, the drug load is between approximately 40% and 50%. In another embodiment, the drug loading is from 1% to 5%. In another embodiment, the drug loading is from 2% to 5%. In another embodiment, the drug load is from 5% to 10%. In another embodiment, the drug load is from 15% to 20%. In another embodiment, the drug load is from 20% to 25%. In another embodiment, the drug loading is from 25% to 30%. In another embodiment, the drug load is from 35% to 40%. In another embodiment, the drug loading is from 40% to 45%. In another embodiment, the drug loading is from 45% to 50%. In another embodiment, the drug loading is from 50% to 55%. In another embodiment, the drug load is from 55% to 60%. In another embodiment, the drug load is from 60% to 65%. In another embodiment, the drug loading is from 65% to 70%. In another embodiment, the drug load is from 70% to 75%. In another embodiment, the drug load is from 75% to 80%. In another embodiment, the drug loading is from 80% to 85%. In another embodiment, the drug loading is from 85% to 90%. In another embodiment, the drug load is from 90% to 95%. In another embodiment, the drug load is from 95% to 99%. In another embodiment, the drug load is from 5% to 15%. In another embodiment, the drug load is from 10% to 20%. In another embodiment, the drug load is from 15% to 25%. In another embodiment, the drug load is from 20% to 30%. In another embodiment, the drug loading is from 25% to 35%. In another embodiment, the drug loading is from 30% to 40%. In another embodiment, the drug load is from 35% to 45%. In another embodiment, the drug loading is from 45% to 55%. In another embodiment, the drug load is from 50% to 60%. In another embodiment, the drug loading is from 55% to 65%. In another embodiment, the drug load is from 60% to 70%. In another embodiment, the drug load is from 70% to 80%. In another embodiment, the drug load is from 80% to 90%. In another embodiment, the drug load is from 90% to 99%. In another embodiment, the drug load is from 5% to 20%. In another embodiment, the drug load is from 10% to 25%. In another embodiment, the drug load is from 15% to 30%. In another embodiment, the drug loading is from 20% to 35%. In another embodiment, the drug load is from 25% to 40%. In another embodiment, the drug load is from 30% to 45%. In another embodiment, the drug loading is from 35% to 50%. In another embodiment, the drug load is from 40% to 55%. In another embodiment, the drug loading is from 45% to 60%. In another embodiment, the drug loading is from 50% to 65%. In another embodiment, the drug load is from 55% to 70%. In another embodiment, the drug load is from 5% to 25%. In another embodiment, the drug load is from 10% to 30%. In another embodiment, the drug load is from 15% to 35%. In another embodiment, the drug load is from 20% to 40%. In another embodiment, the drug loading is from 25% to 45%. In another embodiment, the drug load is from 30% to 50%. In another embodiment, the drug loading is from 35% to 55%. In another embodiment, the drug loading is from 40% to 60%. In another embodiment, the drug loading is from 45% to 65%. In another embodiment, the drug load is 50% to 70%. In another embodiment, the drug load is 2%. In another embodiment, the drug load is 3%. In another embodiment, the drug load is 5%. In another embodiment, the drug load is 6%. In another embodiment, the drug load is 8%. In another embodiment, the drug load is 10%. In another embodiment, the drug load is 12%. In another embodiment, the drug load is 14%. In another embodiment, the drug load is 16%. In another embodiment, the drug load is 18%. In another embodiment, the drug load is 20%. In another embodiment, the drug load is 22%. In another embodiment, the drug load is 24%. In another embodiment, the drug load is 26%. In another embodiment, the drug load is 28%. In another embodiment, the drug load is 30%. In another embodiment, the drug load is 32%. In another embodiment, the drug load is 34%. In another modality, the drug load is 36%. In another embodiment, the drug load is 38%. In another embodiment, the drug load is 40%. In another embodiment, the drug load is 42%. In another embodiment, the drug load is 44%. In another embodiment, the drug load is 46%. In another embodiment, the drug load is 48%. In another embodiment, the drug load is 50%. In another embodiment, the drug load is 52%. In another embodiment, the drug load is 54%. In another embodiment, the drug load is 56%. In another embodiment, the drug load is 58%. In another embodiment, the drug load is 60%. In another embodiment, the drug load is 65%. In another embodiment, the drug load is 70%. Each drug loading represents a separate embodiment of the present invention. The numerical ranges and others used to describe the methods and compositions of the present invention are understood to be inclusive of the limit values. Each value or combination of values within the range represents a separate embodiment of the present invention. A "therapeutic drug" is, in one embodiment, any drug or compound that exhibits any type of therapeutic or beneficial effect when administered to a subject. In another embodiment, the therapeutic drug contained in an implant of the methods and compositions of the present invention is risperidone. In another embodiment, the therapeutic drug is 9-OH-risperidone. In another embodiment, the therapeutic drug is thiothixene. In another embodiment, the therapeutic drug is haloperidol. In another embodiment, the therapeutic drug is hydrochlorothiazide (HCTZ). In another embodiment, the therapeutic drug is corticosterone. In another embodiment, the therapeutic drug is ibuprofen. In another embodiment, the therapeutic drug is aspirin. In another embodiment, the therapeutic drug is pimozide. In another embodiment, the therapeutic drug is aripiprazole. In another embodiment, the therapeutic drug is olanzapine. In another modality, the therapeutic drug is donepezil. In another embodiment, the therapeutic drug is any other therapeutic drug known in the art. The polymers PLA and polymers PLA: PGA exhibit an advantage, in one modality, in that the drugs do not need to be chemically modified before incorporation into the same; rather, they need only to be mixed mechanically in the polymer matrix. Therefore, a wide variety of therapeutic agents can be incorporated. In other embodiments, the therapeutic drug is a dopaminergic agent. In one embodiment, the dopaminergic agent is an agonist. In one embodiment, the dopaminergic agent is an antagonist. In one embodiment, the dopaminergic agent is a partial agonist. In one embodiment, the dopaminergic agent is a monoamine reuptake inhibitor. In one embodiment, the dopaminergic agent is a facilitator of monoamine uptake. In other embodiments, the therapeutic drug is one of the following drugs, or belongs to one of the following classes: antihypertensives, antidepressants, anti-anxiety agents, anticoagulation agents, anticonvulsants, blood glucose lowering agents, decongestants, antihistamines, antitussives, anti-inflammatories, antipsychotic agents, cognitive enhancers, cholesterol reducing agents, anti-obesity agents, autoimmune disorders agents, anti-impotence agents, antibacterial and antifungal agents, hypnotic agents, anti-Parkinson's agents, antibiotics, antiviral agents, anti-neoplastic agents , barbiturates, sedatives, nutrition agents, beta blockers, emetics, anti-emetics, diuretics, anticoagulants, cardiotonic, androgens, corticosteroids, anabolic agents, growth hormone secretadores, anti-infective agents, coronary vasodilators, carbonic anhydrase inhibitors, antiprotozoa, agents gastrointestinal, serotonin antagonists, anesthetics, hypoglycaemic agents, anti-Alzheimer's disease agents, anti-ulcer agents, platelet inhibitors, glycogen phosphorylase inhibitors and phosphodiesterase inhibitors. In other embodiments, the therapeutic drug is one of the following drugs: chlorpropamide, fluconazole, atorvastatin calcium, hydroxyzine hydrochloride, doxepin hydrochloride, amlodipine besylate, piroxicam, celicoxib, valdicoxib, indanyl sodium carbenicillin, bacampicillin hydrochloride, troleandomycin and doxycycline hyclate. In other embodiments, the therapeutic drug is one of the following drugs, or belongs to one of the following classes: platinum compounds (e.g., spiroplatine, cisplatin and carboplatin), methotrexate, fluorouracil, adriamycin, mitomycin, ansamitocin, bleomycin, arabinoside of cytosine, arabinosyl adenine, mercaptopolilisin, vincristine, busulfan, chlorambucil, melphalan (for example, PAM, L-PAM or phenylalanine mustard), mercaptopurine, mitotane, procarbazine hydrochloride, dactinomycin (actinomycin D), daunorubicin hydrochloride, hydrochloride of doxorubicin, paclitaxel and other taxanes, rapamycin, manumicyn A, TNP-470, plicamycin (mitramycin), aminoglutethimide, sodium estramustine phosphate, flutamide, leuprolide acetate, magestrol acetate, tamoxifen citrate, testolactone, trilostane, amsacrine ( m-AMSA), asparginase (L-asparginase), asparginase Erwina, interferon. alpha. -2a, interferon. alpha. -2b, teniposide (VM-26), vinblastine sulphate (VLB), vincristine sulfate, bleomycin sulfate, hydroxyurea, procarbazine and dacarbazine; mitotic inhibitors, for example, etoposide, colchicine and vinca alkaloids, radiopharmaceuticals, for example, radioactive iodine and phosphorous products; hormones, for example, progestins, estrogens and antiestrogens; anti-helminths, antimalarials and anti-tuberculosis drugs; biological, for example, immune sera, antitoxins and antivenoms; rabies prophylaxis products; bacterial vaccines; viral vaccines; respiratory products, for example, xanthine derivatives, theophylline and aminophylline; thyroid agents, for example, iodine products and anti-thyroid agents; cardiovascular products that include chelation agents and mercury diuretics and cardiac glycosides; glucagon; blood products, for example, parenteral iron, hemin, hematoporphyrins and their derivatives; biological response modifiers, for example, muramyl dipeptide, muramyl tripeptide, microbial cell wall components, lymphokines (e.g., bacterial endotoxin, e.g., lipopolysaccharides, macrophage activation factor), subunits of bacteria (such as Mycobacteria, Corinebacteria) , the synthetic dipeptide N-acetyl-muramyl-L-alanyl-D-iso-glutamine; anti-fungal agents, for example, ketoconazole, nystatin, griseofulvin, flucytosine (5-fc), miconazole, amphotericin B, ricin, cyclosporins, and β-lactam antibiotics (eg, sulfazecin); hormones, for example, growth hormone, melanocyte stimulation hormone, estradiol, beclomethasone dipropionate, betamethasone, betamethasone acetate and betamethasone sodium phosphate, vestamethasone disodium phosphate, vetametasone sodium phosphate, cortisone acetate, dexamethasone , dexamethasone acetate, dexamethasone sodium phosphate, flunisolide, hydrocortisone, hydrocortisone acetate, hydrocortisone cypionate, hydrocortisone sodium phosphate, hydrocortisone sodium succinate, methylprednisolone, methylprednisolone acetate, methylprednisolone sodium succinate, parametasone acetate , prednisolone, prednisolone acetate, prednisolone sodium phosphate, prednisolone tebutate, prednisone, triamcinolone, triamcinolone acetonide, triamcinolone diacetate, triamcinolone hexacetonide, fludrocortisone acetate, oxytocin, vasopressin and its derivatives; vitamins, for example, cyanocobalamin neinoic acid, retinoids and derivatives, for example, retinol palmitate and .alpha. -tocopherol; peptides, for example, manganese superoxide dismutase; enzymes, for example, alkaline phosphatase; anti-allergic agents, for example, amelexanox; anticoagulation agents, for example, fenprocoumon and heparin; circulatory drugs, for example, propanol; metabolic enhancers, for example, glutathione; antitubercular agents, for example, para-aminosalicylic acid, isoniazid, capreomycin sulfate cycloserine, ethylamide of ethambutol hydrochloride, pyrazinamide, rifampin and streptomycin sulfate; antivirals, for example, amantadine azidothymidine (AZT, DDI, Foscarnet or Zidovudine), ribavirin and vidarabine monohydrate (adenine arabinoside, ara-A); antianginals, for example, diltiazem, nifedipine, verapamil, erythritol tetranitrate, isosorbide dinitrate, nitroglycerin (glyceryl trinitrate) and pentaerythritol tetranitrate; anticoagulants, for example, fenprocoumon, heparin; antibiotics, for example, dapsone, chloramphenicol, neomycin, cefaclor, cefadroxil, cephalexin, cephradine erythromycin, clindamycin, lincomycin, amoxilin, ampicillin, bacampicillin, carbenicillin, dicloxacillin, cyclacillin, picloxacillin, hetacycline, methicillin, nafcillin, oxacillin, penicillin including penicillin G and penicillin V, ticarcillin rifampin and tetracycline; anti-inflammatory, for example, diflunisal, ibuprofen, indomethacin, meclofenamate, mefenamic acid, naproxen, oxifenbutazone, phenylbutazone, piroxicam, sulindac, tolmetin, aspirin and salicylates; antiprotozoals, for example, chloroquine, hydroxychloroquine, metronidazole, quinine and meglumine antimonate; antirheumatics, for example, penicillamine, narcotics, for example, paregoric; opiates, for example, codeine, heroin, methadone, morphine and opium; cardiac glycosides, for example, desolase, digitoxin, digoxin, digitalin and digitalis; neuromuscular blockers, for example, atracurium mesylate, galamina triethioiodide, hexafluorenium bromide, methocurinium iodide, pancuronium bromide, succinicolinium chloride (suxamethonium chloride), tubocurarine chloride and vecuronium bromide; sedatives (hypnotics), for example, amobarbital, amobarbital sodium, aprobarbital, butabarbital sodium, chloral hydrate, etclorvinol, ethinamate, flurazepam hydrochloride, glutethimide, methotrimeprazine hydrochloride, metiprilon, midazolam hydrochloride, paraldehyde, pentobarbital, sodium pentobarbital, phenobarbital sodium, secobarbital sodium, talbutal, temazepam and triazolam; local anesthetics, for example, bupivacaine hydrochloride; chloroprocaine hydrochloride, etidocaine hydrochloride, lidocaine hydrochloride, mepivicaine hydrochloride, procaine hydrochloride and tetracaine hydrochloride; general anesthetics, for example, droperidol, etomidate, fentanyl citrate with droperidol, ketamine hydrochloride, methohexital sodium and thiopental sodium; and radioactive particles or ions, for example, strontium, iodine, rhenium and yttrium. In another embodiment, the therapeutic drug is a metabolite of risperidone. In another embodiment, the therapeutic drug is a metabolite of one of the above drugs. In one embodiment, the metabolite is an active metabolite. In another embodiment, the therapeutic drug is a drug that is used chronically. In another embodiment, the therapeutic drug is a high potency drug. The term "high potency agent" refers, in one embodiment, to a drug that requires a low concentration of serum to exert a therapeutic effect. In another embodiment, the "high potency agent" refers to a drug that requires a low concentration of tissue to exert a therapeutic effect. In another embodiment, the "high potency agent" refers to a drug that requires a systemic concentration to exert a therapeutic effect. Each possibility represents a separate embodiment of the present invention. In one embodiment, the concentration required for a high potency agent to exert a therapeutic effect is 0.01 mg / kg. In another modality, the concentration is 0.02 mg / kg.

In another modality, the concentration is 0.03 mg / kg. In another modality, the concentration is 0.04 mg / kg. In another embodiment, the concentration is 0.05 mg / kg. In another embodiment, the concentration is 0.06 mg / kg. In another modality, the concentration is 0.07 mg / kg. In another modality, the concentration is 0.08 mg / kg. In another modality, the concentration is 0.09 mg / kg. In another embodiment, the concentration is OJO mg / kg. In another embodiment, the concentration is 0.12 mg / kg. Each definition of "high potency agent" represents a separate embodiment of the present invention. In one embodiment, the concentration required for a high potency agent to exert a therapeutic effect is 1 nanogram (ng) / ml. In another embodiment, the concentration is 1.5 ng / ml. In another embodiment, the concentration is 2 ng / ml. In another embodiment, the concentration is 3 ng / ml. In another embodiment, the concentration is 4 ng / ml. In another embodiment, the concentration is 5 ng / ml. In another embodiment, the concentration is 6 ng / ml. In another embodiment, the concentration is 7 ng / ml. In another embodiment, the concentration is 8 ng / ml. In another embodiment, the concentration is 9 ng / ml. In another embodiment, the concentration is 10 ng / ml. In another embodiment, the concentration is 12 ng / ml. In another embodiment, the concentration is 15 ng / ml. In another embodiment, the concentration is 20 ng / ml. Each definition of "high potency agent" represents a separate embodiment of the present invention. Each therapeutic drug represents a separate embodiment of the present invention. In another embodiment, an implant of the methods and compositions of the present invention contains a combination of therapeutic drugs. In one embodiment, the implant contains two therapeutic drugs. In another embodiment, the implant contains three therapeutic drugs. In another embodiment, the implant contains four therapeutic drugs. In another embodiment, the implant contains more than four therapeutic drugs. In another embodiment, the implant contains a combination of one of the above drugs with an additional drug. In another embodiment, the implant contains a combination of two or more drugs not described above. In another embodiment, the combination of drugs contained in the implant has a synergistic effect. In another embodiment, the combination of drugs contained in the implant has an additive effect. Each possibility represents a separate embodiment of the present invention. As described above, a wide variety of drugs can be incorporated into the PLA polymers and PLA: PGA polymers. Prior to incorporation, the drug (or "active ingredient") can be prepared by any method known in the art. The preparation of pharmaceutical compositions containing an active ingredient, for example, by mixing, granulating or tabletting processes, is well known in the art. The active therapeutic ingredient is mixed, in one embodiment, with excipients that are pharmaceutically acceptable and compatible with the active ingredient. In another embodiment, the active ingredient or one of its physiologically tolerated derivatives such as salts, esters, N-oxides and the like is mixed with additives designed for this purpose, such as vehicles, stabilizers or inert diluents. An active component is, in one embodiment, formulated in the composition as neutralized pharmaceutically acceptable salt forms. The pharmaceutically acceptable salts include the acid addition salts (formed with the free amino groups of the polypeptide or antibody molecule), which are formed with inorganic acids such as, for example, hydrochloric or phosphoric acids, or organic acids, such such as acetic, oxalic, tartaric, mandelic, and the like. Salts formed of free carboxyl groups also derived from inorganic bases such as, for example, sodium, potassium, ammonium, calcium or ferric hydroxides, and organic bases such as isopropylamine, trimethylamine, 2-ethylamino ethanol, histidine, procaine and the like. Each of the above additives, excipients, formulations and methods of administration represents a separate embodiment of the present invention.

In another embodiment, the molar ratio of PLA.GAA of a polymer of the methods and compositions of the present invention is between about 75:25 and about 100: 0. In another modality, the ratio is between 85:15 and 100: 0. In another modality, the proportion is between 50:50 and 100: 0. In another modality, the proportion is between 50:50 and 55:45. In another modality, the proportion is between 55:15 and 60:40. In another modality, the proportion is between 60:40 and 65:35. In another modality, the proportion is between 65:35 and 70:30. In another modality, the proportion is between 70:30 and 75:25. In another modality, the proportion is between 75:25 and 80:20. In another modality, the proportion is between 80:20 and 85:15. In another modality, the proportion is between 85:15 and 90:10. In another modality, the ratio is between 90:10 and 95: 5. In another modality, the proportion is between 95: 5 and 100: 0. In another modality, the proportion is between 96: 4 and 100: 0. In another modality, the ratio is between 97: 3 and 100: 0. In another modality, the proportion is between 98: 2 and 100: 0. In another modality, the proportion is between 99: 1 and 100: 0. In another modality, the proportion is between 50:50 and 60:40. In another modality, the proportion is between 55:45 and 65:35. In another modality, the proportion is between 60:40 and 70:30. In another modality, the proportion is between 65:35 and 75:25. In another modality, the proportion is between 70:30 and 80:20. In another modality, the proportion is between 75:25 and 85:15. In another mode, the proportion is between 80 and 20 90:10. In another mode, the ratio is between 85 and 95: 5. In another modality, the proportion is between 90 and 10 100: 0 In another mode, the ratio is between 50 50 and 65:35. In another mode, the proportion is between 55 and 45 70:30. In another mode, the ratio is between 60 40 and 75:25. In another mode, the ratio is between 65 and 35 80:20 In another mode, the proportion is between 70 and 30 85:15. In another mode, the ratio is between 75-25 and 90:10. In another mode, the proportion is between 80 and 20 95: 5. In another modality, the proportion is between 85 15 and 100: 0 In another mode, the proportion is between 50 50 and 70:30. In another mode, the proportion is between 55 and 45 75:25. In another mode, the ratio is between 60 40 and 80:20. In another mode, the ratio is between 65 and 35 85:15. In another mode, the proportion is between 70 and 30 90:10. In another mode, the ratio is between 75 and 25 95:05 In another mode, the proportion is between 80 and 20 100: 0 In another mode, the ratio is between 50 50 and 75:25. In another mode, the proportion is between 55 and 45 80:20 In another mode, the ratio is between 60 40 and 85:15. In another mode, the ratio is between 65 and 35 90:10. In another mode, the proportion is between 70 and 30 95: 5. In another mode, the ratio is between 75: 25 and 100: 0.

In another modality, the proportion is 50:50. In another modality, the proportion is 52:48. In another modality, the proportion is 54:46. In another modality, the proportion is 56:44. In another modality, the proportion is 58:42. In another modality, the proportion is 60:40. In another modality, the proportion is 62:38. In another modality, the proportion is 64:36. In another modality, the proportion is 66:34. In another modality, the proportion is 68:32. In another modality, the proportion is 70:30. In another modality, the proportion is 72:28. In another modality, the proportion is 74:26. In another modality, the proportion is 76:24. In another modality, the ratio is 78:22. In another modality, the proportion is 80:20. In another modality, the proportion is 82:18. In another modality, the proportion is 84:16. In another modality, the proportion is 86:14. In another modality, the proportion is 88:12. In another modality, the proportion is 90:10. In another modality, the proportion is 92: 8. In another modality, the ratio is 94: 6. In another modality, the proportion is 96: 4. In another modality, the proportion is 97: 3. In another modality, the proportion is 98: 2. In another modality, the proportion is 99: 1. In another modality, the proportion is 100: 0. (for example, substantially less than 1% PGA). As provided in the present invention (example 5), the results thereof have demonstrated the efficacy of the particular PLA: PGA drug ratios of biodegradable implants. In one embodiment, the PLA: PGA ratio is a molar ratio. In another embodiment, the PLA: PGA ratio is a mass ratio. In another embodiment, the PLA: PGA ratio is a weight ratio. In another embodiment, the PLA: PGA ratio is a volume ratio. Each of the above PLA: PGA proportions represents a separate embodiment of the present invention. In another embodiment, the polymer of the methods and compositions of the present invention exhibits an inherent viscosity of between about 0.2-0.9 dl / g in chloroform. In another embodiment, the inherent viscosity is from 0.6-0.85 dl / g. In another embodiment, the inherent viscosity is from 0.2-0.3 dl / g. In another embodiment, the inherent viscosity is 0.25-0.35 dl / g. In another embodiment, the inherent viscosity is from 0.3-0.4 dl / g. In another embodiment, the inherent viscosity is from 0.35-0.45 dl / g. In another embodiment, the inherent viscosity is 0.4-0.5 dl / g. In another embodiment, the inherent viscosity is from 0.45-0.55 dl / g. In another embodiment, the inherent viscosity is from 0.5-0.6 dl / g. In another embodiment, the inherent viscosity is from 0.55-0.65 dl / g. In another embodiment, the inherent viscosity is from 0.6-0.7 dl / g. In another embodiment, the inherent viscosity is from 0.65-0.75 dl / g. In another embodiment, the inherent viscosity is from 0.7-0.8 dl / g. In another embodiment, the inherent viscosity is from 0.75-0.85 dl / g. In another embodiment, the inherent viscosity is from 0.8-0.9 dl / g. In another embodiment, the inherent viscosity is from 0.85-0.95 dl / g. In another embodiment, the inherent viscosity is from 0.2-0.35 dl / g. In another embodiment, the inherent viscosity is from 0.25-0.40 dl / g. In another embodiment, the inherent viscosity is from 0.3-0.45 dl / g. In another embodiment, the inherent viscosity is from 0.35-0.5 dl / g. In another embodiment, the inherent viscosity is from 0.4-0.55 dl / g. In another embodiment, the inherent viscosity is from 0.45-0.6 dl / g. In another embodiment, the inherent viscosity is from 0.5-0.65 dl / g. In another embodiment, the inherent viscosity is from 0.55-0.70 dl / g. In another embodiment, the inherent viscosity is from 0.6-0.75 dl / g. In another embodiment, the inherent viscosity is from 0.65-0.80 dl / g. In another embodiment, the inherent viscosity is from 0.7-0.85 dl / g. In another embodiment, the inherent viscosity is from 0.75-0.9 dl / g. In another embodiment, the inherent viscosity is from 0.8-0.95 dl / g. In another embodiment, the inherent viscosity is from 0.2-0.40 dl / g. In another embodiment, the inherent viscosity is from 0.25-0.45 dl / g. In another embodiment, the inherent viscosity is from 0.3-0.5 dl / g. In another embodiment, the inherent viscosity is from 0.35-0.55 dl / g. In another embodiment, the inherent viscosity is from 0.4-0.6 dl / g. In another embodiment, the inherent viscosity is from 0.45-0.65 dl / g. In another embodiment, the inherent viscosity is from 0.5-0.7 dl / g. In another embodiment, the inherent viscosity is from 0.55-0.75 dl / g.

In another embodiment, the inherent viscosity is from 0.6-0.8 dl / g. In another embodiment, the inherent viscosity is from 0.65-0.85 dl / g. In another embodiment, the inherent viscosity is from 0.7-0.9 dl / g. In another embodiment, the inherent viscosity is from 0.75-0.95 dl / g. In another embodiment, the inherent viscosity is from 0.2-0.45 dl / g. In another embodiment, the inherent viscosity is from 0.25-0.5 dl / g. In another embodiment, the inherent viscosity is from 0.3-0.55 dl / g. In another embodiment, the inherent viscosity is from 0.35-0.6 dl / g. In another embodiment, the inherent viscosity is from 0.4-0.65 dl / g. In another embodiment, the inherent viscosity is from 0.45-0.7 dl / g. In another embodiment, the inherent viscosity is from 0.5-0.75 dl / g. In another embodiment, the inherent viscosity is from 0.55-0.80 dl / g. In another embodiment, the inherent viscosity is from 0.6-0.85 dl / g. In another embodiment, the inherent viscosity is from 0.65-0.9 dl / g. In another embodiment, the inherent viscosity is from 0.7-0.95 dl / g. In another embodiment, the inherent viscosity is 0.2 dl / g. In another embodiment, the inherent viscosity is 0.25 dl / g. In another embodiment, the inherent viscosity is 0.3 dl / g. In another embodiment, the inherent viscosity is 0.35 dl / g. In another embodiment, the inherent viscosity is 0.4 dl / g. In another embodiment, the inherent viscosity is 0.45 dl / g. In another embodiment, the inherent viscosity is 0.5 dl / g. In another embodiment, the inherent viscosity is 0.55 dl / g. In another embodiment, the inherent viscosity is 0.6 dl / g. In another embodiment, the inherent viscosity is 0.65 dl / g. In another embodiment, the inherent viscosity is 0.7 dl / g. In another embodiment, the inherent viscosity is 0.75 dl / g. In another embodiment, the inherent viscosity is 0.8 dl / g. In another embodiment, the inherent viscosity is 0.85 dl / g. In another embodiment, the inherent viscosity is 0.9 dl / g. In another embodiment, the inherent viscosity is 0.95 dl / g. Each of the above inherent viscosities represents a separate embodiment of the present invention. The term "inherent viscosity" refers, in one embodiment, to the measurement of the ability of a polymer in solution to improve the viscosity of the solution. In another embodiment, the intrinsic viscosity increases with the molecular weight of the polymer, is a function of the polymerization conditions, and can vary independently of the PLA: PGA ratio of the polymer. In another embodiment, the intrinsic viscosity is defined as the limiting value of the specific viscosity / concentration ratio in a concentration of zero. Therefore, the viscosity is determined in different concentrations and is then extrapolated to a concentration of zero. In another embodiment, the term "inherent viscosity" is a synonym of "intrinsic viscosity". Each definition of "inherent viscosity" represents a separate embodiment of the present invention.

Methods for measuring inherent viscosity are well known in the art, and are described, for example, in the publication by Meek MF and associates (J Biomed Mater Res A 68 (1): 43-51, 2004) and Deng X and associated (J Control Relase 71 (2): 165-73, 2001). In another embodiment, the inherent viscosity is measured as described in Example 1 of the present invention. In another embodiment, the inherent viscosity is measured in chloroform. In another embodiment, the inherent viscosity is measured in a solution of hexafluoroisopropanol. In another embodiment, the inherent viscosity is measured in any other suitable solvent known in the art. In another embodiment, the solvent is an FDA Class III solvent (low toxicity with minimal need for residual solvent removal). Each method represents a separate embodiment of the present invention. In another embodiment, an implant of the methods and compositions of the present invention has a surface area to volume ratio (SA: V) of between about 1 and 3 (millimeters [mm]) 2 / mm3. In another modality, the proportion is between 0.5-1 mm2 / mm3. In another modality, the proportion is from 0.7-1.2 mm2 / mm3. In another modality, the proportion is from 0.9-1.4 mm2 / mm3. In another modality, the proportion is from 1.1-1.6 mm2 / mm3. In another modality, the proportion is from 1.3-1.8 mm2 / mm3. In another modality, the proportion is from 1.5-2 mm2 / mm3. In another modality, the proportion is from 2-2.5 mm2 / mm3. In another modality, the proportion is from 2.5-3 mm2 / mm3. In another modality, the proportion is from 3-3.5 mm2 / mm3. In another modality, the proportion is from 3.5-4 mm2 / mm3. In another modality, the proportion is from 4-4.5 mm2 / mm3. In another modality, the proportion is from 4.5-5 mm2 / mm3. In another modality, the proportion is from 5-5.5 mm2 / mm3. In another modality, the proportion is from 5.5-6 mm2 / mm3. In another modality, the proportion is from 0.5-1.5 mm2 / mm3. In another modality, the proportion is from 1-2 mm2 / mm3. In another modality, the proportion is from 1.5-2.5 mm2 / mm3. In another modality, the proportion is from 2-3 mm2 / mm3. In another modality, the proportion is from 2.5-3.5 mm2 / mm3. In another modality, the proportion is from 3-4 mm2 / mm3. In another modality, the proportion is from 3.5-4.5 mm2 / mm3. In another modality, the proportion is from 4-5 mm2 / mm3. In another modality, the proportion is from 4.5-5.5 mm2 / mm3. In another modality, the proportion is from 5-6 mm2 / mm3. In another modality, the proportion is from 5.5-6.5 mm / mm3. In another modality, the proportion is from 6-7 mm2 / mm3. In another modality, the proportion is from 6.5-7.5 mm2 / mm3. In another modality, the proportion is from 7-8 mm / mm * In another modality, the proportion is from 0.5-2 mm2 / mm3. In another modality, the proportion is from 1-2.5 mm2 / mm3. In another modality, the proportion is from 1.5-3 mm2 / mm3. In another modality, the proportion is from 2-3.5 mm 'mm "In another modality, the proportion is from 2.5-4 mm' mm" In another modality, the proportion is from 3-4.5 mm 'mm' In another modality, the proportion is from 3.5-5 mm '' mm 'In another modality, the proportion is from 4-5.5 mm' mm "In another modality, the proportion is from 4.5-6 mm '' mnr In another modality, the proportion is from 5 -6.5 mm 'rmm' In another modality, the proportion is from 5.5-7 mm 'mm' In another modality, the proportion is from 6-7.5 mm '' mm 'In another modality, the proportion is from 6.5-8 mm' 'mm' In another mode, the ratio is from 0.5-2.5 mm mm 'In another mode, the ratio is from 1-3 mm mm' In another mode, the ratio is from 1.5-3.5 mm '' mm 'In another mode , the proportion is from 2-4 mm 'mm' In another modality, the proportion is from 2.5-4.5 mm '' mm 'In another modality, the proportion is from 3-5 mm' 'mm' In another modality, the proportion is from 3.5-5.5 mm mm 'In another mode, the p roporción is from 4-6 mm 'mm' In another modality, the proportion is from 4.5-6.5 mm '' mm 'In another modality, the proportion is from 5-7 mm' mm 'In another modality, the proportion is from 5.5 -7.5 mm 'mm' In another mode, the ratio is from 6-8 mm '' mm 'In another mode, the ratio is from 0.5-3.5 mm' mm 'In another mode, the ratio is from 1-4 mm' mm 'In another mode, the ratio is from 1.5-4.5 mm' 'mm' In another mode, the ratio is from 2-5 mm / mm. In another modality, the proportion is from 2.5-5.5 mm2 / mm3. In another modality, the proportion is from 3-6 mm2 / mm3. In another modality, the proportion is from 3.5-6.5 mm2 / mm 'In another modality, the proportion is from 4-7 mm2 / mm3 In another modality, the proportion is from 4.5-7.5 mm2 / mm3 In another modality, the proportion is from 6-8 mm2 / mm3 In another modality, the proportion is from 0.5-4.5 mm2 / mm3. In another embodiment, the proportion is from 1-5 mm2 / mm3. In another modality, the proportion is from 1.5-5.5 mm2 / mm3 In another modality, the proportion is from 2-6 mm2 / mm3 In another modality, the proportion is from 2.5-6.5 mm / mm 'In another modality, the proportion is from 3-7 mm2 / mm3 In another mode, the ratio is from 3.5-7.5 mm2 / mm3. In another modality, the proportion is from 4-8 mm2 / mm3. In another modality, the proportion is from 4.5-8.5 mm2 / mm3. In another modality, the proportion is 0.5 mm2 / mm3. In another modality, the proportion is 0.5 mm2 / mm3. In another modality, the proportion is 0.6 mm2 / mm3. In another modality, the proportion is 0.7 mm2 / mm3. In another embodiment, the proportion is 0.8 mm2 / mm3. In another modality, the proportion is 1.0 mm2 / mm3. In another modality, the proportion is 1.5 mm2 / mm3. In another embodiment, the proportion is 2 mm2 / mm3. In another modality, the proportion is 2.5 mm2 / mm3. In another embodiment, the proportion is 3 mm2 / mm3. In another modality, the proportion is 3.5 mm2 / mm3. In another embodiment, the proportion is 4 mm2 / mm3. In another embodiment, the proportion is 4.5 mm2 / mm3. In another embodiment, the proportion is 5 mm2 / mm3. In another embodiment, the proportion is 5.5 mm2 / mm3. In another embodiment, the proportion is 6 mm2 / mm3. In another modality, the proportion is 6.5 mm2 / mm3. In another embodiment, the proportion is 7 mm2 / mm3. Each of the SA: V proportions above represents a separate embodiment of the present invention. As provided in the present invention (example 6), the results thereof have demonstrated the effectiveness of the SA: V ratio ranges of biodegradable implants. Methods for measuring the SA: V ratio are well known in the art. The SA: V ratio is measured, in one modality, by calculating the surface area and volume of the shape measurements (for example, for a regular shape). In another modality (for example, for a regular form), the surface area is measured using a BET apparatus (Brunauer, Emmett and Teller) (J by Kanel and JW Morse, J Phys E: Sci Instrum 12: 272-273 , 1979). In another embodiment, the surface area is measured using another technique known in the art. In another embodiment, the volume is measured by displacing the water or other fluid. In another embodiment, the volume is measured using any other technique known in the art. Each possibility represents a separate embodiment of the present invention. In another embodiment, an implant of the methods and compositions of the present invention has a length of between about 1-5 mm. The term "length", in one embodiment, refers to the longest dimension of the implant. In another embodiment, the term "length" refers to the length of the straight edge dimension, for example, in the case of an implant with a cylindrical shape. In another embodiment, the "straight edge dimension" refers to not needing to be completely straight, but may be, for example, a light curve. Each possibility represents a separate embodiment of the present invention. In another modality, the length of the implant is between 1-2 mm. In another modality, the length is 0.5-1.0 mm. In another mode, the length is 1.5-2 mm. In another modality, the length is 2-2.5 mm. In another mode, the length is 2.5-3 mm. In another modality, the length is 3-3.5 mm. In another embodiment, the length is 3.5-4 mm. In another modality, the length is 4-4.5 mm. In another embodiment, the length is 4.5-5 mm. In another mode, the length is 5-5.5 mm. In another modality, the length is 0.5-1.5 mm. In another modality, the length is 1.5-2.5 mm. In another modality, the length is 2-3 mm. In another modality, the length is 2.5-3.5 mm. In another modality, the length is 3-4 mm. In another modality, the length is 3.5-4.5 mm. In another embodiment, the length is 4-5 mm. In another modality, the length is 4.5-5.5 mm. In another embodiment, the length is 5-6 mm. In another modality, the length is 0.5-2 mm. In another mode, the length is 1-2.5 mm. In another modality, the length is 0.5-3 mm. In another modality, the length is 2-3.5 mm. In another embodiment, the length is 2.5-4 mm. In another modality, the length is 3-4.5 mm. In another modality, the length is 3.5-5 mm. In another modality, the length is 4-5.5 mm. In another modality, the length is 4.5-6 mm. In another modality, the length is 0.5-2.5 mm. In another modality, the length is 1-3 mm. In another mode, the length is 1.5-3.5 mm. In another modality, the length is 2-4 mm. In another mode, the length is 2.5-4.5 mm. In another modality, the length is 3-5 mm. In another modality, the length is 3.5-5.5 mm. In another modality, the length is 4-6 mm. In another modality, the length is 4.5-6.5 mm. In another modality, the length is 5-7 mm. In another modality, the length is 0.5-3.5 mm. In another modality, the length is 1-4 mm. In another modality, the length is 2-5 mm. In another modality, the length is 3-6 mm. In another modality, the length is 4-7 mm. In another modality, the length is 5-8 mm. In another modality, the length is 0.5-4.5 mm. In another embodiment, the length is 1-5 mm. In another modality, the length is 2-6 mm. In another modality, the length is 3-7 mm.

In another modality, the length is 0.5 mm. In another modality, the length is 0.6 mm. In another modality, the length is 0.7 mm. In another embodiment, the length is 0.8 mm. In another modality, the length is 0.9 mm. In another mode, the length is 1.0 mm. In another mode, the length is 1.2 mm. In another embodiment, the length is 1.4 mm. In another modality, the length is 1.6 mm. In another mode, the length is 1.8 mm. In another mode, the length is 2.0 mm. In another mode, the length is 2.2 mm. In another embodiment, the length is 2.4 mm. In another mode, the length is 2.6 mm. In another mode, the length is 2.8 mm. In another modality, the length is 3.0 mm. In another mode, the length is 3.5 mm. In another embodiment, the length is 4 mm. In another embodiment, the length is 4.5 mm. In another embodiment, the length is 5 mm. In another embodiment, the length is 5.5 mm. In another embodiment, the length is 6 mm. In another embodiment, the length is 7 mm. In another modality, the length is 8 mm. Each of the above lengths represents a separate embodiment of the present invention. In another embodiment, an implant of the methods and compositions of the present invention has a diameter between about 2-4 mm. The term "diameter", in one embodiment, refers to the distance through the cross-sectional area of the implant. In another embodiment, for example, in the case of a disc-shaped implant, the distance across the cross-sectional area may be longer than the length described above. In another embodiment, for example, in the case of a rod-shaped implant, the distance across the cross-sectional area is shorter than the length. In another embodiment, the cross-sectional area need not be a circle, but may be an ellipse, square, rectangle, etc., as described above. Therefore, in another embodiment, the diameter is the geometric average of the longest and shortest diameters of the cross-sectional area. In another embodiment, the diameter is the arithmetic average of the longest and shortest diameters of the same. In another embodiment, the diameter is the longest of the various diameters thereof. In another embodiment, the diameter is the distance across a diagonal of the cross-sectional area, for example, in the case of a square or rectangle. In another embodiment, the diameter is the distance across the longest cross-sectional area, for example, in the case where the diameter varies with respect to the length of the implant. In another embodiment, the diameter is the average distance across the largest cross-sectional area. Each possibility represents a separate embodiment of the present invention. In another embodiment, the diameter is between about 2-4 mm. In another modality, the diameter is 0.5-1 mm. In another embodiment, the diameter is 1-1.5 mm. In another embodiment, the diameter is 1.5-2 mm. In another embodiment, the diameter is 2-2.5 mm. In another embodiment, the diameter is 2.5-3 mm. In another embodiment, the diameter is 3-3.5 mm. In another embodiment, the diameter is 3.5-4 mm. In another embodiment, the diameter is 4-4.5 mm. In another embodiment, the diameter is 4.5-5 mm. In another embodiment, the diameter is 5-5.5 mm. In another embodiment, the diameter is 5.5-6 mm. In another modality, the diameter is 0.5-1.5 mm. In another embodiment, the diameter is 1-2 mm. In another embodiment, the diameter is 1.5-2.5 mm. In another embodiment, the diameter is 2-3 mm. In another embodiment, the diameter is 2.5-3.5 mm. In another embodiment, the diameter is 3-4 mm. In another embodiment, the diameter is 3.5-4.5 mm. In another embodiment, the diameter is 4-5 mm. In another embodiment, the diameter is 4.5-5.5 mm. In another embodiment, the diameter is 5-6 mm. In another modality, the diameter is 0.5-2 mm. In another mode, the diameter is 1-2.5 mm. In another modality, the diameter is 1.5-3 mm. In another embodiment, the diameter is 2-3.5 mm. In another embodiment, the diameter is 2.5-4 mm. In another modality, the diameter is 3-4.5 mm. In another embodiment, the diameter is 3.5-5 mm. In another embodiment, the diameter is 4-5.5 mm. In another embodiment, the diameter is 4.5-6 mm. In another embodiment, the diameter is 1-3 mm. In another embodiment, the diameter is 1.5-3.5 mm. In another embodiment, the diameter is 2-4 mm. In another embodiment, the diameter is 2.5-4.5 mm. In another embodiment, the diameter is 3-5 mm. In another modality, the diameter is 3.5-5.5 mm. In another embodiment, the diameter is 4-6 mm. In another embodiment, the diameter is 1-4 mm. In another embodiment, the diameter is 2-5 mm. In another embodiment, the diameter is 3-6 mm. In another embodiment, the diameter is 4-7 mm. In another modality, the diameter is 0.5 mm. In another embodiment, the diameter is 0.6 mm. In another embodiment, the diameter is 0.7 mm. In another embodiment, the diameter is 0.8 mm. In another embodiment, the diameter is 0.9 mm. In another embodiment, the diameter is 1.0 mm. In another embodiment, the diameter is 1.2 mm. In another embodiment, the diameter is 1.4 mm. In another embodiment, the diameter is 1.6 mm. In another embodiment, the diameter is 1.8 mm. In another embodiment, the diameter is 2.0 mm. In another embodiment, the diameter is 2.2 mm. In another embodiment, the diameter is 2.4 mm. In another embodiment, the diameter is 2.6 mm. In another mode, the diameter is 2.8 mm. In another embodiment, the diameter is 3.0 mm. In another embodiment, the diameter is 3.2 mm. In another embodiment, the diameter is 3.4 mm. In another embodiment, the diameter is 3.6 mm. In another embodiment, the diameter is 3.8 mm. In another embodiment, the diameter is 4.0 mm. In another embodiment, the diameter is 4.2 mm. In another embodiment, the diameter is 5 mm. In another embodiment, the diameter is 5.5 mm. In another embodiment, the diameter is 6 mm. Each of the above diameters represents a separate embodiment of the present invention. In another embodiment, an implant of the methods and compositions of the present invention has a mass of about 0.75 grams (g) or less. As provided in the present invention, it demonstrates the feasibility of using an implant of about 0.75 g or less for the delivery of an effective dose of risperidone for 6 months for a human (example 14). In another embodiment, the present invention demonstrates the feasibility of using an implant of about 1.5 g or less for the administration of an effective dose of risperidone for one year. In another embodiment, the implant has a mass of approximately OJ g or less. In another embodiment, the mass is 0.2 g or less. In another embodiment, the mass is 0.3 g or less. In another embodiment, the mass is 0.4 g or less. In another embodiment, the mass is 0.5 g or less. In another embodiment, the mass is 0.6 g or less. In another embodiment, the mass is 0.7 g or less. In another embodiment, the mass is 0.8 g or less. In another embodiment, the mass is 0.9 g or less. In another embodiment, the mass is 1 g or less. In another embodiment, the mass is 1.1 g or less. In another embodiment, the mass is 1.2 g or less. In another embodiment, the mass is 1.3 g or less. In another embodiment, the mass is 1.4 g or less.

In another embodiment, the mass is 1.5 g or less. In another embodiment, the mass is 1.6 g or less. In another embodiment, the mass is 1.7 g or less. In another embodiment, the mass is 1.8 g or less. In another embodiment, the mass is 1.9 g or less. In another embodiment, the mass is 2 g or less. In another embodiment, the mass is 2.2 g or less. In another embodiment, the mass is 2.4 g or less. In another embodiment, the mass is 2.6 g or less. In another embodiment, the mass is 2.8 g or less. In another embodiment, the mass is 3 g or less. In another modality, the mass is OJ g. In another embodiment, the mass is 0.2 g. In another mode, the mass is 0.3 g. In another embodiment, the mass is 0.4 g. In another embodiment, the mass is 0.5 g. In another embodiment, the mass is 0.6 g. In another embodiment, the mass is 0.7 g. In another embodiment, the mass is 0.8 g. In another embodiment, the mass is 0.9 g. In another embodiment, the mass is 1 g. In another embodiment, the mass is 1.1 g. In another embodiment, the mass is 1.2 g. In another embodiment, the mass is 1.3 g. In another embodiment, the mass is 1.4 g. In another embodiment, the mass is 1.5 g. In another embodiment, the mass is 1.6 g. In another embodiment, the mass is 1.7 g. In another embodiment, the mass is 1.8 g. In another embodiment, the mass is 1.9 g. In another embodiment, the mass is 2 g. In another embodiment, the mass is 2.2 g. In another embodiment, the mass is 2.4 g. In another embodiment, the mass is 2.6 g. In another embodiment, the mass is 2.8 g. In another embodiment, the mass is 3 g. In another embodiment, the mass is between about 0.1-0.3 g. In another embodiment, the mass is 0.2-0.4 g. In another embodiment, the mass is 0.3-0.5 g. In another embodiment, the mass is 0.4-0.6 g. In another modality, the mass is 0.5-0.7 g. In another embodiment, the dough is 0.6-0.8 g. In another embodiment, the dough is 0.7-0.9 g. In another embodiment, the mass is 0.8-1.0 g. In another embodiment, the mass is 0.1-0.4 g. In another embodiment, the mass is 0.2-0.5 g. In another embodiment, the mass is 0.3-0.6 g. In another embodiment, the mass is 0.4-0.7 g. In another embodiment, the mass is 0.5-0.8 g. In another embodiment, the dough is 0.6-0.9 g. In another embodiment, the mass is 0.7-1.0 g. In another embodiment, the mass is 0.1-0.5 g. In another embodiment, the mass is 0.2-0.6 g. In another embodiment, the mass is 0.3-0.7 g. In another embodiment, the mass is 0.4-0.8 g. In another modality, the mass is 0.5-0.9 g. In another embodiment, the mass is 0.6-1.0 g. In another embodiment, the mass is 0.8-1.2 g. In another embodiment, the dough is 1.0-1.4 g. In another embodiment, the mass is 1.2-1.6 g. In another embodiment, the mass is 1.4-1.8 g. In another embodiment, the mass is 1.6-2 g. In another embodiment, the mass is 1.8-2.2 g. In another embodiment, the mass is 2-2.4 g. In another embodiment, the dough is 2.5-2.9 g. In another embodiment, the mass is 0J-0.6 g. In another embodiment, the mass is 0.2-0.7 g. In another mode, the mass is 0.3-0.8 g. In another embodiment, the mass is 0.4-0.9 g. In another embodiment, the mass is 0.5-1.0 g. In another embodiment, the dough is 0.6-1.1 g. In another embodiment, the mass is 0.8-1.3 g. In another embodiment, the mass is 1.0-1.5 g. In another embodiment, the mass is 1.2-1.7 g. In another embodiment, the mass is 1.4-1.9 g. In another embodiment, the mass is 1.6-2.1 g. In another embodiment, the mass is 1.8-2.3 g. In another embodiment, the mass is 2-2.5 g. In another embodiment, the mass is 2.5-3 g. In another embodiment, the mass is 0.1-0.8 g. In another embodiment, the mass is 0.2-0.9 g. In another embodiment, the mass is 0.3-1.1 g. In another embodiment, the mass is 0.5-1.2 g. In another embodiment, the mass is 0.6-1.3 g. In another embodiment, the mass is 0.8-1.5 g. In another embodiment, the dough is 1.0-1.7 g. In another embodiment, the mass is 1.2-1.9 g. In another embodiment, the mass is 1.6-2.1 g. In another embodiment, the dough is 1.8-2.5 g. In another embodiment, the mass is 2-2.7 g. In another embodiment, the mass is 0.1-1.1 g. In another embodiment, the mass is 0.2-1.2 g. In another modality, the dough is 0.3-1.3 g. In another embodiment, the mass is 0.5-1.5 g. In another embodiment, the dough is 0.6-1.6 g. In another embodiment, the mass is 0.8-1.8 g. In another embodiment, the mass is 1.0-2 g. In another embodiment, the dough is 1.5-2.5 g. In another embodiment, the mass is 2-3 g. In another embodiment, the mass is 0.2-1.7 g. In another embodiment, the mass is 0.3-1.8 g. In another embodiment, the mass is 0.5-2 g. In another embodiment, the mass is 0.8-2.3 g. In another embodiment, the mass is 1.0-2.5 g. In another embodiment, the mass is 1.5-3 g. In another embodiment, the mass is 0.2-2.2 g. In another embodiment, the mass is 0.3-2.3 g. In another embodiment, the mass is 0.5-2.5 g. In another embodiment, the mass is 0.8-2.8 g. In another embodiment, the mass is 1-3 g. Each of the above masses represents a separate embodiment of the present invention. In another embodiment, an implant of the methods and compositions of the present invention is fabricated through a process comprising solvent casting. In another embodiment, the implant is manufactured through a process comprising compression molding. In another embodiment, the implant is manufactured through a process comprising melt mixing. In another embodiment, the implant is fabricated from a process comprising an extrusion method of molten mixture that does not require the use of a surfactant. In another embodiment, the implant is fabricated from a process comprising an extrusion method of melt mixing that does not require the use of an emulsion. In another embodiment, the implant is fabricated from a process comprising a melt mixing extrusion method that does not require the use of a surfactant or an emulsion. In another embodiment, the implant is fabricated from a process comprising extrusion molding. In one embodiment, extrusion molding is high pressure extrusion molding. In one embodiment, implants fabricated through compression molding exhibit increased density. In another embodiment, implants manufactured by compression molding exhibit improved uniformity. In another embodiment, a large variety of implant shapes can be manufactured by compression molding. In another embodiment, less material is lost during manufacture in the case of implants manufactured by extrusion. Each possibility represents a separate embodiment of the present invention. In another embodiment, the implants of the present invention exhibit the advantage of having a larger potential drug load than technologies utilizing an emulsion process. In another embodiment, the implants of the present invention exhibit the advantage of having a larger drug loading potential due to the use of a detergent-free process, for example, solvent melting. Each possibility represents a separate embodiment of the present invention. In another embodiment, the present invention provides a method for treating a subject of a disorder associated with the likelihood of noncompliance. The method includes administering to a subject an objective therapeutic drug in a long-term delivery system comprising a rod-shaped, implantable structure and the target therapeutic drug. In another embodiment, the present invention provides the use of an implant or group of implants of the present invention for the preparation of a pharmaceutical composition for treating a subject of a disorder associated with probability of non-compliance. In another embodiment, the present invention provides a method for maintaining a therapeutic level of a drug in a subject for a period of at least about 1 month, wherein the method comprises administering to the subject a group of biodegradable implants, the implant group consisting of biodegradable in one or more individual biodegradable implants that have (a) a therapeutic drug that is in an amount of 10% -60% by mass, relative to the mass of the implant; and (b) a polymer present in an amount of 40% -90% by mass, relative to the mass of the implant, the polymer comprising PLA and optionally PGA in a molar ratio PLA: PGA of between 50:50 and 100: 0 , and wherein the individual biodegradable implants, if there are more than one, do not substantially differ from each other in their molar ratio PLA: PGA, thereby maintaining a therapeutic level of a drug in a subject for a period of at least about 1 month. . In another embodiment, the present invention provides a method for maintaining a therapeutic level of a drug in a subject for a period of at least about 2 months, wherein the method comprises administering to the subject a group of biodegradable implants, the group of implants consisting of biodegradable in one or more individual biodegradable implants having (a) a therapeutic drug that is present in an amount of 10% -60% by mass, relative to the mass of the implant; and (b) a polymer present in an amount of 40% -90% by mass, relative to the mass of the implant, the polymer comprising PLA and optionally PGA in a molar ratio PLA: PGA of between 50:50 and 100: 0 , and wherein the individual biodegradable implants, if there are more than one, do not substantially differ from each other in their molar ratio PLA: PGA, thereby maintaining a therapeutic level of a drug in a subject for a period of at least about 2 months. . In another embodiment, the present invention provides a method for maintaining a therapeutic level of a drug in a subject for a period of at least about 3 months, wherein the method comprises administering to the subject a group of biodegradable implants, the group consisting of biodegradable implants in one or more individual biodegradable implants having (a) a therapeutic drug that is in an amount of 10% -60% by mass, relative to the mass of the implant; and (b) a polymer present in an amount of 40% -90% by mass, relative to the mass of the implant, the polymer comprising PLA and optionally PGA in a molar ratio PLA: PGA of between 50:50 and 100: 0 , and wherein the individual biodegradable implants, if there are more than one, do not substantially differ from each other in their molar ratio PLA: PGA, thereby maintaining a therapeutic level of a drug in a subject for a period of at least about 3 months. . In another embodiment, the present invention provides a method for maintaining a therapeutic level of a drug in a subject for a period of at least about 4 months, wherein the method comprises administering to the subject a group of biodegradable implants, the implant group consisting of biodegradable in one or more individual biodegradable implants having (a) a therapeutic drug that is present in an amount of 10% -60% by mass, relative to the mass of the implant; and (b) a polymer present in an amount of 40% -90% by mass, relative to the mass of the implant, the polymer comprising PLA and optionally PGA in a molar ratio PLA: PGA of between 50:50 and 100: 0 , and wherein the individual biodegradable implants, if there are more than one, do not substantially differ from each other in their molar ratio PLA: PGA, thereby maintaining a therapeutic level of a drug in a subject for a period of at least about 4 months. . In another embodiment, the present invention provides a method for maintaining a therapeutic level of a drug in a subject for a period greater than 4 months, wherein the method comprises administering to the subject a group of biodegradable implants, the group of biodegradable implants consisting of one or more individual biodegradable implants having (a) a therapeutic drug that is present in an amount of 10% -60% by mass, relative to the mass of the implant; and (b) a polymer present in an amount of 40% -90% by mass, relative to the mass of the implant, the polymer PLA and optionally PGA comprising a molar ratio PLA: PGA of between 50:50 and 100: 0, and wherein the individual biodegradable implants, if there are more than one, do not differ substantially from each other in their PLA molar ratio: PGA, thus maintaining a therapeutic level of a drug in a subject for a period greater than 4 months. In another embodiment, the present invention provides the use of an implant or a group of implants of the present invention for the preparation of a pharmaceutical composition for maintaining a therapeutic level of a drug in a subject during one of the above time periods. In another embodiment, the individual implants equivalent to another in another parameter in addition to their molar ratio PLA: PGA, for example, their drug loading, mass, SA: V ratio, length, diameter or inherent viscosity of the polymer. In another modality, the individual implants are equivalent to another in their PLA: PGA ratio, but not in the other parameters. In another embodiment, the individual implants are equivalent to another in two of these other parameters in addition to their PLA: PGA ratio. In another embodiment, the individual implants are equivalent to another in three of these parameters in addition to their PLA: PGA ratio. In another embodiment, the individual implants are equivalent to another in four of these parameters in addition to their PLA: PGA ratio. In another modality, the individual implants are equivalent to another in five of these parameters in addition to their PLA: PGA ratio. In another embodiment, the individual implants are equivalent to another in all these parameters in addition to their PLA: PGA ratio. Each possibility represents a separate embodiment of the present invention. In another embodiment, the individual implants are equivalent to another in their drug loading rather than in their PLA: PGA ratio. In another modality, the individual implants are equivalent to another in their mass instead of in their PLA: PGA ratio. In another embodiment, the individual implants are equivalent to another in their SA: V ratio instead of in their PLA: PGA ratio. In another embodiment, the individual implants are equivalent to another in their length instead of in their PLA: PGA ratio. In another embodiment, the individual implants are equivalent to another in their diameter instead of in their PLA.PGA ratio. In another embodiment, the individual implants are equivalent to others in the inherent viscosity of their polymer instead of their PLA: PGA ratio. In another modality, the individual implants are equivalent to another in 2 of these parameters. In another embodiment, the individual implants are equivalent to another in 3 of these parameters. In another modality, the individual implants are equivalent to another one in 4 of these parameters. In another modality, the individual implants are equivalent to another in all these parameters. Each possibility represents a separate embodiment of the present invention. In another embodiment, the PLA: PGA ratio is substantially non-variant within the individual implants; for example, individual implants are not each composed of sections of different proportions PLA: PGA. In another embodiment, this is true for the drug loading of the individual implants. In another embodiment, this is real for the mass of the individual implants. In another embodiment, this is true for the SA: V ratio of the individual implants. In another embodiment, this is true for the length of the individual implants. In another embodiment, this is true for the diameter of the individual implants. In another embodiment, this is true for the inherent viscosity of the polymer in the individual implants. Each possibility represents a separate modality of the present invention. As provided in the present invention, it demonstrates that prolonged maintenance of therapeutic drug levels can be achieved with a single polymer system (e.g., a group of homogeneous implants). In addition, the simple polymer implant system in rabbits (Figure 3B) demonstrated that the individual polymers approximate a symmetric pattern of serum concentration. In addition, as illustrated in Figure 3B, the evolution indication line describing the data in relation to a coefficient (R2) of 0.86, exhibited maximum release values in approximately 6 months. In another embodiment, the present invention provides a method for maintaining a therapeutic level of a drug in a subject for a period of at least about 3 months, comprising (1) administering to the subject an initial group of one or more biodegradable implants, in where the initial group consists of one or more biodegradable implants that have (a) a therapeutic drug that is in an amount of 10% -60% by mass, relative to the mass of the implant; and (b) a polymer that is in an amount of 40% -90% by mass, relative to the mass of the implant, the polymer PLA and optionally PGA comprising a molar ratio of PLA: PGA of between 50:50 and 100: 0; and (2) administering to the subject a group of one or more biodegradable maintenance implants near the point of peak release of the initial biodegradable implant group, wherein the group of biodegradable maintenance implants consists of additional individual biodegradable implants in the molar proportion of PLA: PGA to the individual biodegradable implants in the group of initial biodegradable implants. In this method, the individual biodegradable implants of the initial group, if there are more than one in number, do not differ substantially from each other in their molar ratio PLA: PGA, thereby maintaining a therapeutic level of a drug in a subject over a period of time. at least about 3 months. In another embodiment, the present invention provides a method for maintaining a therapeutic level of a drug in a subject for a period of at least about one year, comprising (1) administering to the subject an initial group of one or more biodegradable implants, in where the initial group consists of one or more biodegradable implants that have (a) a therapeutic drug that is in an amount of 10% -60% by mass, relative to the mass of the implant; and (b) a polymer that is in an amount of 40% -90% by mass, relative to the mass of the implant, the polymer PLA and optionally PGA comprising a molar ratio of PLA: PGA of between 50:50 and 100: 0; and (2) administering to the subject a group of one or more biodegradable maintenance implants near the peak release point of the initial biodegradable implant group, wherein the group of biodegradable maintenance implants consists of additional individual biodegradable implants in the molar proportion of PLA: PGA to the individual biodegradable implants in the group of initial biodegradable implants. In this method, the individual biodegradable implants of the initial group, if there are more than one in number, do not differ substantially from each other in their molar ratio PLA: PGA, thereby maintaining a therapeutic level of a drug in a subject for a period of at least about one year. The term "peak release point" refers, in one embodiment, to the point at which the release is maximum. In another embodiment, the term refers to the average point of peak release in human subjects, based on studies prior to implant administration. Each possibility represents another embodiment of the present invention. The term "near" the point of peak release refers, in another embodiment, to administration at 1 week of the peak release point. In another embodiment, the term refers to administration at 10 days of the peak release point. In another embodiment, the term refers to administration at 2 weeks of the peak release point. In another embodiment, the term refers to administration at 3 weeks of the peak release point. In another embodiment, the term refers to administration at 4 weeks of the peak release point. In another embodiment, the term refers to the administration at 5 weeks of the peak release point. In another embodiment, the term refers to the administration at 6 weeks of the peak release point. In another embodiment, the term refers to administration at 2 months of the peak release point.

In another embodiment, the term refers to administration at a point at which the release range is within 10% of the maximum level. In another embodiment, the term refers to the point at which the release range is within 5% of the maximum level. In another embodiment, the term refers to a point at which the release range is within 15% of the maximum level. In another embodiment, the term refers to a point at which the release range is within 20% of the maximum level. In another embodiment, the term refers to a point at which the release range is within 25% of the maximum level. In another embodiment, the term refers to a point at which the release range is within 30% of the maximum level. In another embodiment, the term refers to a point at which the release range is within 35% of the maximum level. In another embodiment, the term refers to a point at which the release range is within 40% of the maximum level. In another embodiment, the term refers to a point at which the release range is within 50% of the maximum level. Each possibility represents another embodiment of the present invention. In another embodiment, the present invention provides a method for maintaining a therapeutic level of a drug in a subject for a prolonged period of time, wherein the method comprises (1) administering to the subject an initial group of one or more biodegradable implants, in where the initial group consists of one or more individual biodegradable implants having (a) a therapeutic drug that is in an amount of 10% -60% by mass, relative to the mass of the implant; and (b) a polymer that is present in an amount of 40% -90% by mass, relative to the mass of the implant, the polymer comprising PLA and optionally PGA in the molar ratio PLA: PGA between 50:50 and 100: 0; and (2) administering to the subject a group of one or more biodegradable holding implants near the peak release point of the initial biodegradable implant group, wherein the group of biodegradable maintenance implants consists of additional individual biodegradable implants equivalent in molar ratio PLA: PGA to the individual biodegradable implants in the group of initial biodegradable implants, thus maintaining a therapeutic level of a drug in a subject for a prolonged period of time. In this method, the individual biodegradable implants of the initial group, if there is more than one, do not differ substantially from one another in their molar ratio PLA: PGA. The term "extended period of time" refers, in another embodiment, to a period of at least about 6 months. In another embodiment, the term refers to a period of at least about 4 months. In another modality, the term refers to a period of at least about 5 months. In another embodiment, the term refers to a period of at least about 7 months. In another embodiment, the term refers to a period of at least about 8 months. In another embodiment, the term refers to a period of at least about 9 months. In another modality, the term refers to a period of at least approximately 10 months. In another modality, the term refers to a period of at least approximately 12 months. In another modality, the term refers to a period of at least approximately 14 months. In another embodiment, the term refers to a period of at least about 16 months. In another embodiment, the term refers to a period of at least about 18 months. In another modality, the term refers to a period of at least approximately 21 months. In another modality, the term refers to a period of at least approximately 24 months. In another modality, the term refers to a period greater than 24 months. Each possibility represents a separate embodiment of the present invention. In another modality, the individual biodegradable implants of the maintenance group, if there is more than one, do not differ substantially from each other in their PLA-PGA molar ratio. In another embodiment, the individual biodegradable implants of the initial group and the maintenance group do not differ substantially from each other, both within and between the groups, in their PLA: PGA molar ratio. Each possibility represents a separate embodiment of the present invention. In another embodiment, step (b) is repeated as necessary to maintain the therapeutic level of the drug during the desired period of time in the subject. In another embodiment, the maintenance group is administered near the beginning of the drug release decline of the previous implant group. In another embodiment, the present invention provides the use of (a) a group of initial biodegradable implants of the present invention.; and (b) a group of biodegradable maintenance implants of the present invention for the preparation of a pharmaceutical composition for maintaining a therapeutic level of a drug in a subject during one of the above time periods. In one modality, the maintenance group is administered approximately once every 6 months. In another modality, the maintenance group is administered for a period of approximately 5 months. In another modality, the maintenance group is administered for a period of approximately 4 months. In another modality, the maintenance group is administered for a period of approximately 3 months. In another modality, the maintenance group is administered for a period of approximately 2 months. In another embodiment, the maintenance group is administered for a period of approximately 6 weeks. In another modality, period is approximately 1 month. In another modality, the period is approximately 7 months. In another modality, the period is approximately 8 months. In another modality, the period is approximately 9 months. In another modality, the period is approximately 10 months. In another modality, the period is approximately 11 months. In another modality, the period is approximately 12 months. In another modality, the period is approximately 14 months. In another modality, the period is approximately 16 months. In another modality, the period is approximately 18 months. In another modality, the period is approximately 20 months. In another modality, the period is approximately 22 months. In another modality, the period is approximately 24 months. In another modality, the period is approximately 30 months. In another modality, the period is approximately 36 months. Each possibility represents a separate embodiment of the present invention. In another embodiment, the individual implants of the maintenance group are equivalent to the individual implants in the initial group in another parameter in addition to their molar ratio PLA: PGA, for example, their drug loading, mass, SA: V ratio, length , diameter or inherent viscosity of the polymer. In another embodiment, the individual implants of the maintenance group are equivalent to the individual implants in the initial group in one of these parameters instead of their molar ratio PLA: PGA. In another embodiment, the individual implants of the maintenance group are equivalent to the individual implants in the initial group in their PLA: PGA ratio, but not in the other parameters. In another embodiment, the individual implants of the maintenance group are equivalent to the individual implants in the initial group in two of these other parameters in addition to their PLA: PGA ratio. In another embodiment, the individual implants of the maintenance group are equivalent to the individual implants in the initial group in three of these other parameters in addition to their PLA: PGA ratio. In another embodiment, the individual implants of the maintenance group are equivalent to the individual implants in the initial group in four of these other parameters in addition to their PLA: PGA ratio. In another embodiment, the individual implants of the maintenance group are equivalent to the individual implants in the initial group in five of these other parameters in addition to their PLA: PGA ratio. In another embodiment, the individual implants of the maintenance group are equivalent to the individual implants in the initial group in all these other parameters in addition to their PLA: PGA ratio. In another embodiment, the individual implants in the maintenance group are equivalent to the individual implants in the initial group of two of these other parameters, but not their PLA: PGA ratio. In another modality, the individual implants of the maintenance group are equivalent to the individual implants in the initial group of three of these other parameters, but not its PLA: PGA ratio. In another embodiment, the individual implants in the maintenance group are equivalent to the individual implants in the initial group of four of these other parameters, but not their PLA: PGA ratio. In another embodiment, the individual implants of the maintenance group are equivalent to the individual implants in the initial group of five of these other parameters, but not their PLA: PGA ratio. Each possibility represents a separate embodiment of the present invention. In other embodiments, the individual implants of the maintenance group have any of the characteristics described above for the individual implants of the initial group. Each feature represents a separate embodiment of the present invention. The nearly symmetric nature of the release profile of the polymer groups alone, as demonstrated in the present invention, provides the possibility of using overlapping implants approximately every 6 months to sustain the drug administration indefinitely (Figure 13). In one modality, this method compensates for the constant decline of a group of implants with the gradual generation of a subsequent group. In another embodiment, the period of time through which the therapeutic level of a drug is maintained through the methods of the present invention is one month. In another modality, the period is 1.5 months. In another modality, the period is 2 months. In another modality, the period is 2.5 months. In another modality, the period is 3 months. In another modality, the period is 3.5 months. In another modality, the period is 4 months. In another modality, the period is 5 months. In another modality, the period is 6 months. In another modality, the period is 7 months. In another modality, the period is 8 months. In another modality, the period is 9 months. In another modality, the period is 10 months. In another modality, the period is 11 months. In another modality, the period is 12 months. In another modality, the period is 13 months. In another modality, the period is 14 months. In another modality, the period is 15 months. In another modality, the period is 16 months. In another modality, the period is 17 months. In another modality, the period is 18 months. In another modality, the period begins 1 month after the step of administering the initial group of biodegradable implants. In another modality, the period begins 1 week after the initial administration. In another modality, the period begins 2 weeks after the initial administration. In another modality, the period begins 3 weeks after the initial administration. In another modality, the period begins 5 weeks after the initial administration. In another modality, the period begins 6 weeks after the initial administration. In another modality, the period begins 2 months after the initial administration. In another modality, the period begins 2.5 months after the initial administration. In another modality, the period begins 3 months after the initial administration. Each of the preceding periods represents a separate embodiment of the present invention. In another embodiment, a method of the present invention further comprises administering to the subject a group of one or more different biodegradable starter implants, wherein the starter group implants differ from the implants of the original implant group in the PLA: PGA ratio. , and whereby the implants of the starting group achieve steady state levels of drug release faster than the initial group of implants. In another embodiment, the initial group implants differ from the implants of the original group of implants in their drug loading. In another embodiment, the implants of the starting group differ from the implants of the original group in the SA: V ratio. In another modality, the initial implants group differs from the original group of implants in its mass. In another modality, the initial implants group differs from its original implant group in its length. In another modality, the initial implant group differs from its original implant group in diameter. In another embodiment, the initial implant group differs from its original implant group in the inherent viscosity of its polymer. In another modality, the implants of the initial group differ from the original group of implants in 2 of these characteristics. In another modality, the implants of the initial group differ from the original group of implants in 3 of these characteristics. In another modality, the implants of the initial group differ from the original group of implants in 4 of these characteristics. In another modality, the implants of the initial group differ from the original group of implants in all of these characteristics. Each possibility represents a separate embodiment of the present invention. In another embodiment, the start group implants do not substantially differ from each other in their PLA: PGA, drug load, length, diameter, SA: V ratio and inherent viscosity. In another embodiment, the group of initial implants differ substantially among themselves in one of these parameters. In another embodiment, the group of initial implants differs substantially from each other in more than one of these parameters. In another embodiment, the initial implant group has different release profiles from one another. Each possibility represents a separate modality of the present invention. In other embodiments, the initial implant group has any of the features described above of the individual implants of the initial group. Each feature represents a separate embodiment of the present invention. In another embodiment, in methods of the present invention comprising an initial set of implants and a set of equivalent maintenance implants, the initial set of implants is administered together with the set of starting implants. The term "together with" in one modality refers to administration on the same day as the other group of one or more implants. In another embodiment, the term "together with" refers to administration during a single operation or procedure. In another embodiment, the term refers to the administration one day after the other group of implants. In another modality, the term refers to the administration at 2 days of the other group of implants. In another modality, the term refers to the administration at 3 days of the other group of implants. In another modality, the term refers to the administration at 4 days of the other group of implants. In another modality, the term refers to the one-week administration of the other group of implants. In another embodiment, the term refers to the administration at 2 weeks of the other group of implants. In another embodiment, the term refers to the administration at 3 weeks of the other group of implants. In another modality, the term refers to the one-month administration of the other group of implants. In another modality, the term refers to the administration at 2 months of the other group of implants. Each possibility represents a separate embodiment of the present invention. In another embodiment, the initial implant group allows for an earlier achievement of therapeutic drug levels, as provided in the present invention (Example 16). In another modality, the number of implants required in the initial group of implants is reduced (in relation to the maintenance of the implant group) due to the presence of the initial implant group, since the initial implant group contributes to the Drug levels are not present at the time of administration of the maintenance implant group. The ability of the starting groups to allow faster release was demonstrated in the present invention by comparing the release profiles of the single polymer design with the multiple polymer design. Higher serum levels were observed at earlier time points with the multiple polymer design (Figures 1 and 3A). In another modality, instead of administering a group of initial implants with an initial implant, the number of implants increases (in relation to the group of maintenance implants) to achieve therapeutic levels more quickly.

In another embodiment, the step of administering the initial implant group is reversible. In another embodiment, the step of administering the group of starter implants is reversible. The term "reversible", in one embodiment, refers to the ability to remove the group remains of implants by surgery or other means. In one embodiment, the term "reversible" refers to the ability to remove the remains of one or more of the implants. In another embodiment, the term "reversible" refers to the ability to remove most of the remains of the group of implants. In another embodiment, the term "reversible" refers to the ability to remove most of the remains of one or more of the implants. Each possibility represents a separate embodiment of the present invention. In one embodiment, the subject of the methods of the present invention is a human. In another modality, the subject is a primate. In another embodiment, the subject is a mammal. In another modality, the subject is a rodent. In another modality, the subject is a laboratory animal. In another modality, the subject is a domestic animal. In another modality, the subject is a man. In another modality, the subject is a woman. In another embodiment, the subject is any other type of subject known in the art. Each possibility represents a separate embodiment of the present invention. In other embodiments, the individual implants of any of the groups described above have any of the lengths of an implant of the present invention. In other embodiments, the individual implants have a combined length equal to any of the lengths of an implant of the present invention. In another embodiment, the step of administering the individual implants of any of the foregoing groups is reversible. In another modality, the step of administering any of the above groups is reversible. In one embodiment, the term "reversible" refers to one of the meanings given above. Each possibility represents a separate embodiment of the present invention. In other embodiments, the individual implants of any of the foregoing groups have any of the diameters of an implant of the present invention. In other embodiments, the individual implants have a combined length equal to any of the diameters of an implant of the present invention. In other embodiments, the individual implants of any of the above groups have any of the SA: V ratios of an implant of the present invention. In other embodiments, the individual implants have a combined length equal to any of the SA: V ratios of an implant of the present invention. In other embodiments, the individual implants of any of the foregoing groups have any of the masses of an implant of the present invention. In other embodiments, the individual implants have a combined length equal to any of the masses of an implant of the present invention. In another embodiment, the individual implants of any of the above groups are combined into a single structure (e.g., rod-shaped structure, bundle, etc.). In another embodiment, the structure has any of the lengths of an implant of the present invention. In another embodiment, the structure has any of the diameters of an implant of the present invention. In another embodiment, the structure has any of the SA: V ratios of an implant of the present invention. In another embodiment, the structure has any of the masses of an implant of the present invention. In another modality, the structure allows the reduction of the number of implanted structures. Each possibility represents a separate embodiment of the present invention. In other embodiments, the individual biodegradable implants of any of the groups described aboveyear. , have any of the characteristics of an implant of the present invention. Each feature represents a separate embodiment of the present invention. In her embodiment, a method of the present invention further comprises administration of the therapeutic drug through a different route, together with the initial administration of implants, in order to achieve and maintain therapeutic drug levels until the range of release of the implants. In her embodiment, a different drug with a similar therapeutic effect is administered with the initial group of implants. Any administration route known in the art can be used. Each route represents a separate mode of the present invention. In her embodiment, the present invention provides a method for delivering a therapeutic drug in a substantially linear range over a period of several months in the body tissue of a subject, wherein the method comprises administering to the subject an implant or group of implants of the present invention, thereby releasing a therapeutic drug in a substantially linear range over a period of several months in a body tissue of a subject. In her embodiment, the present invention provides a method for releasing thiothixene in a substantially linear range over a period of several months in the body tissue of a subject, wherein the method comprises administering to the subject a thiothixene containing an implant of the present invention. Nvention, thus releasing thiothixene in a substantially linear range over a period of several months. In her embodiment, the present invention provides a method for releasing haloperidol in a substantially linear range over a period of several months in the body tissue of a subject, wherein the method comprises administering to the subject a haloperidol-containing implant of the present invention. , thus releasing haloperidol in a substantially linear range over a period of several months. In her embodiment, the present invention provides a method for delivering HCTZ in a substantially linear range over a period of several months in the body tissue of a subject, wherein the method comprises administering to the subject an implant containing HCTZ of the present invention. Nvention, thereby releasing HCTZ in a substantially linear range over a period of several months. In her embodiment, the present invention provides a method for releasing ibuprofen in a substantially linear range over a period of several months in the body tissue of a subject, wherein the method comprises administering to the subject an implant containing buprophen of the present invention. invention, thereby releasing buprofen in a substantially linear range over a period of several months. In her embodiment, the present invention provides a method for delivering aspirin in a substantially linear range over a period of several months in the body tissue of a subject, wherein the method comprises administering to the subject an implant containing aspirin of the present! nvention, thus releasing aspirin in a substantially linear range over a period of several months. In her embodiment, the present invention provides a method for delivering corticosterone in a substantially linear range over a period of several months in the body tissue of a subject, wherein the method comprises administering to the subject an implant containing corticosterone of the present invention, thus releasing corticosterone in a substantially linear range over a period of several months. The term "several months" refers, in various embodiments, to any period of time of the present invention. Each period of time represents a separate embodiment of the present invention. In her embodiment, the present invention provides a method for delivering a therapeutic drug in a substantially linear range over a period of several weeks in the body tissue of a subject., wherein the method comprises administering to the subject an implant or groups of implants of the present invention, thereby releasing a therapeutic drug in a substantially liberal range over a period of several weeks in the body tissue of a subject. The therapeutic drug is, in various embodiments, any therapeutic drug of the present invention. Each drug represents a separate embodiment of the present invention. In one embodiment, the substantially linear range of the methods and compositions of the present invention is the range of release of the implant during the constant state release phase. The term "constant state" in one embodiment refers to the period of time during which an implant exhibits a substantially linear release range, as exemplified in the present invention in example 10. In one embodiment, the substantially linear range It is 0. 1 mg / day. In another modality, the range is 0.2 mg / day. In another modality, the range is 0.3 mg / day. In another modality, the range is 0.4 mg / day. In another modality, the range is 0.5 mg / day. In another modality, the range is 0.6 mg / day. In another modality, the range is 0.8 mg / day. In another modality, the range is 1 mg / day. In another modality, the range is 1.2 mg / day. In another modality, the range is 1.5 mg / day. In another modality, the range is 1.8 mg / day. In another modality, the range is 2.0 mg / day. In another modality, the range is 2.5 mg / day. In another modality, the range is 3 mg / day. In another modality, the range is 3.5 mg / day. In another modality, the range is 4 mg / day. In another modality, the range is 5 mg / day. In another modality, the range is 6 mg / day. In another modality, the range is 7 mg / day. In another modality, the range is 8 mg / day. In another modality, the range is 10 mg / day.

Each range represents a separate embodiment of the present invention. In another modality, the range is between approximately 0.1-0.3 mg / day. In another modality, the range is 0.2-0.4 mg / day. In another modality, the range is 0.3-0.5 mg / day. In another modality, the range is 0.4-0.6 mg / day. In another modality, the range is 0.5-0.7 mg / day. In another modality, the range is 0.6-0.8 mg / day. In another modality, the range is 0.7-0.9 mg / day. In another modality, the range is 0.8-1.0 mg / day. In another modality, the range is 0.1-0.4 mg / day. In another modality, the range is 0.2-0.5 mg / day. In another modality, the range is 0.3-0.6 mg / day. In another modality, the range is 0.4-0.7 mg / day. In another modality, the range is 0.5-0.8 mg / day. In another modality, the range is 0.6-0.9 mg / day. In another modality, the range is 0.8-1.1 mg / day. In another modality, the range is 1.0-1.3 mg / day. In another modality, the range is 1.5-1.8 mg / day. In another modality, the range is 0.1-0.5 mg / day. In another modality, the range is 0.2-0.6 mg / day. In another modality, the range is 0.3-0.7 mg / day. In another modality, the range is 0.4-0.8 mg / day. In another modality, the range is 0.5-0.9 mg / day. In another modality, the range is 0.6-1.0 mg / day. In another modality, the range is 0.8-1.2 mg / day. In another modality, the range is 1.0-1.4 mg / day. In another modality, the range is 1.5-1.9 mg / day. In another modality, the range is 2-2.4 mg / day. In another modality, the range is 0.1-0.6 mg / day. In another modality, the range is 0.2-0.7 mg / day. In another modality, the range is 0.3-0.8 mg / day. In another modality, the range is 0.5-1.0 mg / day. In another modality, the range is 0.6-1.1 mg / day. In another modality, the range is 0.8-1.3 mg / day. In another modality, the range is 1.0-1.5 mg / day. In another modality, the range is 1.5-2 mg / day. In another modality, the range is 2-2.5 mg / day. In another modality, the range is 2.5-3 mg / day. In another modality, the range is 3-3.5 mg / day. In another modality, the range is 3.5-4 mg / day. In another modality, the range is 4-4.5 mg / day. In another modality, the range is 0.3-1.3 mg / day. In another modality, the range is 0.5-1.5 mg / day. In another modality, the range is 0.8-1.8 mg / day. In another modality, the range is 1.0-2 mg / day. In another modality, the range is 1.5-2.5 mg / day. In another modality, the range is 2-3 mg / day. In another modality, the range is 2.5-3.5 mg / day. In another modality, the range is 3-4 mg / day. In another modality, the range is 3.5-4.5 mg / day. In another modality, the range is 4-5 mg / day. In another modality, the range is 0.5-2 mg / day. In another modality, the range is 1.0-2.5 mg / day. In another modality, the range is 1.5-3 mg / day. In another modality, the range is 2-3.5 mg / day. In another modality, the range is 2.5-4 mg / day. In another modality, the range is 3-4.5 mg / day. In another modality, the range is 3.5-5 mg / day. In another modality, the range is 0.5-2.5 mg / day. In another modality, the range is 1-3 mg / day. In another modality, the range is 1.5-3.5 mg / day. In another modality, the range is 2-4 mg / day. In another modality, the range is 2.5-4.5 mg / day. In another modality, the range is 3-5 mg / day. In another modality, the range is 1-4 mg / day. In another modality, the range is 1.5-4.5 mg / day. In another modality, the range is 2-5 mg / day. In another modality, the range is 3-6 mg / day. Each of the above ranges represents a separate embodiment of the present invention. In another embodiment, the present invention provides a method for releasing risperidone in a substantially linear range for a period of at least 1 month in the body tissue of a subject, wherein the method comprises administering to the subject an implant containing risperidone or a group of implants of the present invention, thereby releasing risperidone in a substantially linear range for a period of at least 1 month in the body tissue of a subject. In another embodiment, the present invention provides a method for releasing risperidone in a substantially linear range over a period of at least 2 months in the body tissue of a subject, wherein the method comprises administering to the subject an implant containing risperidone or a group of implants of the present invention, thereby releasing risperidone in a substantially linear range over a period of at least 2 months in the body tissue of a subject. In another embodiment, the present invention provides a method for releasing risperidone in a substantially linear range over a period of at least 3 months in the body tissue of a subject, wherein the method comprises administering to the subject an implant containing risperidone or a group of implants of the present invention, thereby releasing risperidone in a substantially linear range over a period of at least 3 months in the body tissue of a subject. In another embodiment, the present invention provides a method for releasing risperidone in a substantially linear range over a period of at least 4 months in the body tissue of a subject, wherein the method comprises administering to the subject an implant containing risperidone or a group of implants of the present invention, thereby releasing risperidone in a substantially linear range over a period of at least 4 months in the body tissue of a subject. In another embodiment, the present invention provides a method for releasing risperidone in a substantially linear range over a period of at least 5 months in the body tissue of a subject, wherein the method comprises administering to the subject an implant containing risperidone or a group of implants of the present invention, thereby releasing risperidone in a substantially linear range for a period of at least 5 months in the body tissue of a subject. In another embodiment, the present invention provides a method for releasing risperidone in a substantially linear range over a period of at least 6 months in the body tissue of a subject, wherein the method comprises administering to the subject an implant containing risperidone or a group of implants of the present invention, thereby releasing risperidone in a substantially linear range over a period of at least 6 months in the body tissue of a subject. In another embodiment, the present invention provides a method for releasing risperidone in a substantially linear range for a period of at least 7 months in the body tissue of a subject, wherein the method comprises administering to the subject an implant containing risperidone or a group of implants of the present invention, thereby releasing risperidone in a substantially linear range for a period of at least 7 months in the body tissue of a subject. In another embodiment, the present invention provides a method for releasing risperidone in a substantially linear range over a period of at least 8 months in the body tissue of a subject, wherein the method comprises administering to the subject an implant containing risperidone or a group of implants of the present invention, thereby releasing risperidone in a substantially linear range for a period of at least 8 months in the body tissue of a subject. In another embodiment, the present invention provides a method for releasing risperidone in a substantially linear range over a period of at least 9 months in the body tissue of a subject, wherein the method comprises administering to the subject an implant containing risperidone or a group of implants of the present invention, thereby releasing risperidone in a substantially linear range over a period of at least 9 months in the body tissue of a subject. In another embodiment, the present invention provides a method for releasing risperidone in a substantially linear range over a period of at least 10 months in the body tissue of a subject, wherein the method comprises administering to the subject an implant containing risperidone or a group of implants of the present invention, thus releasing risperidone in a substantially linear range over a period of at least 10 months in the body tissue of a subject. In another embodiment, the present invention provides a method for releasing risperidone in a substantially linear range over a period of at least 11 months in the body tissue of a subject, wherein the method comprises administering to the subject an implant containing risperidone or a group of implants of the present invention, thereby releasing risperidone in a substantially linear range for a period of at least 11 months in the body tissue of a subject. In another embodiment, the present invention provides a method for releasing risperidone in a substantially linear range over a period of at least 12 months in the body tissue of a subject, wherein the method comprises administering to the subject an implant containing risperidone or a group of implants of the present invention, thereby releasing risperidone in a substantially linear range over a period of at least 12 months in the body tissue of a subject. In another embodiment, the present invention provides a method for releasing risperidone in a substantially linear range over a period of at least 14 months in the body tissue of a subject, wherein the method comprises administering to the subject an implant containing risperidone or a group of implants of the present invention, thereby releasing risperidone in a substantially linear range over a period of at least 14 months in the body tissue of a subject. In another embodiment, the present invention provides a method for releasing risperidone in a substantially linear range over a period of at least 16 months in the body tissue of a subject, wherein the method comprises administering to the subject an implant containing risperidone or a group of implants of the present invention, thereby releasing risperidone in a substantially linear range over a period of at least 16 months in the body tissue of a subject. In another embodiment, the present invention provides a method for releasing risperidone in a substantially linear range over a period of at least 18 months in the body tissue of a subject, wherein the method comprises administering to the subject an implant containing risperidone or a group of implants of the present invention, thereby releasing risperidone in a substantially linear range over a period of at least 18 months in the body tissue of a subject. In another embodiment, the present invention provides a method for treating schizophrenia in a human, wherein the method comprises administering in human an implant or group of implants of the present invention, to thereby treat schizophrenia in a human. In another modality, schizophrenia is catatonic schizophrenia. In another modality, schizophrenia is paranoid schizophrenia. In another modality, schizophrenia is disorganized schizophrenia. In another modality, schizophrenia is undifferentiated schizophrenia. In another modality, schizophrenia is residual schizophrenia. In another modality, schizophrenia is negative or deficit schizophrenia. In another modality, schizophrenia is a psychosis. In another embodiment, schizophrenia is any other type of schizophrenia known in the art. Each possibility represents a separate embodiment of the present invention. As provided, the methods of the present invention are effective in the prolonged administration of risperidone and in the treatment of schizophrenia (Examples 8-9). The serum concentration of risperidone in vivo was within the target range of 2-15 ng / ml (Foster RH and Goa KL (1998) Pharmacoeconomics 14: 97-133) for a substantial part of the release interval (Figures 1 and 3) . In another embodiment, the present invention provides a method for treating a bipolar disorder in a human, wherein the method comprises administering to the human an implant or group of implants of the present invention, thereby treating a bipolar disorder in a human. In another embodiment, the present invention provides a method for treating dementia in a human, wherein the method comprises administering to the human an implant or group of implants of the present invention, thereby treating dementia in a human. In another embodiment, the present invention provides a method for treating delirium in a human, wherein the method comprises administering to the human an implant or group of implants of the present invention, thereby treating delirium in a human. In another embodiment, the present invention provides a method for treating agitation in a human, wherein the method comprises administering to the human an implant or group of implants of the present invention, thereby treating agitation in a human. In another embodiment, the present invention provides a method for treating pulse control disorder in a human, wherein the method comprises administering to the human an implant or group of implants of the present invention, thereby treating pulse control disorder in a human. In another embodiment, the present invention provides a method for treating psychotic depression in a human, wherein the method comprises administering to the human an implant or group of implants of the present invention, thereby treating psychotic depression in a human. In another embodiment, the present invention provides a method for treating schizophrenia in a human, wherein the method comprises carrying out one of the above methods for maintaining a therapeutic level of a drug in a subject, to thereby treat schizophrenia in a human. In another embodiment, the present invention provides a method for bipolar disorder in a human, wherein the method comprises carrying out one of the above methods for maintaining a therapeutic level of a drug in a subject, to thereby treat bipolar disorder in a human. In another embodiment, the present invention provides a method for dementia in a human, wherein the method comprises carrying out one of the above methods for maintaining a therapeutic level of a drug in a subject, to thereby treat dementia in a human . In another embodiment, the present invention provides a method for delirium in a human, wherein the method comprises carrying out one of the above methods for maintaining a therapeutic level of a drug in a subject, to thereby treat delirium in a human . In another embodiment, the present invention provides a method for agitation in a human, wherein the method comprises carrying out one of the above methods for maintaining a therapeutic level of a drug in a subject, to thereby treat agitation in a human . In another embodiment, the present invention provides a method for pulse control disorder in a human, wherein the method comprises carrying out one of the above methods for maintaining a therapeutic level of a drug in a subject., to deal with this form of impulse control disorder in a human. In another embodiment, the present invention provides a method for psychotic depression in a human, wherein the method comprises carrying out one of the above methods for maintaining a therapeutic level of a drug in a subject, to thereby treat psychotic depression in a human. In another embodiment, the present invention provides the use of an implant or group of implants of the present invention for the preparation of a pharmaceutical composition for treating schizophrenia. In another embodiment, the present invention provides a composition comprising an implant or group of implants of the present invention for the treatment of schizophrenia. In another embodiment, the present invention provides the use of an implant or group of implants of the present invention for the preparation of a pharmaceutical composition for treating bipolar disorder. In another embodiment, the present invention provides a composition comprising an implant or group of implants of the present invention for the treatment of bipolar disorder. In another embodiment, the present invention provides the use of an implant or group of implants of the present invention for the preparation of a pharmaceutical composition for treating dementia. In another embodiment, the present invention provides a composition comprising an implant or group of implants of the present invention for the treatment of dementia. In another embodiment, the present invention provides the use of an implant or group of implants of the present invention for the preparation of a pharmaceutical composition for treating delirium. In another embodiment, the present invention provides a composition comprising an implant or group of implants of the present invention for the treatment of delirium. In another embodiment, the present invention provides the use of an implant or group of implants of the present invention for the preparation of a pharmaceutical composition for treating agitation. In another embodiment, the present invention provides a composition comprising an implant or group of implants of the present invention for the agitation treatment. In another embodiment, the present invention provides the use of an implant or group of implants of the present invention for the preparation of a pharmaceutical composition for treating impulse control disorder. In another embodiment, the present invention provides a composition comprising an implant or group of implants of the present invention for the treatment of impulse control disorder. In another embodiment, the present invention provides the use of an implant or group of implants of the present invention for the preparation of a pharmaceutical composition for treating psychotic depression. In another embodiment, the present invention provides a composition comprising an implant or group of implants of the present invention for the treatment of psychotic depression. The treatment period of any of the foregoing diseases provided by a method of the present invention can be any of the time periods of the present invention. Each period represents a separate embodiment of the present invention. The term "treat", in one modality, refers to therapeutic intervention, in another modality, the term refers to prophylactic intervention. In another embodiment, the term refers to a decrease in symptoms of a disease or disorder. In another embodiment, the term refers to a decrease in symptoms, disease or disease secondary to the disorder or condition being treated. In another embodiment, the term "treatment" refers to slowing down the progress of a disease Each possibility represents a separate embodiment of the present invention The methods for diagnosing and assessing the severity of the above disorders are well known in the art., and are described, for example, in the publication of Diagnostic and Statistical Manual of Mental Disorders (DSM), published by the American Psychiatric Association, Washington D.C. Each method represents a separate embodiment of the present invention. In another modality, the schizophrenia of another of the above disorders is diagnosed through the method described above in the description of the methods to evaluate the efficacy of risperidone therapy. Methods for evaluating the efficacy of risperidone therapy in human animals are well known in the art. The efficacy of risperidone therapy in animals can be assessed, for example, through evaluations of PPI locomotor activity (described below), rotary bar (rotarod), and catalepsy. The locomotor activity, in one modality, is measured in a monitoring system of activity in "domestic cage" (MedAssociates, St. Albans, VT). This system allows a clean, standard household cage to be placed in a photoraise structure with two levels of sensors fitted on an 8-ray forming strip with a separation of 3.175 cm (1.25 inches). A computer detection system monitors the interruptions of the lightning rods for the ambulation parameter. The total ambulations are determined by the number of photoraise interruptions that the animals make while they are moving around the cage. The data is recorded in software designed on Med Associates personal computer and monitored, for example, at 5 minute intervals for a total of 30 minutes per activity monitoring session. The rats usually received several days of habituation to the apparatus and tasks before their first exposure to amphetamine. In another modality, rotarod is used to evaluate the efficacy of risperidone therapy. In one embodiment, the mill wheel apparatus of the rotary bar (rotarod) of acceleration (Stoelting Co., Wood Dale, IL) is used to determine the motor function. The rats are placed on the stationary bar in order to acclimate to the apparatus. The speed is then adjusted to gradually increase from 2 to 20 rpm. The maximum classification is set to maintain balance and posture (5 minutes; Lelas S, Wong H and associates, J Pharmacol Exp Ther 309: 293-302, 2004). The development of tests ends after the period or when the animal falls off the bar. In another modality, catalepsy radiation is used to evaluate the efficacy of risperidone therapy. Catalepsy is tested in animals (eg rats) to evaluate the motor effects of risperidone implants. Rats are placed with their front legs against a part of the cage, and the amount of time required to restore a normal posture is recorded. The increased latency to return to the normal position with the four legs in the bottom part of the cage is interpreted as an indication of motor damage secondary to risperidone. In another modality, the acoustic response to scares is used to evaluate the efficacy of risperidone therapy. The acoustic response to scares is a reflexive, quantifiable movement after an acoustic stimulus with high volume. The inhibition of previous pulse (PPI) occurs when the response to shock is reduced due to the previous presentation of a less intense sensory stimulus (Hoffman HS, Searle JL (1965) J Comp Physiol Psychol 60: 53-58). PPI can be attenuated by the administration of dopamine agonists (DA), such as apomorphine (APO) and amphetamine (AMPH), and this effect is reversed by dopamine receptor antagonists such as haloperidol and risperidone (Mansbach RS, Geyer MA (1989 Neuropsychopharmacol 2: 299-308, Swerdlow NR and associates, (1991) J Pharmacol Exp Ther 256: 530-536, Swerdlow NR and associates, Neuropsychopharmacol 18: 50-56). Therefore, the attenuation of PPI by DA receptor agonists is an effective animal model for the deficits in sensory-activation processes observed in schizophrenia (Braff DL, Geyer MA (1990) Arch Gen Psychiatry 47: 181-188). Methods for aggravating auditory evoked potentials are known in the art. In one modality, the recording of auditory evoked potentials is achieved by stereotaxic implantation of tripolar electrode assemblies. In another modality, these assemblies are used for the recording without anesthesia of auditory evoked potentials. These methods are well known in the art and are described, for example, in the publication of (Connolly and associates, 2003; Connolly and associates, 2004; Maxwell and associates, 2004; Siegel and associates, 2005). A method of further evaluation of the efficacy of risperidone in animals is behavioral observations, which are known in the art and are described, for example, in the publication by Elmer Gl, Brockington A and associates (Cocaine cross-sensitization to dopamine uptake inhibitors: unique effects of GBR12909, Pharmacol Biochem Behav 53: 911-918, 1996). For example, the following behaviors are observed and classified with respect to their presence or absence during intervals of every 5 minutes: calm, sniffing; licked bites cleanliness; locomotion (the four legs in movement); lifting (both front legs outside the floor of the cage); head down (posture, walk or run of the animal with its nose below the horizontal line for more than 5 minutes); wobbling (rhythmic wobbles in movements of the animal's body head for more than 3 seconds); rodeos (walking or running in continuous circles for more than 5 seconds). In another embodiment, the efficacy of risperidone therapy is assessed by quantification of dopamine D2 receptor and / or serotonin 5HT1A / 2A / 2C expression in brain samples (e.g., cortex, hippocampus, stratum and / or cerebellum). Risperidone increases the expression of the dopamine receptor and decreases the expression of the serotonin receptor 5HT1A / 2A / 2C-The Western blots of the serotonin receptor can use polyclonal antibodies AB5406 (Chemicon, Temecula, CA), PC176L (Calbiochem, CA), or AB5655 (Chemicon). Western blots of the error receptor can use the polyclonal antibody WR-3526, (Research and Diagnostic Antibodies, Berkeley, CA). Each possibility represents a separate embodiment of the present invention. Methods to assess the efficacy of risperidone therapy in humans are described, for example, in the Heresco-Levy U and associates publication (Biol Psychiatry 2005 57 (6): 577-85), Moller HJ and associates (Int Clin Psychopharmacol 2005 20 (3): 121-30); and HirschfeldRM and associates (Am J Psychiatry, 2004 161 (6): 1057-65). In another modality, the efficacy of risperidone therapy in humans evaluated the severity of the disorder for which risperidone was described, using DSM-IV. Each of the above methods for evaluating the efficacy of risperidone therapy in animals can be used for humans and vice versa.

Each of the above methods for evaluating the efficacy of risperidone represents a separate embodiment of the present invention. In another embodiment, the present invention provides an implant having a drug loading of a therapeutic drug between 20-30% by mass, inclusive, and between 70% -80% by mass, inclusive of a polymer, the polymer comprising PLA and optionally PGA in a PLA: PGA ratio of between 80:20 and 100: 0 per mass, inclusive, the implant having a radius of R0 according to the equation: where: 2"erf (x)" refers to ^ i or ßdí; dMd / dt is the desired constant state release rate of the therapeutic drug at time t, D is the water diffusion coefficient in the matrix, k is the reaction range and Cw is the concentration of water in the implant in the time t; ^ = DV2c -Ice where k is determined by the formula: Q1- W W where S is the solubility of the therapeutic drug in water; and where k is a constant between approximately 0.05-0.33.

In one embodiment, the therapeutic drug contained in the previous implant is risperidone. In another embodiment, the therapeutic drug is haloperidol, in which case D is 1.7 x 10? -10 and k is 0.07 (Example 10). In another embodiment, the therapeutic drug is thiothixene, in which case D is 9 x 10? -10, and k is 0.06. In another embodiment, the therapeutic drug is HCTZ, in which case D is 2.1 x 10? -6 and k is 0.26. In another embodiment, the therapeutic drug is cortisone, in which case D is 2.5 x 10? -7, and k is 0.33. In another embodiment, the therapeutic drug is ibuprofen, in which case D is 7.0 x 10? -6, and k is 0.16. In another modality, the therapeutic drug is aspirin, in which case D is 8.0 x 10? -2, and k is 0.06. In another embodiment, it is any other therapeutic drug known in the art. Each possibility represents a separate embodiment of the present invention. In another embodiment, k, the degradation reaction range coefficient depends on the properties of the drug as provided by a combination of drug solubility and the presence of OH groups (Example 11). For drugs with the same solubility in water, the range of polymer hydrolysis increases with the density of OH groups, while for drugs with the same OH group, the density k decreases with solubility. In another embodiment, k is determined empirically, as described in Example 10. In another embodiment, the presence of drug affects the range of polymer degradation. In one embodiment, the drug affects the degradation range of the polymer by affecting the diffusion of water in the polymer matrix. In another embodiment, the drug affects the range of polymer degradation affecting the range of the degradation reaction. In another embodiment, the drug affects the range of polymer degradation through a combination of the above mechanisms. Each possibility represents a separate embodiment of the present invention. In another embodiment, the present invention provides a method for designing an implant for administering a target range of therapeutic drug release, using an equation of the present invention (e.g. equation 4, 5a or 5b). In another embodiment, the present invention provides a method for designing an implant to achieve a target range serum concentration of a therapeutic drug, using an equation of the present invention (e.g., Eq. 8, 9 or 10, Example 12). In another embodiment, the present invention provides a method for achieving a drug release range dMd / dt at time t, wherein the method comprises administering an implant whose radius has been determined using an equation of the present invention (e.g. 4, 5a or d). In another embodiment, the present invention provides a method for achieving a concentration of serum x at time t, wherein the method comprises administering an implant whose radius has been determined using an equation of the present invention (e.g., 9 or 10). Any of the methods of the present invention can utilize any of the implants thereof. Each combination of a method of the present invention with an implant of the present invention, represents a separate embodiment of the present invention. In another embodiment, the present invention provides a kit comprising a reagent used in carrying out a method of the present invention. In another embodiment, the present invention provides an equipment comprising an implant of the present invention. Experimental details section Example 1: Prolonged haloperidol release of PLGA implants in monkeys Materials and experimental methods Subjects Two monkeys (Macaca fascicularis, Ranges Research Facility) were used, each of which received 6 implants containing PLGA copolymer (poly (d) acid). , l-lactic-g I colic)). For the experimental monkey, the implants contained 40% haloperidol per mass, the others consisting of 60% of one of the PLGA polymers illustrated in Table 2 below. The implants administered to the control monkey contained 100% of the PLGA copolymers illustrated in Table 2. The PLGA polymers were provided by Medisorb® AIkermes, (Cincinnati, OH). The dosage of haloperidol averaged 1 mg / kg / day for 12 months to achieve a serum concentration of 2-10 ng / ml. Table 2. Molar proportions of polylactic acid: polyglycolic acid (PLA: PGA) and inherent viscosities of the PLGA polymers in the implants used in the primate experiment. The bound inherent viscosities are expressed in units of dl / g in chloroform, and are measured at a temperature of 30 ° C, 0.5 dl / g using a Cannon-Fenske glass capillarity viscometer size.

Implant number PLA molar ratio: PGA Inherent viscosity (IV) 1 75:25 0.66-0.80 2 85:15 0.66-0.80 3 90:10 High level (0.87) 4 90:10 Low level (0.68) 5 95: 5 0.66-0.80 6 100: 0 0.66-0.80 Implant Fabrication Polymers and haloperidol (Sigma, St. Louis, MO) were mixed in proportions of 60/40 by mass and the solvent was melted from acetone (Fisher Scientific, Pittsburgh, PA). The resulting film was compression molded for disc-shaped implants with 20 mm diameter with an average thickness of 1.22 ± 0.0 mm, mass 493 ± 2 mg and density of 1.28 ± 0.0 g / cc.

Pharmacokinetic determination: Blood was drawn twice a month. The blood was centrifuged and frozen with serum at a temperature of -80 ° C until analysis. Risperidone concentrations of serum and risperidone of 9-OH were determined in duplicate at each time point for each animal. The specimens were separated by centrifugation and the haloperidol levels were assayed by high pressure liquid chromatography (HPLC) with ultraviolet (UV) detection (Figure 1). Trials of the control animals produced zero drug levels. Results Throughout the examples, the implants were well tolerated, and no adverse skin reactions were expected. As illustrated in FIG. 1, the release of haloperidol was measured for a total of 443 days. The average serum concentration was 10.5 ± 1.5 ng / ml during the first 224 days, with the exception of one value (27.1 ng / ml on day 40). During the subsequent 176 days, serum haloperidol levels were maintained at a lower average concentration 4.0 ± 0.4 ng / ml. Levels decreased during the last 45 days of the study (average serum concentration 1.2 ± 0.3 ng / ml). In this way, 14 months of haloperidol release were achieved in monkeys using biodegradable implants.

Example 2: Prolonged haloperidol release from PLGA implants in rabbits Materials and experimental methods Experimental design Two implant systems were tested, the first containing five different simple polymer implants (similar to Example 1), and the second containing five implants that they contain a single polymer. The subjects of simple polymer model was to reduce the initial peak, while maintaining the release for one year. Subjects Rabbits (N = 12, Covance, Denver, PA) ranged in weight from 4.0 to 5.7 kg. Five animals received implants composed of a single polymer, 100% PLA, with haloperidol loading at 40% for a total drug content of 418 ± 7 mg / kg, producing a daily dose of 1.13 ± 0.02 mg / kg / day for administration anticipated 365 days Five additional received animals received implants from a combined polymer system that included 75:25, 85: 15, 90: 10 upper IV, 90:10 lower IV and 100: 0 PLGA. The average dose in this group was 473 ± 4 mg / kg with an expected supply of 365 days. Producing an average dose of 1.29 ± 0.03 mg / kg / day. Two rabbits received implants without a drug as a control. One control received 100% PLA implants to mimic the simple polymer condition, the other implants received were composed of 75:25, 85: 15, 90: 10 upper IV, 90: 10 lower IV and 100: 0 to reflect the system of combined polymer. Fabrication of the implant The implants were prepared using the procedures described in example 1, in this case with an average mass of 536 ± 2 mg and a density of 1.24 ± 0.00 g / cc. The implants are strapped to help locate the implant sites at necropsy. Pharmacokinetic determination Solid phase extraction (SPE) was carried out using the position vacuum manifold SPE with 20-waters and Waters Oasis MCX SPE cartridges (cartridges 3 ml / 60 μg). The cartridges were conditioned with methanol and water, samples containing 5% phosphoric acid were charged, then the cartridges were washed with 2% methanol in 0.1N hydrochloric acid. Subsequently 100% acetonitrile, they were subsequently eluted with 5% NH 4 OH in 100% acetonitrile. The samples were dried under nitrogen in a water bath at a temperature of 80 ° C, reconstituted in 100 μl of mobile phase, vortexed and centrifuged for 5 minutes. 75 μl of the reconstituted samples were loaded in an autosampler, and 50 μl was injected. HPLC was carried out using a Waters XTerra RP 185um column, 4.6 X 150 mm, flow range 1.0 ml / min, run time 30 min. The mobile phase and the sample regulator had 55% H2O compounds with 35% acetonitrile and 10% 100 mM ammonium bicarbonate, pH 10. The peaks were detected at a wavelength of 280 nm. The standard solutions of risperidone and risperidone 9-OH were prepared in normal rat serum (range 1.25-50 ng / ml) were extracted, and incubated within each run to provide the curve and standard retention time of each compound. The retention times of risperidone and risperidone 9-OH were 8.6 and 5.9 min, respectively. Histopathology Five rabbits were sacrificed after nine months to obtain interim pathological analyzes, with seven rabbits remaining sacrificed after four additional months. The rest of the implants were found strapped in place in all the animals that received implants (figure 2).

In the elimination, the average residual implant was 17% of its original mass at 282 days and 5% of its original mass at 423 days after implantation. HPLC / UV and NMR spectroscopy confirmed the presence of haloperidol and PLGA cleavage products in residual implants. HPLC analyzes of drug content in residual implants indicated that the implants removed at 282 days had an average of risperidone at 10% by weight and those that were removed at 423 days had an average of risperidone at 9% by weight. The NMR was carried out at a temperature of 25 ° C on a Varian Unity Inova 300 Mhz instrument and the spectra were analyzed using the Vnmr 6.1b software (Varian, Inc., Palo Alto.CA) (Figure C3). Control samples of PLA (AIkermes 100DL High IV) and haloperidol were run in DMSO and chloroform (CDCI3) to define peaks of interest for each compound (Figure 3D-E, respectively). The implants were removed from the rabbits and initially dissolved in DMSO-d6 and subsequently the residual solids were removed by filtration and dissolved in chloroform. All expected haloperidol peaks were present in DMSO. Small peaks of 5.2-5.4 ppm were indicative of the -CH peak in PLA, since the corresponding -CH3 peaks from PLA could have been obscured by haloperidol peaks at low polymer concentrations. The CDCI3 sample contained characteristic haloperidol peaks at 81. and 7.4 ppm at a lower magnitude than the DMSO sample, presumably because most of the haloperidol was extracted in DMSO. The chloroform fraction contained peaks in 0.9, 1.2, 3.9 and 4.5, consistent with lactic acid, the degradation product of PLA. The implants did not originate capsule formation, leading to a simple elimination process. HPLC / UV and NMR spectroscopy confirmed the presence of haloperidol and PLGA cleavage products in residual implants. Histological analyzes showed that all organ systems in all rabbits were within normal limits. Results A similar experiment was carried out in rabbits, in this case comparing five different simple polymer implants (similar to Example 1) with five implants comprised of a single polymer. The rabbits that were administered the multiple polymer system had haloperidol levels of 4.0 ± 0.6 ng / ml at 360 days. An initial period of higher concentration occurred during the first 198 days (average serum level 6.1 ± 0.7 ng / ml) (Figure 3A). The levels were subsequently tapered at an average of 1.1 ± 0.3 ng / ml over the 320 days, falling below the detection level at 360 days. B) Rabbits that were administered the simple polymer system exhibited a more symmetric release profile and had an average serum concentration of 2.5 ± 04 ng / ml, falling below the detection level at 340 days, as observed for the multiple polymer system (Figure 3B). Therefore, discoveries made with rabbits confirmed the findings in monkeys, showing that 12 months of haloperidol release can be achieved using biodegradable implants. These results also show that at least in some cases, a more symmetric release profile can be achieved with a simple polymer system than with a multiple polymer system. Example 3: Implant geometry effect in the release range Materials and experimental methods Implants containing 40% haloperidol and 60% 50:50 PLGA polymer were manufactured by solvent casting. The material was compression molded into disks or slowly extruded into rods using a high pressure piston extruder (DACA Instruments, Goleta, CA) at a temperature of 100 ° C. The rods and discs corresponded in weight. The surface area to volume (SA: V) proportions of these geometries are 1.92 for discs (3 mm radius, 1.6 mm thick) and 1.56 for rods (1.8 radius, 4.5 mm length). To measure the release profiles, the implants were placed in 500 milliliters (ml) of phosphate-buffered saline (PBS), pH 7.0, 37 ° C, 40 rpm in the dark. Results The effect of implant geometry (rods versus discs) in the release of haloperidol was reviewed. The release profiles were almost identical for both geometries (figure 4), demonstrating that the rods have release profiles very similar to the discs. Therefore, rod-shaped implants can be used to administer therapeutic levels of maintenance of a drug in a subject for a prolonged period of time. Example 4: Stability of risperidone in physiological aqueous solution To evaluate the long-term stability of risperidone in physiological solution, 10 mg of Risperidone was dissolved in 100 μl of acetonitrile for a subsequent solution in 1,000 ml of PBS (0.9% NaCl, 0.01 M NaOH, 0.01 M NaH2PO4, pH 7.0) to produce a final solution of 10,000 nanograms (ng) / ml. The solution was stirred at 40 revolutions per minute in an amber safety bottle against light at a temperature of 37 ° C. The drug concentration of 1 ml of sample was measured three times per week by spectroscopy (Amersham Biosciences, Buckinghamshire, UK). The concentration of the drug exhibited only a slight change (1.4% at 343 days, equivalent to 0.004% per day; Line indicative of linear evolution: y = -0.0004x + 9.777). The studies were replicated using UV and HPLC spectroscopy (Figure 5). There was a correlation coefficient of 0.99 between HPLC and UV spectroscopy, indicating that the UV spectroscopy method is an accurate method for in vitro analysis of risperidone concentration. Therefore, risperidone is stable for prolonged periods in physiological solution.

Example 5: Effect of PLG: PGA ratio on risperidone release The release of risperidone from different polymers including PLGA 50:50, 65:35 and 75:25 was evaluated to evaluate the effects of the PLA: PGA ratio on the release of risperidone in vitro The implants were prepared as described for Example 1, in this case with 20% risperidone (RBI, Flanders, NJ) and 80% PLGA (AIkermes). Three replicas of each type of implant were placed in bottles safely against the separate light of 500 ml PBS and shaken at a temperature of 37 ° C, 40 rpm). Aliquots of 1 ml of each bottle were taken 3 times per week and analyzed by UV spectrophotometry, after which 1 ml of regulator was reintroduced to maintain a constant volume. The 75:25 polymer exhibited the slower release profile (Figure 6A). In a further study, the consistency of the effect between mice was determined. Eight mice were administered with 75:25 PLA: PGA, risperidone implants of 20% drug loading, and serum concentrations of risperidone and risperidone 9-OH were evaluated after 42 days. The results are shown in Table 1, together with the release range mg / kg / day, calculated by dividing the weight of risperidone in the implant / mouse weight / the estimated number of days of release (120).

Table 1 Eight mice in the upper part were given implants containing risperidone, five mice in the lower part were given control implants that did not contain risperidone. Risperidone implant mouse serum 42 days after implant After Concentration Concentration Mouse # mg / kg / day of day risperidone (ng / ml) risperidone 9-OH (ng / ml) 1648 42 2.5 6.0 5.7 1649 42 2.5 10.1 12.6 1650 42 3.2 5.0 7.4 1651 42 2.5 6.3 7.0 1652 42 2.6 6.2 7.1 1653 42 2.8 10.2 11.8 1654 42 3.2 7.0 5.2 1655 42 2.7 7.8 8.2 Average 7.3 8.1 1642 42 0 0 0 1643 57 0 0 0 1644 42 0 0 0 1646 57 0 0 0 1647 42 0 0 0 Average 0 0 Example 6: Effect of ratio of surface area to volume on risperidone release Methods and experimental materials The studies used 4 bars per condition with surface area to volume ratios (SA: V) of 2.75 ml and 6.17, using both a load of risperidone drug 30%, PLGA 75: 25%. The bars were placed in separate bottles of PBS at a temperature of 37 ° C in rpm. Samples of 0.3 ml were extracted 3 times per week, analyzed by HPLC and UV spectrometry (Bio-teck Instruments, Winooski, VT).

Results To determine the effect of the SA: V ratio on risperidone release, risperidone release was measured from bars with identical composition although at different SA: V ratios. The release pattern between these 2 SA: V ratios differed during the first 44 days of release with the smaller radius bars (larger SA: V) exhibiting faster release (Figure 6B). Therefore, larger diameter rods, which have a similar SA: V ratio, provide longer administration than bars of smaller diameter. These results confirm and increase the results of Example 3, demonstrating that the release of biodegradable implants is a function of the SA: V ratio, as described later in equation (8). Therefore, the bars as well as the discs can be used to achieve prolonged drug release in biodegradable implants. Example 7: Determination of optimal risperidone drug loading in implants To determine the optimal risperidone concentration of implants, the implants were prepared using a simple polymer (85:15 PLGA) combined with risperidone in proportions of 10%, 20%, 30%. %, 40%, 50% or 60% of drug by weight (figure 7). The implants each had a mass of approximately 50 mg, and therefore contained drug masses of 5, 10, 15, 20, 25 and 30 mg, respectively. A large fraction of the total drug load of the 10% and 60% drug load implants was released in the first 30 days, while the drug load release of 20%, 30%, 40%, and 50% released their risperidone more slowly. The more linear release pattern was achieved with implants loaded with risperidone at 40% and 50%, with similar slopes throughout the time tested. Example 8: Risperidone implants increase PPI and P20 amplitude and blog amphetamine-induced disruption of N40-evoked potentials at 14 and 21 days after implantation Materials and experimental methods Risperidone implants produced serum risperidone concentration of 7.3 ± 0.68 ng / ml (mean ± SEM) and risperidone 9-OH serum of 8.1 ± 0.95 ng / ml at 42 days after implantation. The brain levels were 6.2 ± 1.45 &; 4.6 ± 0.52 ng / gm of risperidone and risperidone 9-OH, respectively. The disc-shaped implants (SA: V ratio of 2.34) were made from 85: 15 PLGA, 0.66-0.80 IV, with a drug loading of risperidone at 20%. Mice (C57BL / 6J) received either implant containing risperidone (n = 8) or polymer alone (n = 8) prior to stereotactic implantation of electro-tripolar assemblies (PlasticsOne Inc., Roanoke, VA) for registration without anesthesia of auditory evoked potentials (Connolly and associates, 2003; Connolly and associates, 2004; Maxwell and associates, 2004; Siegel and associates, 2005). Studies regarding inhibition in reaction by shock and previous pulse (PPI) of the acoustic response by scares were carried out between 14 and 21 days before implantation as described in the publication of (Gould TJ and associates, Sensorimotor gating deficits in transgenic mice expressing a constitutively active form of Gs alpha Neuropsychopharmacol 29: 494-501). The record of evoked potentials was carried out 28 days after electrode implantation. The registration of the drug exposure test began six minutes after the injection to amphetamine 2 mg / kg i.p. and was compared with the pre-amphetamine registration session. The stimuli were generated using the Micro 1401 hardware and the Spike 5 software (CED, Cambridge, England), and were supplied through loudspeakers attached to the top of the cage. A series of 50 clicks of white noise (10 ms duration) in pairs of 500 ms was presented with a separation of 9 seconds of interpar interval at 85 db compared to the background of 70 db. Waveforms between 1 and 500 Hz were filtered, the baseline was corrected in the generation of stimuli and individual sweeps of motion artifacts were rejected based on criteria of two times of square root amplitude. The average waves were created from pre-stimuli of 50 ms to post-stimuli of 200 ms. The mice were left fifteen minutes in acclimation to the Faraday cage before the generation of the stimulus. Results Mice (C57BL / 6J) received either implant containing risperidone (n = 8) or polymer alone, subsequently underwent a record without evoked auditory anesthesia using implanted tripolar electrode assemblies. Although the risperidone implants did not alter the amplitude of the reaction by shock (Figure 8A), they increased PPI relative to controls (Figure 8B). In addition, risperidone implants increased the amplitude of P20 (the human analog P50) in control animals (Figure 9A), and reduced the amplitude N40 induced by attenuated amphetamine (the human analogue N100) (Figure 9B). Abnormalities in components P50 and N100 reflect the abnormal neuronal architecture related to the generation and modulation of auditory responses and are indicators of more widespread neurological damage in schizophrenia (Adler LE, Olincy A and associates, Schizophr Bull 24, 189-202, 1998; Freedman R, Alder LE and associates, Harv Rev Psychiatry 2: 170-192, 1994). Example 9: Risperidone implants increase the PPI v P20 amplitude and blog the amphetamine-induced interruption of N40-evoked potentials at later time points. Experiments were carried out to determine the effect of the risperidone implants of example 8 at startup, PPI, P20 and N40, at later time points after implantation. In this case, significant effects were observed for all these parameters in animals receiving the risperidone implants, in a manner consistent with the greater release range and subsequently a higher plasma concentration achieved at later time points, as shown in kos examples from 5 to 7. Example 10: The range of release of hydrolysable biodegradable implants can be determined based on the solubility of the drug and the range of degradation of the implant. Methods v Experimental Materials Drugs Six drugs were reviewed: 1). Tiotixeno: N, N-dimethyl-9- [3- (4-methyl-piperazin-1-yl) -propylidene] -thioxanthene-2-sulphonamide. 2). Haloperidol: 4- [4- (4-chlorophenyl) -4-hydroxy-1-piperidi I] -1- (4-fluorophenyl) -butan-1 -one. 3). Hydrochlorothiazide (HCTZ): 9-chloro-5,5-dioxo-5? 6-thia-2,4-diazabicyclo [4.4.0] deca-6,8,10-triene-8-sulphonamide. 4). Corticosterone: 11-hydroxy-17- (2-hydroxyacetyl) -10, 13-dimethyl-1,2,6,7,8,9,10,11,12, 13,14,15,16,17-tetradecahydrocyclopenta [ a] phenanthren-3-one.

). Ibuprofen: 2- [4- (2-methylpropyl) phenyl] propanoic acid. 6). Aspirin: 2-acetyloxybenzoic acid. The properties of the drugs are described in Table 3. All drugs were obtained from Sigma-Aldrich, Inc. Table 3. Properties of drugs used in this example Drug Molecular formula But Solubility in D ** k ** Water molecular density (mg / mL) * OH group (OH groups / unit mass) Halopepdol C21H23CIFN02 37587 013 17 * 1010 007 266 * 103 Tiotixeno C23H29N3O2S2 44364 014 9 * 10"10 006 0 HCTZ C7H8CIN303S2 29775 200 2 no-6 026 0 Corticosterone C21H30O4 34647 050 25 * 107 033 577 * 103 Ibuprofen C13H18O2 20629 047 7 * 10"6 016 485 * 103 Aspirin C9H8O4 18016 499 8 * 102 006 555 * 10"3 * Measured after 14 days as described below. ** k is units of 1 / day and D without dimension. Obtained by adjusting the data treated in Figure 10 for equation (4), as shown in Figure 11. Ultraviolet (UV) scanning The drugs were dissolved in PBS, pH 7.4 at the expected in vitro solubility. Absorbance scans were performed on drug solutions within the range of 200 nm to 400 nm, using a blank cuvette containing saline as a reference. A characteristic UV trace of each drug was generated, and the wavelength at which the relevant peak was highest was used in subsequent in vitro tests. The standard curves are prepared for each drug in PBS so that the absorbances can be converted to concentration using the Lambert-Bear law. Fabrication of polymer / drug tablet 400 mg 50:50 PLGA and 100 mg of the drug were melted with solvent to obtain 20% by mass of drug loading. Polymers and drugs were dissolved in 45 milliliters (mL) of acetone (Fisher Scientific, Inc.) and vortexed, then poured into an evaporation dish and placed in a vacuum oven at a temperature of 40 ° under vacuum (7.62). cm) (3 inches Hg) with trace airflow. After seven days, the dishes were removed from the oven. The evaporation of the residue was a mixture of thin film of polymer and drug with homogeneous appearance. The film was weighed carefully to confirm the total removal of the solvent and compressed into four uniform disk-shaped tablets with 1 mm thickness and 1.2 mm in diameter, using a tablet press coated with Teflon® adjusted to 25 (kilograms). pounds) klb and at a temperature of 60 ° C. The tablets were weighed carefully and measured to determine the densities. Negative control tablets with a 0% drug load were manufactured in the same way, using 500 mg of polymer and without drug. Drug Solubility in Water The ascending drug mass, which ranges from 0.5 to 200 mg, of each drug was mixed in a covered glass jar (Wheaton, Inc.) containing 10 to 50 mL distilled water and subjected to moderate mixing for 14 days at a temperature of 21 ° C. Aliquots of 1 mL were removed at fixed time intervals and analyzed by UV spectroscopy to determine the maximum saturation concentration. In vitro Drug Release Assay Trials were carried out in triplicate using three from each group of four uniform tablets. Each tablet was added to a covered, amber glass jar (Wheaton, Inc.) containing 500 mL of a PBS solution and subjected to moderate agitation in the dark at a temperature of 37 ° C. Aliquots of 1 mL were analyzed by UV spectroscopy at fixed time intervals, and the positive control jars contained PBS and 10 mg of drug, the maximum expected release for a tablet with 20% drug loading with a mass of 50 mg. and they were also used to determine the stability of each drug in saline during the course of the experiment. Results The release of six matrix drugs was reviewed PLGA, f, the fraction of the drug released from the tablet, is plotted in Figure 10 as a function of time t. Over long periods of time all the drugs were released and f = 1. Before this total release, the limit was a region where the release rate was very constant, as can be seen through a linear relationship between the fraction of drug released (? f) and time (? t). The results show that the release of linear drug release can be obtained with a single type of biodegradable polymer. Two additional features of the previous drug release measurement emerge: First, some drugs (for example thiothixene) were released as soon as the experiment began, while others (for example haloperidol) exhibited an induction time, during which time released a non-measurable amount of drug. In addition, during the constant state release (constant? F /? T), different drugs exhibited different release ranges. As a result, a variation was observed both in the constant state release range and in the general time period through which the drug is released. The visual observations confirmed that the tablets containing different drugs dissolved in different ranges, and became invisible to the eye after different periods of time that correlated with the time in which f = 1 as measured by UV spectroscopy. Therefore, the drug release range of the polymers can be characterized by two global parameters: the delay period (for example, the time required to reach the constant state release range) and the constant state release range . The same polymer was used in each of the previous matrices. Therefore, differences in the release rates of the delay period and constant release of the matrices were due to the drug component of the matrix. The differences in the release range of a drug matrix can be attributed to different ranges of drug diffusion and milk-making within the polymer matrix, and / or to different ranges of polymer degradation. The polymer release ranges vary between the matrices used in this experiment, as evidenced by the different ranges of disappearance of the tablets. Therefore, the presence of the drug affects the degradation range of the polymer. To understand the effect of a drug incorporated in the polymer degradation, the following model of the degradation process was developed, based on the data of the present invention: Mobility (diffusion) of the drug in the polymer matrix is probably insignificant in comparison with the range of polymer degradation. Therefore, drug release occurs mainly through polymer degradation. The degradation of PLGA polymer in lactic acid and glycolic acid occurs through a reaction with water: (C3H4O2) x (C2H2O2) and +2 H2O? CH3CHOHCOOH + HCHOHCOOH.

Therefore, the degradation range depends on the availability of water molecules. In systems where the diffusion of the water in the tablet is suppressed, this indicates erosion on the surface. In systems where the diffusion capacity of the water in the polymer is high, this leads to erosion by volume. The degradation reaction will probably be a first order reaction between the polymer and water and therefore is proportional to the local concentration of both species. However, since the polymer comprises the majority of the tablet, its concentration is fixed anywhere. Therefore, the degradation reaction is proportional to the local concentration of water (a function of diffusion capacity) to measure a constant. When defining the water diffusion coefficient in the polymer tablet as D, the water diffusion / reaction equation is written as (1): dc cw ~ kcM dt (1) where k is the reaction range, which includes the local polymer concentration, is constant. The appropriate boundary conditions are that the water concentration at the peptide edge is set by the solution value cw °, and that initially (at t = 0) the water concentration in the particle is zero. Equation (1) indicates that in systems where D is close to 0, there is no diffusion in the polymer particle, cw is zero within the tablet, and all reactions take place at the polymer / solution interface. In systems where the diffusion range is large compared to the reaction range, the water will penetrate and degrade the entire volume of the particle through volume erosion. The water concentration profile was solved assuming that the tablet is a semi-infinite medium. This assumption is suitable for the initial and constant state stages of degradation when the diffusion distance of the water is small compared to the dimensions of the tablet. By defining the distance of the polymer / solution interface as x, it was found that: The amount of polymer that reacted, in any given place (x), with water and subsequently degraded was obtained through integration with time: where dMp (x, t) is the change in polymer mass at point x. Therefore, the general mass of the degraded polymer is described by AMp (3-b) and the amount of drug released Md (negligible drug diffusion) is 69 Where f is the fraction of the weight of the drug in the particle. Initially, when t is small, Md is described by whereas at later time points, the release range is determined by KDl t Md * Ik 1/2 ~ t (5.b) In this way, it was determined that initially the amount of drug released increases with time to the power of (3/2), with a range of release (the slope) that depends only on the water diffusion coefficient D. As it increases the In time, the amount of drug released becomes linear with time. In this regime, the system reaches a "constant state" when the degradation range and the amount of drug released are constant over time. Therefore, the range of release varies with the ratio between diffusion and reaction constants.

The model described in equation (4) is adjusted with the drug release data shown in figure 10 for the six groups tested, with values of D and k that are described in table 2 (the haloperidol and aspirin curves are illustrated in figure 11). This is remarkable because the drugs tested are diverse; for example, haloperidol and aspirin are very different. Deviations observed at later time points arise from the finite size of the tablets. Therefore, the drug release range of biodegradable matrices can be counted through a model that contains only two adjustment parameters: D and k. Example 11: Parameters D and k in the release equation can be determined from the solubility of the drug and its identity of hydroxyl groups. It was observed that the parameter k, the coefficient of the degradation reaction, varied by less than one order of magnitude for all the drugs (0.05-0.33); in contrast, D, the diffusion coefficient, varied 8 orders of magnitude (table 2). The diffusion constant of the molecules in solid polymer media is described by D0e sup [-de], where D0 is a proportion coefficient, e is an activation or interaction energy and d is a thermodynamic constant that depends, among other things, of the system temperature. In this case, the polymer matrix is the same, as is the temperature; therefore, D0 and d are the same for all polymer / drug tablets. However, the activation energy e, is sensitive to the specific interactions between the diffusers and the matrix, and therefore varies with the type and loading of the drug (mass fraction). The solubility of the drug in water (assuming an ideal mixture) can also be described in terms of e: S, the solubility, is equal to S0e- sup [-de], where S0 is a proportion coefficient and s is a thermodynamic constant . The combination of the relationship of D and S leads to the following relationship: where the term in the parenthesis is, in this case, a system constant. As illustrated in Figure 12, the solubility data was adjusted to equation (6). The dependence of D on solubility was described through a power law, with a coefficient of approximately 5.3. In conclusion, the model described through equation (4) can be used to anticipate the range of drug release during constant state for PLGA implants containing 20% drug loading. D is proportional to the solubility at the power of 5.3 and k is a number within the range of approximately 0.05-0.33.

Example 12: Determination of drug release from polymer PLGA implants and resulting serum drug concentration as a function of time and implant properties Since the approach of examples 10-11 was to review the effect of drug / polymer interactions / water in the degradation and release range, the original model used an implant of infinitely large size. The present example describes the time-dependent concentration of the drug in vivo. For this purpose, the previous model was modified to take into account (1) the size of the finite implant (2) absorption and drug species (metabolic range). The range of drug release from an implant is proportional to the surface area of the implant (SA). The correction to change the implant mass, the SA of the implant, A, can be described as in equation 7, where R (t) is the radius of the implant as a function of time t, R0 is the initial radius, D is the water diffusion coefficient in the matrix, k is the reaction range and Cw is the concentration of water. (7) The range of drug release per unit time can therefore be calculated as equation 8. where "erf (x)" refers to j Qxe? t. The metabolic range of risperidone can be described as an exponential decay of the drug in the blood, with a range of characteristic decay t that varies as a function of drug and metabolic range, producing a complex function for the effective drug concentration shown in the equation 9. The function can be asymmetric, and its degree of symmetry is adjusted through the value of t, the typical metabolization time for the determined drug. A high value of t indicates a slow metabolic range, and therefore the function is more symmetric. A low value of t indicates rapid metabolism and the function becomes more asymmetric as the peak moves closer to t = 0.

The concentration of drug as a function of time is a complex function. The error function can be approximated as erf (x) ~ 1 -e "7x 4, producing equation 10 for the drug concentration, ai is a constant equal to the total drug content of the implant, the variable a2 is a constant equal to metabolic range, the a3 variable reflects the diffusion of the implant drug and the variable a reflects the release of polymer and influences the total release interval.Adjusting the rabbit haloperidol data, the coefficient t80.027 was extracted, which indicates a life mean of haloperidol serum in rabbits of approximately 130 minutes, consistent with the published data (Wurzburger RJ, Miller RL and associates, J Pharmacol Exp Ther 217: 757-763) .This equation fits with the above in vivo rabbit data with a Correlation coefficient (R2) of 0.87.

Example 13: Determination of the contribution of polymer composition and inherent viscosity in drug release of PLGA polymer implants The polymer composition and inherent viscosity are varied as described in examples 1 to 7 to determine the additional contributions of these variables to the release of PLGA polymer implant drugs. Additional equations are produced, incorporating these variables. Example 14: Scale of risperidone implants for human subjects There are considerable interspecies differences in the metabolism of risperidone, both with rabbits and with monkeys, requiring approximately 15 to 30 times more doses than for humans for equivalent plasma concentrations (Bacopoulos NG, Redmond DE , and associates, J Pharmacol Exp Ther 212: 1-5; Jibiki I, Kubota T, and associates, Jpn J Psychiatry Neurol 47: 627-629; Klintenberg R, Gunne L, Andren PE (2002) Mov Disord 17: 360-365). Therefore, the absolute doses used in previous animal studies approximate the amount of drug needed for a human, despite differences in body mass. Since humans require approximately 1 mg / kg / month of risperidone (usually approximately 1.8 mg / day) when administered as a depot preparation, an implant system containing 600 mg can provide one year of treatment for a patient of 50 kg. Therefore, the implant design used in animal studies requires approximately 1.5 grams of material with a 40% drug load for one year of risperidone. At a density of 1.2 g per cc and diameter 3.6 mm, this requires approximately 6.5 cm of implant bars. Risperidone implants within the following parameters are administered to humans: drug load between 30% -60%, inclusive. PLA molar ratio: PGA between approximately 50:50 and 100: 0, inclusive. In the form of a rod. SA ratio: V between 1.5 and 2. For example, rod-shaped implants with a length of approximately 3-5 mm, inclusive and diameter between 2 and 3.6 mm, inclusive, exhibit an SA: V target ratio. Through the administration of 1 or more implants, a substantially symmetrical concentration profile is achieved, as seen in example 2, with peak levels reached in approximately 6 months and therapeutic risperidone levels achieved between 2 and 8 months post implant (figure 13A). Example 15: Cyclic Administration of Risperidone Implants Achieves Long-Term Therapeutic Risperidone Levels The symmetric release profile described in Example 14 was used to provide long-term therapeutic drug levels by introducing a new group of implants approximately every 6 months (Fig. 13B). for example, two 3.2 cm long rods with 100% PLA were administered every 6 months. As illustrated, each subsequent implant group increases the medication levels in the same range that the contribution of the previous group is declining, so that the overall release range remains approximately constant (Figure 13C). Example 16: Improvement of initial drug levels by inclusion of faster release polymers in the initial implant A limitation of a simple polymer system is a delay in attaining therapeutic levels after initial implantation. Therefore, additional implants that provide a faster time for peak concentration are included in the initial implant. One or more of the implants illustrated in Table 4 are included. The release ranges of the delivery implants in Table 4 and the resulting serum concentrations are derived from Equations 8 through 10 by varying parameters a1 and a4, which they are related to the drug content (total dose) and polymer degradation (PLGA proportion and inherent viscosity). Table 4. Additional polymer implants used with initial implant. The implants contain between 40 and 60% load of risperidone inclusive, and exhibit an objective administration of 0.15 mg / day. Each rod has a diameter of 3.6 mm with a density of 1.2 grams per cubic centimeter (g / cc), producing rods with approximately 125 implants. Polymer Days for Days for Mg total mass mass total implant release 0%, 40%, maximum length 50%, 60% implant 0%, 40%, 50%, 60% 50:50 L 20 40 60, 60, 48, 40 0.5, 0.5, 0.4, 0.3 50:50 H 28 55 83, 83, 66, 55 0.6, 0.6, 0.5, 0.4 65:35 L 45 90 135, 135, 108.90 1.1, 1.1.0.8.0.7 65:35 L 55 110 165, 165, 132, 110 1.1, 1.4, 1.1.0.9 75:25 L 60 120 180, 180, 144, 120 1.5, 1.5, 1.2, 1.0 75:25 H 70 140 210,210, 168, 140 1.7, 1.7, 1.3, 1.1 85:15 L 75 150 225,225, 180, 150 1.8, 1.8, 1.4, 1.2 85:15 H 90 180 270,270,216, 180 2.1.2.1, 1.7, 1.4 100: 0 L 190 380 570, 570, 456, 380 4.5.4.5.3.6.3.0 Positive controls Days of exposure = 30, 60, 90, 120, 180, 360 For example, Figure 14A illustrates the drug release of four fast-release implants that have half-lives of approximately 2, 4, 8 and 12 weeks and intervals of total release of approximately 4, 8, 16 and 24 weeks, respectively. For example, a group of implants containing half of the first six months of medication includes 4 implants with an average length of 0.8 cm, composed of 50:50, 65:35, 75:25 and 85:15 PLGA respectively. This group is provided in combination with the slower release implants, which provide the other half of the medication. When this combination of implants is administered in a first implant, therapeutic drug levels are achieved within a few days of the implant, and are sustained indefinitely through the implant of slower release implants at 6-month intervals (Figure 14B). . Example 17: Risperidone-PLGA biodegradable implants. Sterile drugs provide prolonged risperidone release In vitro release profiles of risperidone implants from sterile implants were measured. As illustrated in Figure 17, the implants released drug from day 0 to 58, after which no more drug was released. Therefore, sterile PLGA-risperidone implants provide a release profile suitable for the methods of the present invention. To further characterize the properties of sterile versus non-sterile implants, the mice were implanted with either sterile or non-sterile PLGA-risperidone implants using the methods described in example 5. The implants were removed at 14, 27, 56 or 83 days, the mice were sacrificed, and the serum risperidone concentration was evaluated. In the first 3 groups, which were sacrificed at 56 days, serum levels were 7-10 ng / ml at 14 days and increased to 15-20 ng / ml at 27 and 56 days. When the implants were removed after 83 days, there was no drug detectable in serum (Figure 18), consistent with both in vitro release patterns (previous examples) and with residual risperidone content (examples found below). In summary, sterile and non-sterile implants supplied drug for 56 days, while maintaining consistency and elimination capacity up to 83 days. Therefore, sterile and non-sterile implants did not exhibit significant differences. Accordingly, all implant properties demonstrated in the above examples apply to both sterile and non-sterile implants. Example 18: residual risperidone content in implants after elimination Residual risperidone content was evaluated after elimination of the mice from the previous example. As illustrated in Figure 19, the percentage of drug loading decreased with time from its initial value of 30% (for example, the drug was released in a faster range than the polymer degraded). Therefore, the implants remained coherent and removable after the period during which the drug was released, showing that the implants of the present invention can be removed during the desired delivery interval. However, because they are biodegradable, the implants do not require removal. Example 19: In vitro stability of risperidone at low pH To determine if the low pH environment can affect the rispendone stability, risperidone was stored at pH 4.4 to 7.4 for 172 days and it was found to be completely stable (Figure 20). Similar results are observed in pH values of 2.0 and 3.0 during a 68-day experiment. Therefore, risperidone is stable at both neutral and low pH.

Claims

CLAIMS 1. A long-term, implantable administration system for improving adherence of medication in disorders associated with a probability of non-compliance, characterized in that it comprises: a therapeutic drug in a rod-shaped, implantable structure, wherein the structure in rod form further comprises a polymer, the polymer comprising lactic acid (PLA) and optionally glycolic acid (PGA) in a molar ratio PLGA: PGA of between 50:50 and 100: 0, thereby forming a long delivery system term to improve medication adherence in subjects who have disorders associated with a probability of non-compliance.
2. The implantable long-term administration system as described in claim 1, characterized in that the rod-shaped structure is removable throughout the period of administration of the drug.
3. The implantable long-term administration system as described in claim 1, characterized in that the therapeutic drug is present in an amount of 30% -60% of the mass of the implant.
4. The implantable long-term administration system as described in claim 1, characterized in that the therapeutic drug exhibits improved solubility in an environment with reduced pH.
5. The implantable long-term administration system as described in claim 1, characterized in that the therapeutic drug is risperidone, risperidone 9-OH or an active metabolite thereof.
6. The implantable long-term administration system as described in claim 1, characterized in that the therapeutic drug is thiothixene, haloperidol, hydrochlorothiazide (HCTZ), corticosterone, ibuprofen, aspirin or an active metabolite thereof.
7. The implantable long-term administration system as described in claim 1, characterized in that the molar ratio PLA: PGA is between 75:25 and 100: 0.
8. The implantable long-term administration system as described in claim 1, characterized in that the therapeutic drug is an antidepressant.
9. The implantable long-term administration system as described in claim 1, characterized in that the therapeutic drug is an anti-anxiety agent.
10. The implantable long-term administration system as described in claim 1, characterized in that the therapeutic drug is an anti-psychotic agent.
11. The implantable long-term administration system as described in claim 1, characterized in that the therapeutic drug is a birth control drug.
12. The implantable long-term administration system as described in claim 1, characterized in that the implant has a surface area to volume ratio between 1 and 4 (millimeters [mm]) 2 / mm3.
13. The implantable long-term administration system as described in claim 1, characterized in that the implant has a length between 1 to 3 centimeters.
14. The implantable long-term administration system as described in claim 1, characterized in that the implant has a diameter between 2 and 4 millimeters.
15. A biodegradable implant comprising a therapeutic drug and a polymer, the polymer comprising polylactic acid (PLA) and optionally polyglycolic acid (PGA) in a molar ratio PLGA: PGA between 50:50 and 100: 0, wherein the therapeutic drug it is found in an amount of 10% -90% of the mass of the implant, and the polymer is in an amount of 40% -90% of the mass of the implant.
16. The biodegradable implant as described in claim 15, characterized in that the implant has the shape of a rod.
17. The biodegradable implant as described in claim 15, characterized in that the implant has a substantially circular cross section.
18. The biodegradable implant as described in claim 15, characterized in that the implant has a substantially elliptical cross section.
19. The biodegradable implant as described in claim 15, characterized in that the implant has a surface area to volume ratio of between 1 and 4 (millimeters [mm] 2 / mm3.)
20. The biodegradable implant as described in claim 15, characterized in that the implant has a length of between 1-3 centimeters
21. The biodegradable implant as described in claim 15, characterized in that the implant has a diameter between 2-4 millimeters
22. The implant biodegradable as described in claim 15, characterized in that the molar ratio PLA: PGA is between 75:25 and 100: 0.
23. The biodegradable implant as described in claim 15, characterized in that the implant is removable during the period of administration of the drug.
24. The biodegradable implant as described in claim 15, characterized in that the implant exhibits an internal environment with reduced pH.
25. The biodegradable implant as described in claim 24, characterized in that the internal environment with reduced pH facilitates the release of a drug with increased solubility at a reduced pH.
26. The biodegradable implant as described in claim 15, characterized in that the implant is fabricated through a process comprising a selected step of casting, mixed with cast iron or an extrusion method of mixing with solvent casting that does not require the use of a surfactant or an emulsion.
27. The biodegradable implant as described in claim 15, characterized in that the therapeutic drug is present in an amount of 30-60% of the mass of the implant.
28. The biodegradable implant as described in claim 15, characterized in that the therapeutic drug is risperidone, risperidone 9-OH or an active metabolite thereof.
29. The biodegradable implant as described in claim 15, characterized in that the therapeutic drug is thiothixene, haloperidol, hydrochlorothiazide (HCTZ), corticosterone, ibuprofen, aspirin or an active metabolite thereof.
30. The biodegradable implant as described in claim 15, characterized in that the therapeutic drug is an antidepressant.
31. The biodegradable implant as described in claim 15, characterized in that the therapeutic drug is an anti-anxiety agent.
32. The biodegradable implant as described in claim 15, characterized in that the therapeutic drug is an anti-psychotic agent.
33. The biodegradable implant as described in claim 15, characterized in that the therapeutic drug is a drug for birth control.
34. A method for treating schizophrenia in a human, wherein the method comprises administering the biodegradable implant as described in claim 14 to a human, whereby schizophrenia is treated in a human.
35. A method for treating bipolar disorder, dementia, delirium, agitation, impulse control disorder or psychotic depression in a human, wherein the method comprises administering the biodegradable implant as described in claim 14 to the human, thereby treating a bipolar disorder, dementia, delirium, agitation, impulse control disorder or psychotic depression in a human.
36. A method for treating a subject of a disorder associated with probability of non-compliance, the method of administration comprising the subject of a therapeutic drug in a long-term administration sm, wherein the long-term administration sm comprises a rod-shaped, implantable structure, comprising the rod-shaped structure, implantable the therapeutic target-polymer drug, the polymer comprising polylactic acid (PLA) and optionally polyglycolic acid (PGA) in a molar ratio PLA: PGA between 50: 50 and 100: 0, so that the subject is treated with respect to the disorder associated with probability of non-compliance.
37. The method as described in claim 36, characterized in that the subject is a human.
38. The method as described in claim 36, characterized in that the administration step is reversible throughout the period of administration of the drug.
39. The method as described in claim 36, characterized in that the therapeutic drug is present in an amount of 30% -60% of the mass of the individual biodegradable implants.
40. The method as described in the claim 36, characterized in that the therapeutic drug is risperidone, risperidone 9-OH or an active metabolite thereof.
41. The method as described in claim 36, characterized in that the molar ratio PLA: PGA is between 85:15 and 100: 0.
42. The method as described in claim 36, characterized in that the rod-shaped structure has a surface area to volume ratio of between 1 and 14 (millimeters [mm] 2 / mm3)
43. The method as described in the claim 36, characterized in that the rod-shaped structure has a length of between 1-3 centimeters.
44. The method as described in claim 36, characterized in that the rod-shaped structure has a diameter between 2-4 millimeters.
45. The method as described in claim 36, characterized in that the rod-shaped structure has a mass of about 0.75 grams or less.
46. The method as described in claim 36, characterized in that the long-term administration system further comprises a starting group of one or more different biodegradable rod-shaped structures, wherein the different rod-shaped structures differ of the biodegradable rod-shaped structure group of claim 36 in drug loading, PLA: PGA ratio or ratio of surface area to volume, mass, length, diameter or inherent viscosity and whereby the different rod-shaped structures achieve steady state levels of drug release faster than the group of rod-shaped structures of claim 36.
47. The method as described in claim 36, characterized in that the one or more different biodegradable rod-shaped structures, if there are more than one, differ substantially from each other in the molar ratio.
48. A method for treating schizophrenia in a human, characterized in that it comprises carrying out the method of claim 36 in the human, during which schizophrenia is treated in a human.
49. A method for maintaining a therapeutic level of a therapeutic drug in a subject for a period of at least about 1 month, wherein the method comprises administering to the subject a group of biodegradable implants, the group consisting of biodegradable implants consisting of one or more individual biodegradable implants, each of the individual biodegradable implants comprising the therapeutic drug of a polymer, the polymer comprising polylactic acid (PLA) and optionally polyglycolic acid (PGA) in a molar ratio PLA: PGA between 50:50 and 100: 0, wherein the therapeutic drug is in an amount of 10% -60% of the mass of the individual biodegradable implants, and the polymer is present in an amount of 40% -90% of the mass of the individual biodegradable implants wherein the individual biodegradable implants, are more than one, do not differ substantially from one another in the molar ratio PLA: PGA, maintaining in this way a therapeutic level of a therapeutic drug of a subject during a period of at least about 1 month.
50. The method as described in claim 49, characterized in that the subject is a human.
51. The method as described in the claim 49, characterized in that the administration step is reversible throughout the period of drug administration.
52. The method as described in claim 49, characterized in that the individual biodegradable implants each exhibit an internal environment of reduced pH.
53. The method as described in claim 52, characterized in that the internal environment of reduced pH facilitates the release of a drug with improved solubility at a reduced pH.
54. The method as described in claim 49, characterized in that the individual biodegradable implants are rod-shaped.
55. The method as described in claim 49, characterized in that the therapeutic drug is present in an amount of 30% -60% of the mass of the individual biodegradable implants.
56. The method as described in claim 49, characterized in that the therapeutic drug is risperidone, risperidone 9-OH or an active metabolite thereof.
57. The method as described in claim 49, characterized in that the molar ratio PLA: PGA is between 85:15 and 100: 0.
58. The method as described in claim 49, characterized in that the individual biodegradable implants have a surface area to volume ratio of between 1 and 4 (millimeters [mm]) 2 / mm3.
59. The method as described in claim 49, characterized in that the individual biodegradable implants have a length between 2-4 millimeters.
60. The method as described in claim 49, characterized in that the individual biodegradable implants have a diameter between 2-4 millimeters.
61. The method as described in claim 49, characterized in that the individual biodegradable implants have a combined mass of about 0.75 grams or less.
62. The method as described in claim 49, characterized in that they also comprise administering to a subject a group of one or more different biodegradable starting implants, wherein the different biodegradable implants differ from the group of biodegradable implants of claim 46. in drug loading, PLA: PGA ratio, ratio of surface area to volume, mass, length, diameter or inherent viscosity and whereby the different biodegradable implants reach steady state levels of drug release faster than the group of implants biodegradable of claim 49.
63. The method as described in claim 62, characterized in that the different biodegradable implants, if there are more than one, differ substantially from each other in the molar ratio PLG: PGA.
64. A method for treating schizophrenia in a human, characterized in that it comprises carrying out the method of claim 49 in the human, thereby treating schizophrenia in a human.
65. A method for maintaining a therapeutic level of a drug in a subject for a period of at least about 3 months, characterized in that it comprises a. administering to the subject an initial group of one or more biodegradable implants, wherein the initial group consists of one or more individual biodegradable implants, each of the individual biodegradable implants comprising a therapeutic drug and a polymer, the polymer comprising a polylactic acid (PLA) ) and optionally polyglycolic acid (PGA) in a molar ratio PLA: PGA of between 50:50 and 100: 0, wherein the therapeutic drug is in an amount of 10% -60% of the mass of the individual biodegradable implants, and the polymer is present in an amount of 40% -90% of the mass of the individual biodegradable implants, and wherein the individual biodegradable implants, if there are more than one, do not differ substantially from one another in the molar ratio PLA: PGA; b. administering to the subject a group of one or more of the biodegradable maintenance implants near the point of peak release of the initial biodegradable implant group, wherein the group of biodegradable maintenance implants consist of equivalent individual biodegradable implants in the PLA molar ratio: PGA with the individual biodegradable implants in the group of initial biodegradable implants; and c. repeat step (b) as necessary, to thereby maintain a therapeutic level of a drug in the subject for a period of at least about 3 months.
66. The method as described in claim 65, characterized in that the subject is a human.
67. The method as described in claim 65, characterized in that the administration step is reversible throughout the period of drug administration.
68. The method as described in claim 65, characterized in that the individual biodegradable implants of the initial group each exhibit an internal environment with a reduced pH.
69. The method as described in claim 68, characterized in that the internal environment with reduced pH facilitates the release of a drug with improved solubility at a reduced pH.
70. The method as described in the claim 65, characterized in that the individual biodegradable implants of the initial group are rod-shaped.
71. The method as described in claim 65, characterized in that the individual biodegradable implants of the initial group are disc-shaped.
72. The method as described in claim 65, characterized in that the therapeutic drug is present in an amount of 30% -60% of the mass of the individual biodegradable implants of the initial group.
73. The method as described in the claim 65, characterized in that the therapeutic drug is risperidone, risperidone 9-OH or an active metabolite thereof.
74. The method as described in claim 65, characterized in that the molar ratio PLA: PGA is between 85:15 and 100: 0.
75. The method as described in claim 65, characterized in that the individual biodegradable implants of the initial group have a surface area to volume ratio of between 1 and 4 (millimeters [mm]) 2 / mm3.
76. The method as described in claim 65, characterized in that the individual biodegradable implants of the initial group have a length between 1-5 millimeters.
77. The method as described in claim 65, characterized in that the individual biodegradable implants of the initial group have a diameter between 2-4 millimeters.
78. The method as described in claim 65, characterized in that the individual biodegradable implants of the initial group have a combined mass of about 0.75 grams or less.
79. The method as described in claim 65, characterized in that in addition to administering, together with the initial group of biodegradable implants, a starting group of one or more of the different biodegradable implants, wherein the different biodegradable implants differ from the group of initial biodegradable implants in the drug loading, PLA: PGA ratio, ratio of surface area to volume, mass, length, diameter or inherent viscosity, and whereby the different biodegradable implants reach steady state levels of drug release more faster than the initial group of biodegradable implants.
80. The method as described in claim 79, characterized in that the one or more different biodegradable implants, if there are more than one, differ substantially from one another in the molar ratio PLA: PGA.
81. A method for treating schizophrenia in a human, characterized in that it comprises carrying out the method as described in claim 65 for the human, to treat schizophrenia in a human.