Drug delivery formulations

Abstract

To provide a pharmaceutical formulation for treating psychiatric diseases and disorders.SOLUTION: The pharmaceutical formulation is an injection formulation comprising risperidone, a triblock copolymer, and a diblock copolymer, wherein the concentration of the risperidone is from 250 to 400 mg / mL, and the injection volume is 1 mL or less, the formulation being subcutaneously administered to the subject at a frequency of no more than once every 21 days.SELECTED DRAWING: Figure 1

Description

Technical Field

[0001] (Cross - reference to related applications) This application claims the benefit of U.S. Provisional Application No. 62 / 900,061, filed on September 13, 2019, which is hereby incorporated by reference in its entirety. for all purposes.

[0002] (Field of the Invention) The present invention relates to a method of treating psychiatric diseases and disorders responsive to risperidone with a high - concentration low - volume risperidone pharmaceutical composition comprising triblock copolymers and diblock copolymers.

Background Art

[0003] (Background of the Invention) Risperidone is an atypical antipsychotic that is a serotoninergic (5 - HT2A receptor) and dopaminergic (D2, D3, and D4 receptor) antagonist. This substance also binds to alpha - 1 - adrenergic receptors, histamine - H1 receptors, and to a lesser extent, alpha - 2 - adrenergic receptors. It has no affinity for cholinergic receptors. Risperidone has been approved by the FDA since 1994 for the treatment of schizophrenia in adults and adolescents aged 13 - 17 years and is marketed under the name Risperdal (registered trademark). It is currently available in oral and injectable versions and is approved for several other indications, including the treatment of cognitive disorders, anxiety disorders, some bipolar disorders, depression, and manic or psychotic episodes.

[0004] Risperidone is used for the treatment of schizophrenia due to its safety profile and medium - to long - term treatment recommendations. ​​​​​​​​​It is used in the first-choice treatment. Long-acting injectable (LAI) products have been approved by the FDA. Risperdal Consta® is an injectable risperidone product for bi-weekly intramuscular (IM) administration. Risperdal Consta is provided in doses of 12.5 mg, 25 mg, 37.5 mg, and 50 mg risperidone / vial, together with a syringe with 2 mL of diluent. This product requires multiple reconstitution steps and oral supplementation at the start of treatment. Intramuscular injection is usually painful and anxiety-provoking, especially for the target group. Perseris® is an injectable risperidone product for monthly subcutaneous administration. It is provided in two syringes that require significant mixing and resuspension before administration. Perseris® is provided in two dose strengths of 90 mg (0.6 mL) and 120 mg (0.8 mL). Drug delivery systems containing polymers such as diblock and triblock copolymers are used to deliver various drugs and are usually formulated to deliver a specific drug, whether it is a hydrophobic drug or a hydrophilic drug. Depending on the drug solubility, these drug formulations differ in polymer concentration, type of polymer utilized, molecular weight of the polymer and solvent used in the formulation. The type of environment to which the drug is delivered is an important consideration when formulating a drug delivery system. Thus, there are drug delivery compositions prepared using temperature-sensitive polymers, phase-sensitive polymers, pH-sensitive polymers, and light-sensitive polymers. For example, K. Al-Tahami and J.

[0005]

[0006] The literature of Singh, "Smart Polymer Based Delivery Systems for Peptide and Proteins", Recent Patents on Drug Delivery & Formulation, 1: pages: 65 - 71, Bentham Science Publishers, LTD. 2007 is referred to. See reference.

[0007] U.S. Patent No. 9,023,897 and U.S. Patent Publication No. US2019 / 160171 describe pharmaceutical formulations made of biodegradable triblock and diblock polymers useful for the delivery of various activities are described.

[0008] There is a need for long - acting risperidone formulations that assist patient compliance, reduce patient administration anxiety, and are easy for medical professionals to prepare and administer. As an issue when treating neuropsychiatric diseases or disorders using risperidone, for example, it is possible to subcutaneously inject a long - acting formulation having a high - dose active agent with a low injection volume and an injectable viscosity is mentioned. Another issue is the development of a long - acting subcutaneous injection formulation having a low initial burst of the active agent. If the long - acting formulation has to be removed (due to adverse events or other reasons), this long - acting formulation must be removable from the patient. The methods disclosed herein meet these needs and others.

Summary of the Invention

[0009] (Summary of the Invention) Provided herein is a method for treating a neuropsychiatric disease or disorder of a subject, comprising To the subject, at a frequency of once or less every 21 days, a) risperidone at a concentration of about 250 to 400 mg / mL in terms of risperidone conversion or a pharmaceutically acceptable salt thereof; b) a biodegradable triblock copolymer having the formula: poly(lactic acid)v - poly(ethylene glycol)w - poly(lactic acid)x (wherein v and x are the number of repeating units in the range of 24 to 682, and w is the number of repeating units in the range of 4 to 273, and v = x or v ≠ x); c) a biodegradable diblock copolymer having the formula: methoxypoly(ethylene glycol)y - poly(lactic acid)z (wherein y and z are the number of repeating units, where y is the number of repeating units in the range of 3 to 45 and z is the number of repeating units in the range of 7 to 327); including; and wherein the ratio of the biodegradable triblock copolymer of (b) to the biodegradable diblock copolymer of (c) is 1:3 to 1:8 or 1:1 to 1:19 or 3:2 to 1:19 in the formulation that is insoluble in an aqueous environment, a pharmaceutical formulation of 1 mL or less : which comprises subcutaneous administration. Particularly, the active ingredient of the injection formulation of the present invention is risperidone present at a concentration of 250 mg / mL or more, for example, about 250 mg / mL to 400 mg / mL or about 300 mg / mL to about 400 mg / mL, or a pharmaceutically acceptable salt thereof in an amount equivalent to 250 mg / mL to 400 m

[0010] g / mL of risperidone. Regarding the injection formulation of the present invention, the active ingredient is present for 21 to 90 days (about 3 weeks to about 3 months) or 30 to 90 days ( (about 1 month to about 3 months).

[0011] (about 1 month to about 3 months). It has a release duration of about 1 month to about 3 months. In some embodiments, the release duration is , about 28 to 31 days (about 4 weeks to about 1 month). In some embodiments, the release duration is about 56 to 63 days (about 8 weeks to about 2 months to about 9 weeks). In some embodiments, the release duration is about 84 to 94 days (about 12 weeks to about 13 weeks or about 12 weeks to about 3 months).

[0012] Other aspects and embodiments are described below or will be readily obtained from the description of the following preferred embodiments .

Brief Description of the Drawings

[0013] (Brief Description of the Drawings)

Figure 1

Figure 2

Modes for Carrying Out the Invention

[0014] (Detailed Description of the Invention) (Definitions) As used herein, the term "biodegradable" means that triblock and diblock copolymers corrode or degrade in vivo after a certain period of time to form smaller non-toxic components .

[0015] The term "parenteral administration" includes intramuscular, intraperitoneal, intra-abdominal, subcutaneous, intravenous, and intra-arterial . This also includes intracutaneous, intracavitary, intravitreal, intracerebral, intrathecal, epidural, and intraosseous administration . In some embodiments, the administration is subcutaneous.

[0016] The term "about" is to be used only to disclose a range defined by the absolute values of two endpoints. For example, the expression "about 300 to about 400" also discloses the values 300 and 400. When used to modify a single number, the term "about" can refer to plus or minus 10% of the indicated value and includes the indicated number. For example, "about 15%" can indicate a range of 13.5% to 16.5%, and "about 1" means 0.9 to 1.1. should be made. For example, the expression "about 300 to about 400" also discloses the values 300 and 400. When used to modify a single number, the term "about" can refer to plus or minus 10% of the indicated value and includes the indicated number. For example, "about 15%" can indicate a range of 13.5% to 16.5%, and "about 1" means 0.9 to 1.1.

[0017] The term "subject" includes all members of the Kingdom Animalia.

[0018] The active ingredient according to the present invention is risperidone and its pharmaceutically acceptable salts.

[0019] As used herein, "psychiatric disorder or disorder" refers to psychosis, regardless of its etiology. Specific psychiatric disorders and disorders known to be responsive to risperidone include, for example, schizophrenia, schizoaffective disorder, bipolar disorder, and childhood excitability related to the autism spectrum. As used herein, "psychiatric disorder or disorder" refers to psychosis, regardless of its etiology. Specific psychiatric disorders and disorders known to be responsive to risperidone include, for example, schizophrenia, schizoaffective disorder, bipolar disorder, and childhood excitability related to the autism spectrum. include, for example, schizophrenia, schizoaffective disorder, bipolar disorder, and childhood excitability related to the autism spectrum. include, for example, schizophrenia, schizoaffective disorder, bipolar disorder, and childhood excitability related to the autism spectrum.

[0020] The term "implant" means that the drug delivery composition is injectable, in situ formed, biodegradable, and becomes a solid (or semi-solid) implant in situ. Therefore, the formulations disclosed herein are flowable liquids that can be easily injected via a syringe without excessive force. The term "implant" means that the drug delivery composition is injectable, in situ formed, biodegradable, and becomes a solid (or semi-solid) implant in situ. Therefore, the formulations disclosed herein are flowable liquids that can be easily injected via a syringe without excessive force. Therefore, the formulations disclosed herein are flowable liquids that can be easily injected via a syringe without excessive force. Therefore, the formulations disclosed herein are flowable liquids that can be easily injected via a syringe without excessive force.

[0021] As used herein, "repeating unit" is the basic repeating unit of a polymer. For example, lactic acid (LA) is a repeating unit in poly(lactic acid), and ethylene oxide (EO) is a repeating unit in poly (ethylene oxide). (ethylene glycol).

[0022] "End-capped polyethylene glycol" (cPEG) refers to PEG in which one terminal hydroxyl group is reacted, and includes alkoxy-capped PEG, urethane-capped PEG, ester-capped PEG, and similar compounds. The capping group is a chemical group that does not contain a chemical function that is prone to react with cyclic esters such as lactide, glycolide, caprolactone, etc. or other esters and mixtures thereof. By reacting an end-capped PEG polymer with lactide, a diblock cPEG-PLA copolymer is produced. For example, mPEG-PLA refers to a methoxy-capped PEG-polylactide diblock copolymer.

[0023] The abbreviation "PEG" refers to poly(ethylene glycol), poly(ethylene oxide), or poly(oxyethylene), and these terms are used interchangeably herein.

[0024] The abbreviation "PLA" refers to polylactide, polylactic acid, or poly(lactic acid), and these terms are used interchangeably herein.

[0025] The abbreviations "T" or "TB" refer to triblock copolymers, while the abbreviations "D" or "DB" refer to diblock copolymers.

[0026] As used herein, the term "diblock" refers to, for example, an end-capped PEG-polyester copolymer. "mPEG" refers to methoxypolyethylene glycol. The PEG in a diblock copolymer is capped with a known capping entity other than a methoxy group. It may be. Examples of end - capped polyethylene glycols include alkoxy - capped PEG, for example, methoxy PEG or ethoxy PEG, urethane - capped PEG, ester - capped PEG, amine - capped PEG, and amide - capped PEG. This list of end - capped PEG is not exhaustive, and those skilled in the art will recognize additional end - capped PEGs not listed.

[0027] The term "triblock" refers to, for example, a polyester - PEG - polyester copolymer , preferably a poly(lactic acid) - PEG - poly(lactic acid) copolymer.

[0028] The biodegradable drug delivery composition used in the method of the present invention is described in U.S. Patent No. 9,023,897, which is hereby incorporated by reference in its entirety into the specification.

[0029] The structure of the biodegradable triblock / diblock copolymer of the present invention can be represented as follows: : Av - Bw - Ax (which refers to the triblock copolymer poly(lactic acid)v - poly(ethylene oxide)w - poly(lactic acid)x, and is also specified herein as PaRb (where "a" is the size of PEG in kDa units and "b" is the molar ratio LA / EO (v + x / w)) Cy - Az (which refers to the diblock mPEG - PLA copolymer: methoxy - poly(ethylene glycol)y - poly(lactic acid)z, and is also specified herein as dPaRb (where "a" is the size of PEG in kDa units and "b" is the molar ratio LA / EO (z / y))). The methoxy group, or other capping groups cap one of the two hydroxyl groups of PEG. Poly( ​ The lactic acid) chain extends only from the free hydroxyl group.

[0030] The number of repeating units of y and z (degree of polymerization (DP)) in the diblock composition can vary. Thus, y can, for example, range from 7 to 43 or 3 to 45, and z can range from 32 to 123 or 7 to 327. For example, y can be 25 and z can be 123, or y can be 34.5 and z can be 123, or y can be 45 and z can be 32. The degree of polymerization of PEG (DP-PEG) is calculated by dividing the PEG molecular weight of the cap PEG by the molecular weight of the EO unit (44 Da). The degree of polymerization of PLA (DP-PLA ) is calculated by multiplying DP-PEG by the LA / EO ratio.

[0031] The LA / EO ratio refers to the molar ratio of lactic acid units to ethylene oxide units present in each of the block copolymers present in the biodegradable drug delivery composition. This is determined experimentally by NMR and can range from 0.5 to 3.5 for the LA / EO molar ratio of the triblock copolymer. In another embodiment, the LA / EO molar ratio in the triblock can range from 0.5 to 2.5 in the pharmaceutical formulations described herein. In yet another embodiment, the LA / EO ratio in the triblock can range from 0.5 to 22.3. In another embodiment, the LA / EO ratio in the diblock can range from 2 to 6. In another embodiment, the LA / EO ratio in the diblock can range from 3 to 5 in the pharmaceutical formulations described herein.

[0032] ​​It can be. In another aspect, the LA / EO ratio in the diblock ranges from 0.8 to 13 It can be.

[0033] The degree of polymerization or DP is the number of repeating units in the average polymer chain at time t during the polymerization reaction It is. For example, the degree of polymerization of PEG is about 45 to 170, or it can be 4 to 273 or 3 to 45 while for PLA, it can be about 84 to 327, or it can be 24 to 682 or 7 to 327.

[0034] The method of the present invention uses biodegradable pharmaceutical compositions comprising triblock copolymers and diblock copolymers. The biodegradable triblock copolymer has the formula: Av-Bw-Ax (where A is poly( lactic acid), B is poly(ethylene glycol), v and x are the number of repeating units of poly(lactic acid), in the range of 24 to 682; and w is the degree of polymerization of poly(ethylene glycol) (number of repeating units ), in the range of 4 to 273, and v = x or v ≠ x). The degree of polymerization of DP-PEG is calculated by dividing the PEG molecular weight by the EO unit molecular weight (44 Da). v + x is equal to the degree of polymerization of PLA (number of repeating units). DP-PLA is calculated by multiplying DP-PEG by the LA / EO ratio ). The size of PEG in the triblock copolymer can be from 194 Da to 12,000 Da. .

[0035] The triblock copolymer has the formula: Cy-Az (where A is a polyester (i.e., PLA)

[0036] , C is end-capped polyethylene glycol, and y and z are 7 to 371 or 3 to 327 . It can be combined with a biodegradable diblock copolymer having (the number of repeating units in the range of). This combination has a triblock copolymer to diblock copolymer ratio in the range of 1:3 to 1:8 or 1:1 to 1:19 or 3:2 to 1:19. In some embodiments, the triblock copolymer to diblock copolymer ratio is 3:2 to 1:5. In some embodiments , the triblock copolymer to diblock copolymer ratio is 3:2 to 1:4.5. In some embodiments, the triblock copolymer to diblock copolymer ratio is 3:2 to 1:4. In some embodiments, the triblock copolymer to diblock copolymer ratio is 3:2 to 1:3.5. In some embodiments, the triblock copolymer to diblock copolymer ratio is 3:2 to 1:3. In some embodiments, the triblock copolymer to diblock copolymer ratio is 3:2 to 1:2.5. In some embodiments, the triblock copolymer to diblock copolymer ratio is 3:2 to 1:2. In some embodiments, the triblock copolymer to diblock copolymer ratio is 3:2 to 1:1.5. In some embodiments, the triblock copolymer to diblock copolymer ratio is 3:2 to 1:1. .

[0037] In some embodiments, the psychiatric disorder or impairment is schizophrenia, schizoaffective disorder, or bipolar disorder. In other embodiments, the psychiatric disorder or impairment is schizophrenia or bipolar disorder. In other embodiments, the psychiatric disorder or impairment is schizophrenia . In other embodiments, the psychiatric disorder or impairment is schizoaffective disorder Yes. In other embodiments, the psychiatric disorder or condition is bipolar disorder. In some embodiments, the psychiatric disorder is dementia. In some embodiments, the psychiatric disorder is bipolar disorder. In some embodiments, the psychiatric disorder is depression. In some embodiments, the psychiatric disorder is manic disorder. In some embodiments, the psychiatric disorder is a psychotic episode. As used herein, the treatment method refers to alleviating the symptoms of a psychiatric disorder or condition. In some embodiments, the treatment method includes a delay in time to recurrence compared to a subject not receiving a pharmaceutical formulation. In some embodiments, the treatment method includes a decrease in the impending recurrence rate estimated using the Kaplan- Meier method. In some embodiments, the treatment method includes a decrease in the observed impending recurrence rate. In some embodiments, the treatment method includes maintaining stability, including meeting all of the following criteria for at least 4 consecutive weeks: outpatient status; PANSS total score ≤ 80; presence of minimal specific psychotic symptoms on the PANSS, measured by a score ≤ 4 for each of the following items: conceptual disorganization, suspiciousness, hallucinatory behavior, and unusual thought content; clinical global impression - severity (CGI-S) score ≤ 4 (moderate disease); and clinical global impression - suicide severity (CGI-SS) score part 1 ≤ 2 (mild suicidal desire) and part 2 ≤ 5 (minimal worsening). The percentage is

[0038] In some embodiments, the present invention is directed to a subcutaneous administration method for treating a psychiatric disorder or condition in a subject. In particularly preferred embodiments, the subject is a human. In some embodiments, the subject is an adult over 18 years of age. In some embodiments, the subject is a human adolescent between 13 and 18 years of age. The method of the present invention involves subcutaneous administration of a high-concentration, low-volume formulation of risperidone to a subject. In some embodiments, the subcutaneous administration is to the abdomen of the subject. In other embodiments, the subcutaneous administration is to the upper arm of the subject. Subcutaneous administration of the risperidone formulation of the present invention can result in in situ formation of a solid or semi-solid implant. In these embodiments, the solid or semi-solid formulation is removable (i.e., can be removed from the subject) after administration to the subject. Medical practitioners in the art can determine the preferred method and time for removal. In some embodiments of the method of the present invention, the administration is at a frequency of once or less every 21 days. In these embodiments, the administration provides treatment of the psychiatric disorder or condition for at least 21 days. In some embodiments, the administration is at a frequency of once or less every 28 days. In these embodiments, the administration provides treatment of the psychiatric disorder or condition for at least 28 days. In some embodiments, the administration is at a frequency of once or less every 30 days. In these embodiments, the administration provides treatment of the psychiatric disorder or condition for at least 30 days. In other embodiments, the administration is at a frequency of once or less every 45 days.

[0039]

[0040]

[0041] In these embodiments, administration results in treatment of a psychiatric disorder or condition for at least 45 days. In other embodiments, administration is at a frequency of once every 56 days or less. In these embodiments, administration results in treatment of a psychiatric disorder or condition for at least 56 days. In other embodiments, administration is at a frequency of once every 60 days or less. In these embodiments, administration results in treatment of a psychiatric disorder or condition for at least 60 days.

[0042] According to the method of the invention, a pharmaceutical preparation of 1 mL or less is administered to a subject as described herein. In some embodiments, 1 mL of a pharmaceutical preparation is administered to a subject. In other embodiments, a pharmaceutical preparation of 0.9 mL or less is administered to a subject. In other embodiments, a pharmaceutical preparation of 0.8 mL or less is administered to a subject. In other embodiments, a pharmaceutical preparation of 0.7 mL or less is administered to a subject. In other embodiments, a pharmaceutical preparation of 0.6 mL or less is administered to a subject. In other embodiments, a pharmaceutical preparation of 0.5 mL or less is administered to a subject. In other embodiments, a pharmaceutical preparation of 0.4 mL or less is administered to a subject. In other embodiments, a pharmaceutical preparation of 0.3 mL or less is administered to a subject. In other embodiments, a pharmaceutical preparation of 0.2 mL or less is administered to a subject. In other embodiments, a pharmaceutical preparation of 0.1 mL or less is administered to a subject. In some embodiments, a pharmaceutical preparation of 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0. 7, 0.8, 0.9, or 1 mL is administered to a subject. In some embodiments, a pharmaceutical preparation of 0.1, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.2, 0.21, 0.22, 0.23 is administered to a subject. , 0.24, 0.25, 0.26, 0.27, 0.28, 0.29, 0.3, 0.31, 0.32, 0.33, 0.34, 0.35, 0.36, 0 .37, 0.38, 0.39, 0.4, 0.41, 0.42, 0.43, 0.44, 0.45, 0.46, 0.47, 0.48, 0.49, 0.5 , 0.51, 0.52, 0.53, 0.54, 0.55, 0.56, 0.57, 0.58, 0.59, 0.6, 0.61, 0.62, 0.63, 0 .64, 0.65, 0.66, 0.67, 0.68, 0.69, 0.7, 0.71, 0.72, 0.73, 0.74, 0.75, 0.76, 0.77 , 0.78, 0.79, 0.8, 0.81, 0.82, 0.83, 0.84, 0.85, 0.86, 0.87, 0.88, 0.89, 0.9, 0. 91, 0.92, 0.93, 0.94, 0.95, 0.96, 0.97, 0.98, 0.99, or 1 mL of the pharmaceutical preparation is administered . In some embodiments, the pharmaceutical preparation comprises risperidone or a salt thereof at 250 mg / mL to 400 mg / mL in terms of risperidone conversion .

[0043] According to the method of the present invention, the pharmaceutical preparation to be administered comprises risperidone or a pharmaceutically acceptable salt thereof . In some embodiments, the pharmaceutical preparation comprises risperidone as risperidone base . In other embodiments, the pharmaceutical preparation comprises risperidone as a pharmaceutically acceptable salt of risperidone . In still other embodiments, the pharmaceutical preparation comprises risperidone as a mixture of risperidone base and a pharmaceutically acceptable salt of risperidone .

[0044] The pharmaceutically effective amount of risperidone can vary depending on the degree of the subject's medical condition and the time required to deliver risperidone . The method of the present invention is particularly suitable for delivery of 1 mL or less ​A formulation having a concentration of risperidone (or a salt thereof) of at least 250 mg / mL in terms of risperidone at the end of the capacity is targeted. Although there is no strict upper limit to the amount of risperidone (or a salt thereof), the formulation should be such that it is suitable for injection via a syringe needle with a viscosity suitable for effectively treating psychiatric diseases or disorders without exposing the subject to the risk of risperidone overdose. In the biodegradable drug delivery composition of the present invention, the concentration of risperidone or a pharmaceutically acceptable salt thereof used is at least 250 mg / mL in terms of risperidone, preferably at least 300 mg / mL in terms of risperidone. In some embodiments, the concentration of risperidone or a pharmaceutically acceptable salt thereof used in the biodegradable drug delivery composition of the present invention is 250 - 300 mg / mL in terms of risperidone. In other embodiments, the concentration of risperidone or a pharmaceutically acceptable salt thereof used in the biodegradable drug delivery composition of the present invention is 300 - 400 mg / mL in terms of risperidone. In other embodiments, the concentration of risperidone or a pharmaceutically acceptable salt thereof used in the biodegradable drug delivery composition of the present invention is 300 - 350 mg / mL in terms of risperidone. In other embodiments, the concentration of risperidone or a pharmaceutically acceptable salt thereof used in the biodegradable drug delivery composition of the present invention is 350 - 400 mg / mL in terms of risperidone. The concentration of risperidone or an equivalent amount of risperidone salt in the formulation is about 250 mg / mL - 400 mg / mL.

[0045] Risperidone or a pharmaceutically acceptable salt thereof used in the biodegradable drug delivery composition of the present invention should be such that it is suitable for injection via a syringe needle with a viscosity suitable for effectively treating psychiatric diseases or disorders without exposing the subject to the risk of risperidone overdose. In the biodegradable drug delivery composition of the present invention, the concentration of risperidone or a pharmaceutically acceptable salt thereof used is at least 250 mg / mL in terms of risperidone, preferably at least 300 mg / mL in terms of risperidone. In some embodiments, the concentration of risperidone or a pharmaceutically acceptable salt thereof used in the biodegradable drug delivery composition of the present invention is 250 - 300 mg / mL in terms of risperidone. In other embodiments, the concentration of risperidone or a pharmaceutically acceptable salt thereof used in the biodegradable drug delivery composition of the present invention is 300 - 400 mg / mL in terms of risperidone. In other embodiments, the concentration of risperidone or a pharmaceutically acceptable salt thereof used in the biodegradable drug delivery composition of the present invention is 300 - 350 mg / mL in terms of risperidone. In other embodiments, the concentration of risperidone or a pharmaceutically acceptable salt thereof used in the biodegradable drug delivery composition of the present invention is 350 - 400 mg / mL in terms of risperidone. The concentration of risperidone or a pharmaceutically acceptable salt thereof used in the biodegradable drug delivery composition of the present invention should be such that it is suitable for injection via a syringe needle with a viscosity suitable for effectively treating psychiatric diseases or disorders without exposing the subject to the risk of risperidone overdose. In the biodegradable drug delivery composition of the present invention, the concentration of risperidone or a pharmaceutically acceptable salt thereof used is at least 250 mg / mL in terms of risperidone, preferably at least 300 mg / mL in terms of risperidone. In some embodiments, the concentration of risperidone or a pharmaceutically acceptable salt thereof used in the biodegradable drug delivery composition of the present invention is 250 - 300 mg / mL in terms of risperidone. In other embodiments, the concentration of risperidone or a pharmaceutically acceptable salt thereof used in the biodegradable drug delivery composition of the present invention is 300 - 400 mg / mL in terms of risperidone. In other embodiments, the concentration of risperidone or a pharmaceutically acceptable salt thereof used in the biodegradable drug delivery composition of the present invention is 300 - 350 mg / mL in terms of risperidone. In other embodiments, the concentration of risperidone or a pharmaceutically acceptable salt thereof used in the biodegradable drug delivery composition of the present invention is 350 - 400 mg / mL in terms of risperidone. The concentration of risperidone or a pharmaceutically acceptable salt thereof used in the biodegradable drug delivery composition of the present invention should be such that it is suitable for injection via a syringe needle with a viscosity suitable for effectively treating psychiatric diseases or disorders without exposing the subject to the risk of risperidone overdose. In the biodegradable drug delivery composition of the present invention, the concentration of risperidone or a pharmaceutically acceptable salt thereof used is at least 250 mg / mL in terms of risperidone, preferably at least 300 mg / mL in terms of risperidone. In some embodiments, the concentration of risperidone or a pharmaceutically acceptable salt thereof used in the biodegradable drug delivery composition of the present invention is 250 - 300 mg / mL in terms of risperidone. In other embodiments, the concentration of risperidone or a pharmaceutically acceptable salt thereof used in the biodegradable drug delivery composition of the present invention is 300 - 400 mg / mL in terms of risperidone. In other embodiments, the concentration of risperidone or a pharmaceutically acceptable salt thereof used in the biodegradable drug delivery composition of the present invention is 300 - 350 mg / mL in terms of risperidone. In other embodiments, the concentration of risperidone or a pharmaceutically acceptable salt thereof used in the biodegradable drug delivery composition of the present invention is 350 - 400 mg / mL in terms of risperidone. The concentration of risperidone or a pharmaceutically acceptable salt thereof used in the biodegradable drug delivery composition of the present invention should be such that it is suitable for injection via a syringe needle with a viscosity suitable for effectively treating psychiatric diseases or disorders without exposing the subject to the risk of risperidone overdose.

[0046] The concentration of risperidone or an equivalent amount of risperidone salt in the formulation is about 250 mg / mL - 400 mg / mL. ​260 mg / mL to 400 mg / mL, 270 mg / mL to 400 mg / mL, 280 mg / mL to 400 mg / mL, 290 mg / mL to 400 mg / mL, 300 mg / mL to 400 mg / mL, 310 mg / mL to 440 mg / mL, 315 mg / mL to 440 mg / mL, 320 mg / mL to 400 mg / mL, 330 mg / mL to 400 mg / mL, 340 mg / mL to 400 mg / mL, 350 mg / mL to 400 mg / mL, 360 mg / mL to 400 mg / mL, 370 mg / mL to 400 mg / mL, 380 mg / mL to 400 mg / mL, 390 mg / mL to 400 mg / mL, 260 mg / mL to 340 mg / mL, 270 mg / mL to 340 mg / mL, 280 mg / mL to 340 mg / mL can be in the range. In various embodiments the concentration of risperidone or an equivalent amount of risperidone salt in the formulation is 250, 251, 252, 2 53, 254, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 2 69, 270, 271, 272, 273, 274, 275, 276, 277, 278, 279, 280, 281, 282, 283, 284, 2 85, 286, 287, 288, 289, 290, 291, 292, 293, 294, 295, 296, 297, 298, 299, 300, 3 01, 302, 303, 304, 305, 306, 307, 308, 309, 310, 311, 312, 313, 314, 315, 316, 3 17, 318, 319, 320, 321, 322, 323, 324, 325, 326, 327, 328, 329, 330, 331, 332, 3 33, 334, 335, 336, 337, 338, 339, 340, 341, 342, 343, 344, 345, 346, 347, 348, 3 49, 350, 351, 352, 353, 354, 355, 356, 357, 358, 359, 360, 360, 361, 362, 363, 3 64, 365, 366, 367, 368, 369, 370, 371, 372, 373, 374, 375, 376, 377, 378, 379, 3 80, 381, 382, 383, 384, 385, 386, 387, 388, 389, 390, 391, 392, 393, 394, 395, 3 96, 397, 398, 399, or 400 (unit: mg / mL).

[0047] In some embodiments, the concentration of risperidone or an equivalent amount of risperidone salt in the formulation is greater than 400 mg / mL, for example, 410, 420, 430, 440, 450, 460, 470, 480, 490, or 500 (unit is mg / mL).

[0048] The length of the polyester chain is defined by its polyester to ethylene oxide molar ratio, which, for triblock copolymers, is 0.5 - 3.5 or 0.5 - 2.5 or 0.5 - 22.3 and for diblock copolymers, is 3 - 5 or 2 - 6 or 0.8 - 13. Thus, for example, when polylactic acid is used, the chain length is defined by the lactic acid / ethylene oxide molar ratio.

[0049] The mass of the end - cap polyethylene glycol can range from 164 Da to 2,000 Da or 100 Da to 2 kDa. This can range from the lower range of 100 - 300 Da or can range from 1 kDa - 2 kDa.

[0050] The size of the polyethylene glycol chain in the biodegradable drug delivery composition ranges from 200 Da to 12 kDa, or this can range from 400 Da to 12 kDa or 194 Da to 12 kDa.

[0051] ​​​ The triblock copolymer is present in an amount of 3.0% to 45% (w / w%) of the total weight of the composition. Alternatively in another embodiment, the triblock copolymer is present in an amount of 6% to 10% (w / w%) of the total weight of the composition. In yet another embodiment, the triblock copolymer is present in an amount of 20% to 40% (w / w%) of the total weight of the composition. In some embodiments, the triblock copolymer is present in an amount of 3% to 20% (w / w%) of the total weight of the formulation. In another embodiment, the triblock co polymer is present in an amount of 5% to 17% (w / w%) of the total weight of the formulation. In another embodiment, the tri block copolymer is present in an amount of 7% to 12% (w / w%) of the total weight of the formulation. In another embodiment, the triblock copolymer is present in an amount of 5% to 15% (w / w%) of the total weight of the formulation. Further in yet another embodiment, the triblock copolymer is about 3%, 3.5%, 4%, 4 .5%, 5%, 5.5%, 6%, 6.5%, 7%, 7.5%, 8%, 8.5%, 9%, 9.5%, 10%, 10.5%, 11%, 11.5%, 12%, 12.5%, 13%, 13.5%, 14%, 14.5%, 15%, 15.5%, 16%, 16.5 %, 17%, 17.5%, 18%, 18.5%, 19%, 19.5%, 20% (w / w%) of the total weight of the formulation.

[0052] The diblock copolymer can be present in an amount of 8% to 50% (w / w%) of the total weight of the composition in the biodegradable pharmaceutical composition. In another embodiment, the diblock copolymer is present in an amount of 10% to 20% (w / w%) of the total weight of the composition. In yet another embodiment, the diblock copolymer is present in an amount of 20% to 40% (w / w%) of the total weight of the composition. In some embodiments, The diblock copolymer can be present in an amount of 6% to 30% (w / w%) of the total weight of the formulation in the biodegradable pharmaceutical formulation. In another aspect, the diblock copolymer is present in an amount of 8 % to 30% (w / w%) of the total weight of the formulation. In some aspects of the method of the present invention, the diblock copolymer is present in an amount of about 8% to 25% (w / w%) of the total weight of the formulation. In another aspect, the diblock copolymer is present in an amount of 10% to 25% (w / w%) of the total weight of the formulation. In some aspects of the method of the present invention, the diblock copolymer is present in an amount of about 10% to 20% (w / w%) of the total weight of the formulation. In yet another aspect, the diblock copolymer is present in the total weight of the formulation in an amount of 6%, 6.5%, 7%, 7.5%, 8%, 8.5%, 9%, 9.5%, 10%, 10.5%, 11%, 11.5%, 12%, 12.5%, 13%, 13.5%, 14%, 14.5%, 15%, 15.5%, 16%, 16.5%, 17%, 17.5 %, 18%, 18.5%, 19%, 19.5%, 20%, 20.5%, 21%, 21.5%, 22%, 22.5%, 23%, 23.5%, 24%, 24.5%, 25%, 25.5%, 26%, 26.5%, 27%, 27.5%, 28%, 28.5%, 29 %, 29.5%, 30% (w / w%) of the total weight of the formulation.

[0053] The polymer is present in an amount of 20% to 50% (w / w%) of the total weight of the composition in the pharmaceutical formulation. In another aspect, the total weight of the polymer present in the biodegradable pharmaceutical composition is 30% to 50% (w / w%) of the total weight of the composition. In yet another aspect, the polymer is present in the biodegradable pharmaceutical composition in an amount of 40% to 50% (w / w%) of the total weight of the composition.

[0054] In a preferred embodiment, the total amount of the triblock and diblock copolymers is present in an amount of 20% to 45% (w / w%) of the total weight of the formulation. In other preferred embodiments, the total amount of the triblock and diblock copolymers present in the pharmaceutical formulations used herein is 20% to 30% (w / w%). In some embodiments of the method of the present invention, the triblock and diblock copolymers are present in a total amount of about 25% to about 45% (w / w%) of the total weight of the formulation. Also in another embodiment, the polymer is about 20%, 20.5%, 21%, 21.5%, 22%, 22.5%, 23%, 23.5%, 24%, 24.5%, 25%, 25.5%, 26%, 26.5 %, 27%, 27.5%, 28%, 28.5%, 29%, 29.5%, 30%, 30.5%, 31%, 31.5%, 32%, 32.5%, 33%, 33.5%, 34%, 34.5%, 35%, 35.5%, 36%, 36.5%, 37%, 37.5%, 38 %, 38.5%, 39%, 39.5%, 40%, 40.5%, 41%, 41.5%, 42%, 42.5%, 43%, 43.5% 44%, 44.5%, or 45% (w / w%) in the biodegradable drug formulation.

[0055] The ratio of the biodegradable triblock copolymer (b) to the biodegradable diblock copolymer (c) is 1:3 to 1:8 or 1:1 to 1:19 or 3:2 to 1:19 in the pharmaceutical formulations of the present invention.

[0056] In one embodiment, the ratio of the biodegradable triblock copolymer to the biodegradable diblock copolymer is 3:2, 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, and 1:8 or 1:1, 1:2, 1:3, 1:4 , 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:11, 1:12, 1:13, 1:14, 1:15, 1:16, 1:17, 1:18 and selected from 1:19.

[0057] In some embodiments, the ratio of the biodegradable triblock copolymer to the biodegradable diblock copolymer is 3:2. In other embodiments, the ratio of the biodegradable triblock copolymer to the biodegradable diblock copolymer is 1:4. In still other embodiments, the ratio of the biodegradable triblock copolymer to the biodegradable CA diblock copolymer is 2:3.

[0058] The pharmaceutical formulations used in the methods of the present disclosure can further comprise a pharmaceutically acceptable carrier, adjuvant, or vehicle. Acceptable carriers can be, for example, physiological saline, buffered physiological saline, and the like. Adjuvants can be formulated simultaneously when mixing the drug. In this regard, adjuvants that can be used include alum, aluminum phosphate, calcium phosphate, MPL™, CpG motif, modified toxins, saponins, endogenous stimulatory adjuvants such as cytokines, Freund's complete and incomplete adjuvants, ISCOM-type adjuvants, muramyl peptides, and the like.

[0059] The pharmaceutical formulations used in the methods of the present invention also include organic solvents. In a preferred embodiment, the organic solvent is a water-soluble organic solvent. Organic solvents that can be used in the methods described herein include benzyl alcohol, benzyl benzoate, diethylene glycol dimethyl ether (Diglyme), diethylene glycol monoethyl ether (DEGMEE), ) Dimethyl isosorbide (DMI), dimethyl sulfoxide (DMSO), ethyl acetate, ethyl benzoate, ethyl lactate, ethylene glycol monoethyl ether acetate, glycerol formal, methyl ethyl ketone, methyl isobutyl ketone, N-ethyl-2-pyrrolidone, N-methyl- 2-pyrrolidinone (NMP), pyrrolidone-2, tetra glycol, triacetin, tributyrin , tripropionin (tripro), or triethylene glycol dimethyl ether (triglyme) and mixtures thereof: are selected from the group. A preferred organic solvent is the water-soluble organic solvent DMSO .

[0060] The organic solvent is present in an amount of 40% - 74% (w / w%) of the total composition. In another aspect, the organic solvent used in the preparation of the biodegradable drug delivery composition is present in an amount of 50% - 60% (w / w% ) of the total composition. In yet another aspect, the solvent used in the preparation of the biodegradable drug delivery composition is present in an amount of 60% - 70% (w / w%) of the total composition. The organic solvent can be present in an amount of 15 % - 45% or 40% - 74% (w / w%) of the total formulation. In another aspect, the organic solvent used in the preparation of the pharmaceutical formulation is present in an amount of 40% - 50% (w / w%) of the total formulation . In some embodiments, the organic solvent is DMSO. Triglycerides such as triacetin or tripropionin can also be included with DMSO. The amount of DMSO that can be used in the pharmaceutical formulation of the method of the present invention can be 35% - 55% (w / w%), preferably 35% - 45 % (w / w%). In one aspect, DMSO is in an amount of 10% - 15% (w / w%) of tri

[0061] and the like. % (w / w%). In one embodiment, DMSO is present in an amount of 10% - 15% (w / w%) of tri It may contain glycerides, such as triacetin, tripropionin, or mixtures thereof .

[0062] In the biodegradable drug delivery composition of the present invention, which is also referred to herein as a pharmaceutical formulation the amount of risperidone is gradually released over a long period of time. This slow release can be continuous or discontinuous, linear or non-linear, and can vary depending on the composition of the triblock copolymer and diblock copolymer. Thus, the higher the lactic acid content of the triblock and diblock copolymers compared to the polyethylene glycol content, and the greater the amount of triblock and diblock copolymers present in the biodegradable drug composition, the longer the release of the active ingredient or drug will be. That is, the greater the LA / EO molar ratio and the greater the weight percentage of the triblock and diblock copolymers, the longer the time it takes for the active ingredient to be released from the drug composition . The volume can also affect the release, and the active ingredient is released over a longer period of time from a larger volume than from a smaller volume [see the data in Example 2 below for reference . . . .

[0063] In one aspect, the biodegradable drug delivery composition can deliver risperidone for at least 21 days . In one aspect, the biodegradable drug delivery composition can deliver risperidone for 21 days to about 90 days. In another aspect, the biodegradable drug delivery composition can deliver risperidone for about 21 - 30 days or about 28 - 31 days . In another aspect, the biodegradable drug delivery composition can deliver risperidone for at least 30 days . In another aspect In such a manner, the biodegradable drug delivery composition can deliver risperidone for about 56 to 63 days. In another aspect, the biodegradable drug delivery composition can deliver risperidone for at least 60 days. In one aspect, the biodegradable drug delivery composition can deliver risperidone for at least 90 days.

[0064] In the method of the present invention, administration results in the release of a therapeutically effective amount of risperidone from the formulation to treat a psychiatric disorder or condition in a subject over a prolonged period. In some embodiments, administration is effective to treat a psychiatric disorder or condition in a subject for 21 days to 90 days. In some embodiments, administration is effective to treat a psychiatric disorder or condition in a subject for 28 days to 90 days. In other embodiments, administration is effective to treat a psychiatric disorder or condition in a subject for 28 or 30 days to 56 or 60 days. In some embodiments, administration is effective to treat a psychiatric disorder or condition in a subject for 28 days or 30 days. In other embodiments, administration is effective to treat a psychiatric disorder or condition in a subject for 45 days. In other embodiments, administration is effective to treat a psychiatric disorder or condition in a subject for 56 days or 60 days. In other embodiments, administration is effective to treat a psychiatric disorder or condition in a subject for 84 days or 90 days. Administration may be repeated, for example, after each period of 28 days or 56 days.

[0065] In the most preferred embodiment of the method of the present invention, the release of risperidone from the pharmaceutical formulation is such that a therapeutically effective level of risperidone is achieved within 24 hours of subcutaneous administration. If a therapeutically effective level of risperidone is achieved within 24 hours of subcutaneous administration, alternative immediate release risperidone formulations (e.g., immediate release oral formulations or immediate release injectable formulations) are not required to ensure sufficient risperidone levels in the subject. That is, "loading doses" or supplemental oral doses of risperidone are not necessarily required in the methods of the present invention. Thus, in some embodiments, the method is carried out in the absence of a loading dose of or supplemental oral risperidone.

[0066] Using the methods of the present invention, a therapeutically effective amount of risperidone will be released by the target date. Thus, in an amount of a "30-day formulation", about 50 w% of risperidone (or a salt thereof), or about 50 w% to about 80 w%, such as 50, 55, 60, 65, 70, 75, or 80 w%, will preferably be released cumulatively by 30 days after administration in a release profile that is nearly linear. As used herein, the term "cumulatively released" refers to the total amount of risperidone (by weight) released by a particular time point as a percentage of the total amount of risperidone in the formulation. Cumulative release can be measured, for example, by the in vitro release (IVR) methods known in the art and described herein. Thus, in an amount of a "60-day formulation", about 75 w% of risperidone (or a salt thereof), or about 75 w% to about 98 w%, such as 75, 70, 85, 90, 91 92, 93, 94, 95, 96, 97, or about 98 w%, will preferably be released cumulatively by 60 days after administration in a release profile that is nearly linear. Thus, the present invention provides for a sustained and uniform release of risperidone over a desired period. ​​​​

[0067] In some embodiments, less than about 15 w% of the risperidone in the formulation is cumulatively released 24 hours after administration. In other embodiments, about 7 w% to about 15 w%, such as 7, 8, 9, 10, 11, 12, 13, 14, or 15 w% of the risperidone in the formulation is cumulatively released 24 hours after administration.

[0068] In some embodiments, about 50 w% to about 80 w% of the risperidone (or a salt thereof) in the formulation, such as 50, 55, 60, 65, 70, 75, or 80 w%, is cumulatively released 30 days after administration. In some embodiments, about 50 w% to about 80 w % of the risperidone (or a salt thereof) in the formulation, such as 50, 55, 60, 65, 70, 75, or 80 w%, is cumulatively released 28 days after administration.

[0069] In some embodiments, about 70 w% to about 98 w% of the risperidone (or a salt thereof) in the formulation, such as 75, 70, 85, 90, 91, 92, 93, 94, 95, 96, 97, or about 98 w%, is cumulatively released 60 days after administration. In some embodiments, about 70 w% to about 98 w% of the risperidone (or a salt thereof) in the formulation, such as 75, 70, 85, 90, 91, 92, 93, 94, 95, 96, 97, or about 98 w%, is cumulatively released 56 days after administration.

[0070] The pharmaceutical formulations used in the methods of the present disclosure are injectable solutions at room temperature and can be injected via a syringe without excessive force. The composition also forms in situ, is biodegradable, and becomes a solid or semi-solid implant when injected into an animal.

[0071] ​​​ In some embodiments of the method of the present invention, the pharmaceutical formulation is administered from a pre-filled syringe (PFS). The PFS contains an appropriate amount of the pharmaceutical formulation and is preferably a syringe ready for subcutaneous administration by a medical professional. In some embodiments of the method of the present invention, the pharmaceutical formulation is administered from a single pre-filled syringe. In other embodiments, the pharmaceutical formulation is administered from multiple pre-filled syringes, for example, two, three, four, five, or six, or more pre-filled syringes. According to the present disclosure, the volume of the pharmaceutical formulation in the pre-filled syringe is 1 mL or less. In some embodiments, the volume of the pharmaceutical formulation in the pre-filled syringe is 0.1 mL to 0.9 mL.

[0072] In some embodiments, the volume of the pharmaceutical formulation in the pre-filled syringe is 0.1 mL to 0.8 mL. In some embodiments, the volume of the pharmaceutical formulation in the pre-filled syringe is 0.1 mL to 0.5 mL. In some embodiments, the volume of the pharmaceutical formulation in the pre-filled syringe is about 0.1 mL. In some embodiments, the volume of the pharmaceutical formulation in the pre-filled syringe is about 0.2 mL. In some embodiments, the volume of the pharmaceutical formulation in the pre-filled syringe is about 0.3 mL. In some embodiments, the volume of the pharmaceutical formulation in the pre-filled syringe is about 0.4 mL. In some embodiments, the volume of the pharmaceutical formulation in the pre-filled syringe is about 0.5 mL. In some embodiments, the volume of the pharmaceutical formulation in the pre-filled syringe is about 0.6 mL. In some embodiments, the volume of the pharmaceutical formulation in the pre-filled syringe is about 0.7 mL. In some embodiments, the volume of the pharmaceutical formulation in the pre-filled syringe is about 0.8 mL. In some embodiments, the volume of the pharmaceutical formulation in the pre-filled syringe is about 0.9 mL. In some embodiments, the volume of the pharmaceutical formulation in the pre-filled syringe is about 1 mL. . In some embodiments, the volume of the pharmaceutical formulation in the prefilled syringe is about 0.9 mL . In some embodiments, the volume of the pharmaceutical formulation in the prefilled syringe is about 1.0 mL . In some embodiments, the amount of risperidone in the pharmaceutical formulation is in a volume of about 0.14 mL and is 50 mg. In some embodiments, the amount of risperidone in the pharmaceutical formulation is about 0.28 mL and is 100 mg in a volume thereof. In some embodiments, the amount of risperidone in the pharmaceutical formulation is 150 mg in a volume of about 0.42 mL. In some embodiments, the ris peridone amount in the pharmaceutical formulation is 200 mg in a volume of about 0.56 mL. In some embodiments, the pharmaceutical formulation has a risperidone amount of 250 mg in a volume of about 0.7 mL. In some embodiments, the amount of risperidone in the pharmaceutical formulation is 300 mg in a volume of about 0.84 mL.

[0073] Many mental disorders are chronic diseases that require continuous treatment to suppress symptoms and prevent recurrence. Thus, the method of the present invention can be carried out over a long period of time. In some embodiments, the method is carried out over at least 6 months. In other embodiments, the method is carried out over at least 12 months. In other embodiments the method is carried out over at least 15 months. In other embodiments the method is carried out over at least 24 months.

[0074] Further provided is for use in the treatment of a psychiatric disorder or condition, 1 mL or less of: a) risperidone or a pharmaceutically acceptable salt thereof at a concentration of about 250 - 400 mg / mL in terms of risperidone b) formula: poly(lactic acid)v-poly(ethylene glycol)w,-poly(lactic acid)x (wherein v and x are the number of repeating units in the range of 24 to 682, and w is the number of repeating units in the range of 4 to 273, and v = x or v ≠ x) : having a biodegradable triblock copolymer; c) formula: methoxypoly(ethylene glycol)y-poly(lactic acid)z (wherein y and z are the number of repeating units, where y is the number of repeating units in the range of 3 to 45 and z is the number of repeating units in the range of 7 to 327) : having a biodegradable diblock copolymer; including, and wherein the ratio of the biodegradable triblock copolymer of (b) to the biodegradable diblock copolymer of (c) is 1:3 to 1:8 or 1:1 to 1:19 or 3:2 to 1:19 in the formulation that is insoluble in an aqueous environment is a pharmaceutical formulation.

[0075] The method for preparing the pharmaceutical formulation used in the method of the present invention is disclosed in, for example, U.S. 9,023,897, which is incorporated herein by reference into the specification.

[0076] Some mPEG-OH is contaminated with a small amount of OH-PEG-OH. According to the method of the present invention, by using the contaminated mPEG-OH, the final product is mPEG-PLA contaminated with a small amount of PLA-PEG-PLA, which is encompassed by the present invention .

[0077] Regarding the foregoing embodiments, each of the embodiments disclosed herein is considered applicable to each of the other disclosed embodiments. For example, in the embodiments of the method, the columns The recited elements can be used in embodiments of the pharmaceutical compositions or formulations described herein, and vice versa. And vice versa.

[0078] The following examples are for illustrative purposes and are intended to be non-limiting. Those skilled in the art will readily recognize various features that can be changed or modified to produce essentially the same results.

Examples

[0079] (Example) (Example 1. In Vitro Release (IVR) Model) The in vitro model was set up based on the USP II dissolution test technique. In this technique, the in vitro release of a drug formulation is monitored in a tube containing an aqueous buffer maintained at +37 °C under constant agitation. Approximately 100 or 170 mg of the formulation was injected into the interior of a 50 mL Falcon® tube pre-filled with 50 mL of Krebs-Ringer-Tris buffer (KRT, pH 7.4) using a 0.5-mL syringe fitted with a 23G needle, and incubated at +37 °C under constant orbital agitation (180 rpm). Since the copolymer is insoluble in water, the depot formed freely immediately after contact with the buffer. This is intended to mimic implant formation in the subcutaneous tissue in vivo.

[0080] The in vitro release of each formulation was performed in duplicate. At predetermined time points, the release buffer was sampled and replaced with fresh buffer. Special care was taken to ensure that no fragments of the depot (if present) were lost during buffer replacement. At the end of the IVR, a mass balance was evaluated and the remaining depot was analyzed to confirm that the amount of active agent remaining in the depot correlated with the cumulative release. ​ The amount of the active agent in it was determined by HPLC. Briefly, the remaining depot preparation was dissolved in 10 mL of acetonitrile. The solution was mixed using a vortex mixer until completely dissolved, and then 10 mL of ultrapure water was added. The mixture was shaken again before HPLC analysis.

[0081] (Preparation of Stock Solution, Standard, and Quality Control Samples) To obtain a 200 μg / mL risperidone solution, risperidone was dissolved in an acetonitrile / H2O mixture (50 / 50 v / v) to prepare a stock solution. This "mother solution" was stored at +2 to 8 °C and showed stability over at least 5 months. Starting from this mother solution, calibration standards were prepared by dilution into the same sample solvent mixture as described above. Six dilutions were performed to obtain calibration standards of 1, 5, 10, 25, 50, 100, and 200 μg / mL. By further diluting the 10 μg / mL standard, additional working solutions containing 0.10, 0.25, 0.50, and 0.75 μg / mL were similarly prepared. These further diluted samples were specifically used to examine the detection limit (LOD) and quantification limit (LOQ) of the chromatographic method.

[0082] A series of three accuracy standards (10, 100, and 200 μg / mL) were also independently prepared by dilution of the starting mother solution (200 μg / mL) using the same sample solvent as above. Using these standards, the accuracy level of the developed method was evaluated.

[0083]

[0084] (Apparatus and Chromatography Conditions)

[0084] (Apparatus and Chromatography Conditions) A Waters 2487 dual-wavelength UV detector set at 280 nm (corresponding to the maximum absorption wavelength of risperidone) An HPLC apparatus with a Waters 269S separation module was used. The separation column (150 mm × 4.6 mm) was packed with Kinetex C18 having a particle size of 5 μm. Table 1 below summarizes the mobile phase gradients used in this test. A flow rate of 1 mL / min was used and the column temperature was set at +30 °C. The injection volume of the sample was 10 μL. Table 1

Table 1

[0085] According to the above conditions, the retention time of risperidone was set at 5.5 minutes. Linearity was evaluated throughout the analysis of standards (1, 5, 10, 25, 50 , 100, and 200 μg / mL). Calibration was set based on the respective standard peak areas 2 >[[]] 0.9999 was obtained. Precision was determined by calculating the relative standard deviation (RSD) between the average measured concentrations of three precision standards, namely 10, 100, and 200 μg / mL. The RSD was <0.1% for all precision standards and the recovery was in the range of 99.7 - 101.9% of the target concentration. The LOD was calculated to be 0 .1 μg / mL (corresponding to three times the average baseline noise). The LOQ was evaluated as the lowest concentration that enables 90% recovery of the target drug concentration. It was found that the LOQ was 0.5 μg / mL .

[0086] Injectionability was measured according to the standard operating procedure (SOP, using a texture meter (LA - PR - EQ - 6 - 1 - EN)). This method was inspired by a previous study by F. Cilurzo et al. The measurement of injectionability ​The apparatus used was a Friction Tester FTPlus (Lloyd Instruments) connected to Nexygen Plus software. Briefly, the injectability test was performed by fixing the crosshead speed at 1.1 mL / min and using a 1-mL CODAN syringe fitted with a 23G or 25G needle. The syringe was pre-filled with at least 0.5 mL of the formulation to be tested. Then, the dynamic glide force (DGF) (i.e., the average force in Newton (N) units required to sustain the movement of the plunger to expel the formulation from the syringe) was measured in each test. F. Cilurzo et al. showed that "this parameter represents manual syringe delivery to patients" (Cilurzo, F et al., Injectability Evaluation: An Open Issue. AAPS PharmSciTech. 2011 2: 604-609). loyd Instruments). was fixed at 1.1 mL / min and a 1-mL CODAN syringe fitted with a 23G or 25G needle was used as such. The syringe was pre-filled with at least 0.5 mL of the formulation to be tested. Then, the dynamic glide force (DGF) (i.e., the average force in Newton (N) units required to sustain the movement of the plunger to expel the formulation from the syringe) was measured in each test. F. Cilurzo et al. showed that "this parameter represents manual syringe delivery to patients" and that (Cilurzo, F et al., Injectability Evaluation: An Open Issue. AAPS PharmSciTech. 2011 2: 604-609).

[0087] (Example 2. Risperidone formulation) For injection volumes of ≤ 1 mL, formulations of risperidone having an amount of risperidone of at least 250 mg / mL, for example at least 300 mg / mL, and up to about 400 mg / mL maximum.

[0088] (Preparation of risperidone particles) The particles of risperidone can be prepared using micronization, microgranulation, or milled sourcing.

[0089] (Dose adjustment by large volume injection) As evident by the change in 75% cumulative release between the 125 mg depot and the 250 mg depot, the injection volume ​A two-fold increase in the amount resulted in a disproportionate increase in the release rate. The 250 mg depot formulation released its risperidone cargo over a longer period than the 125 mg depot formulation.

[0090] Exemplary formulations are shown in Table 2. The percentages shown are weight percentages from the total formulation composition. Table 2

Table 2

[0091] The cumulative release of the formulations shown in Table 2 is provided in Tables 3 and 4. "Average" refers to the % of total release. Table 3

Table 3

Table 4

[0092] (Example 3 Excision Test) The possibility of excising the composition from the subcutaneous (sc) space was tested. Without wishing to be bound by any particular theory, medical professionals may consider implant excision after administration in case of adverse events.

[0093] The composition was subcutaneously injected into the interscapular and flank regions of rats, dogs, mini-pigs, and pigs.

[0094] In one test, ultrasound and MRI, clinically relevant imaging techniques in mini-pigs ​​​​​​Positioning and feasibility of excision of sc - injected implants for long - acting release of risperidone. Two pigs (Sus scrofa), Yucatan minipigs, were each sc - injected with risperidone formulations of 50 and 150 mg, corresponding to volumes of 40 and 420 μL, respectively, into the flank of the animals. Furthermore, these animals were each sc - injected with three vehicle formulations (non - API control formulations) having a volume range of 70 - 840 μL for a total of five implants per animal (two risperidone, three vehicle).

[0095] The position of the implants was identified using MRI (Magnetom Sonata Syngo 1.5 T; Siemens), ultrasound (FujiFilm Vevo MD device for frequencies of 15, 30, and 50 MHz), and the Siemens Acuson SC2000 apparel (for 9 - MHz frequency) imaging modalities at 4 hours after injection and on days 1, 3, 6, 14, 20, 27, and 35. Excision of the implants was performed on day 14 after injection, and PK samples were collected up to 72 hours before and 72 hours after to confirm complete removal.

[0096] MRI provided useful visual support regarding the depth and size of the implants throughout the study. Ultrasonic imaging 4 hours after administration was difficult, and implants with volumes of 70 - 140 μL were difficult to locate. Between days 1 - 6, the echogenicity of the depot fluctuated but was visible using lower frequencies (9 and 15 MHz). Between days 14 - 35, ultrasonic images using both 9 - MHz and 15 - MHz probes were clear and useful for positioning implants with low injection volumes. Probes with higher frequencies (30 and 50 MHz) were less useful for visualizing the implants. implants less well. was not useful for the positioning of the implant. The risperidone implant was surgically removed on the 14th day after injection, after imaging and palpation at the position of the injection site. The trace of the implant could not be imaged, and the plasma level of risperidone decreased immediately after resection. The resection site healed within a few days after surgery, and the recovery of the animals monitored up to 2 weeks after resection was good. Overall, the sc implant was positioned by clinically relevant imaging techniques such as ultrasound using 9 MHz and 15 MHz probes, and it was demonstrated that MRI was feasible. The resection was good and complete, and removal of risperidone from the systemic circulation was possible if necessary.

[0097] (Example 4 Pharmacokinetic Study) (Part 1) To evaluate the safety, tolerance, and pharmacokinetics of the sustained-release suspension of risperidone disclosed herein for subcutaneous injection, and (Part 2) to evaluate the effect of manipulation of the injection site and administration site on the pharmacokinetics of risperidone, a clinical trial consisting of two parts was conducted.

[0098] This trial was conducted on 53 healthy volunteers and 6 other patients who received an injection of the formulation vehicle without risperidone.

[0099] Part 1 of this trial was an open-label, non-randomized, dose-escalation study (5 cohorts), and Part 2 of this trial was an open-label, non-randomized, dose-escalation study (2 cohorts).

[0100] (Example 5 SAD / MAD Study) In patients with schizophrenia or schizoaffective disorder, the subcutaneous use disclosed herein To evaluate the safety, tolerability, and pharmacokinetics of a sustained-release injection suspension of risperidone , sequential single-dose escalation and multiple-dose escalation studies were conducted.

[0101] The study population consisted of 99 patients with schizophrenia, and 88 patients were included in the safety component of this study .

[0102] The study design was an open-label single-dose escalation (SAD) study and a multiple-dose escalation (MAD) study (8 cohorts ).

[0103] Combining the studies of Examples 3 and 4, several points were shown: · The safety profile of the formulations disclosed herein was consistent with other risperidone formulations ; · There were no serious adverse reactions associated with the formulations disclosed herein · The treatment method showed a desirable risk / benefit profile · No significant changes in pharmacokinetic parameters were observed during the changes in the injection area · Verification of dosage and target period: 1-month (Q1M) and 2-month (Q2M) products

[0104] The results of the clinical trials of Examples 4 and 5 indicate that the formulations disclosed herein with 1-month and 2-month release profiles at various doses reach a peak within the first 24 hours, resulting in a rapid establishment of clinically relevant risperidone plasma concentrations that avoid the need for oral supplementation after the start of treatment, and then slowly decrease over 1-2 months, respectively. The doses were selected based on the comparability to those observed with oral risperidone over plasma concentration and 24-hour dosing intervals, aiming to ensure sufficient exposure over the entire administration period . .

[0105] ​​Safety, including local tolerability at the injection site, was tested in two clinical trials of Examples 4 and 5. From the results of the two trials on a total of 147 subjects, a safety profile consistent with the known safety profile of risperidone was shown, along with good local tolerability at the injection site. Two serious adverse events were reported from Cohort 8 of the trial in Example 5, and both events were evaluated by both the investigator and the sponsor, neither of whom was involved with the risperidone formulation. No other serious adverse events were noted in patients who received the risperidone formulation in this trial. The safety analysis of the trial in Example 5 is shown in Table 5. Table 5

Table 5

[0106] Abd = abdominal sc injection Table 5

Table 5

[0107] (Example 6: Phase 3 Clinical Trial Using Risperidone Formulation) (Purpose of the Trial:) The purpose of the trial is to evaluate the efficacy, safety, and tolerability of various dosage regimens of the subcutaneous risperidone formulation described herein compared to placebo during maintenance treatment in adult and adolescent patients with schizophrenia.

[0108] (Trial Design:) A double-blind, randomized relapse prevention trial comparing two risperidone formulations of the present disclosure at therapeutic doses including placebo SC (once monthly, Q1M) in a 1:1:1 ratio.

[0109] (Trial Population:) Male and female patients, 13 - 65 years of age, with a confirmed diagnosis of schizophrenia, clinically stable, and eligible for risperidone treatment.

[0110] (Investigational Drug:) Risperidone at 250 - 400 mg / mL in the formulations disclosed in this specification. The investigational drug is presented in a glass vial containing a certain amount of risperidone formulation or a prefilled syringe containing a certain amount of risperidone formulation during (PFS). The investigational drug is tested for the comparability of risperidone exposure at subcutaneous administration once every 28 - 30 days (Q1M) or once every 56 - 60 days (Q2M) with oral risperidone tablets.

[0111] (Primary and Secondary Evaluation Items:) (Primary Evaluation Item:) 1. Time to imminent relapse [Time frame: 15 months] Calculated as the earliest day on which the patient meets ≥1 imminent relapse criteria

[0112] (Secondary Evaluation Items:) 1. Time to imminent relapse [Time frame: 15 months] As defined under the main objective in the full population (adults and youths) 2. Time to imminent relapse in youths with schizophrenia 3. Imminent relapse rate [Time frame: 24 weeks] This rate is estimated using the Kaplan - Meier method. 4. Observed imminent relapse rate [Time frame: 15 months] Calculated as the number of patients who relapsed by the end point divided by the number of patients in each treatment group 5. Percentage of patients maintaining stability [Time frame: 15 months] Stability is defined as meeting all of the following criteria for at least 4 consecutive weeks: Outpatient status; PANSS total score ≤80; specific psychiatric symptoms in PANSS, measured by a score ≤4 for each of the following items: disturbance of conceptual integration, suspiciousness, hallucinatory behavior and minimal presence of unnatural thought content; Clinical Global Impression - Severity (CGI - S) score ≤4 (moderate Degree of disease); and the overall clinical impression - severity of suicidal tendency (CGI-SS) score in Part 1 ≤2 (mild suicidal desire) and ≤5 (minimal worsening) in Part 2. The percentage is calculated as the number of patients who maintained stability at the endpoint divided by the number of patients in the given treatment group and is calculated as the number of patients who maintained stability at the endpoint divided by the number of patients in the given treatment group . 6. Percentage of patients achieving remission [time frame: 15 months] Positive symptoms, negative symptoms, and overall symptom remission are examined, including criteria for severity and duration, and are defined by Andreasen et al. (2005). All remission criteria can be obtained from the PANSS items. 7. Percentage of participants with adverse events [time frame: 15 months]

[0113] All of the compositions and methods disclosed and claimed in this specification can be made and implemented without undue experimentation in view of the present disclosure. The compositions and methods of the present invention are described with reference to preferred embodiments, but it will be apparent to those skilled in the art that variations can be applied without departing from the spirit and scope of the present invention.

[0114] All patents, patent applications, and publications disclosed in this specification are incorporated herein by reference to the same extent as if each individual publication was specifically and individually indicated to be incorporated by reference. The present invention is specifically disclosed by preferred embodiments and optional features, but it is to be understood that modifications and variations of the concepts disclosed herein can be used by those skilled in the art, and that such modifications and variations are considered to be within the scope of the present invention as defined by the appended claims. This application provides an invention in the following aspects. (Aspect 1) A method for treating a target psychiatric disorder or disorder, comprising administering to the subject once or less every 21 days at a frequency of a) risperidone at a concentration of about 250 - 400 mg / mL in terms of risperidone equivalents or a pharmaceutically acceptable salt thereof; b) a biodegradable triblock copolymer having the formula: poly(lactic acid)v - poly(ethylene glycol)w - poly(lactic acid)x (wherein v and x are the number of repeating units in the range of 24 - 682, and w is the number of repeating units in the range of 4 - 273, and v = x or v ≠ x) ; c) a biodegradable diblock copolymer having the formula: methoxypoly(ethylene glycol)y - poly(lactic acid)z (wherein y and z are the number of repeating units, where y is the number of repeating units in the range of 3 - 45 and z is the number of repeating units in the range of 7 - 327); : and wherein the ratio of the biodegradable triblock copolymer of (b) to the biodegradable diblock copolymer of (c) is 1:3 - 1:8 or 1:1 - 1:19 or 3:2 - 1:19 in the formulation that is insoluble in an aqueous environment, and the pharmaceutical formulation is 1 mL or less : and subcutaneously administering the formulation. : The method as described above. (Aspect 2) The method according to aspect 1, wherein the risperidone is risperidone base. (Aspect 3) The method according to aspect 1 or 2, wherein the concentration of the risperidone or the pharmaceutically acceptable salt thereof is 30 0 mg / mL - 400 mg / mL in terms of risperidone equivalents. (Aspect 4) The method according to any one of aspects 1 - 3, wherein the triblock copolymer is present in an amount of about 3% - 20% (w / w%) of the total weight of the formulation. : (Aspect 5) The triblock copolymer is present in an amount of about 5% to 15% (w / w%) of the total weight of the formulation , the method according to aspect 4 (Aspect 6) The diblock copolymer is present in an amount of about 8% to 25% (w / w%) of the total weight of the formulation , the method according to any one of aspects 1 to 5 (Aspect 7) The diblock copolymer is present in an amount of about 10% to 20% (w / w%) of the total weight of the formulation , the method according to aspect 6 (Aspect 8) The triblock and diblock copolymers are present in a total amount of about 20% to about 50% (w / w %), the method according to any one of aspects 1 to 7 (Aspect 9) The triblock and diblock copolymers are present in a total amount of about 20% to 30% (w / w% ), the method according to aspect 8 (Aspect 10) The formulation further comprises a water-soluble organic solvent which is DMSO, the method according to any one of aspects 1 to 9 method (Aspect 11) The formulation further comprises triacetin, tripropionin, or a mixture thereof, the aspect method according to 10 (Aspect 12) The organic solvent is present in an amount of about 35% to about 55% (w / w%) of the total weight of the formulation, aspect 10 or method according to 11 (Aspect 13) The administration is effective for treating the subject's psychiatric disorder or condition for 21 to 90 days, the aspect method according to any one of aspects 1 to 12 (Aspect 14) The administration is effective for treating the subject's psychiatric disorder or condition for 28 to 90 days, the aspect The method according to any one of aspects 1 to 12. (Aspect 15) The administration is effective for treating the psychiatric disorder or disorder of interest for 28 to 56 days, aspect The method according to any one of aspects 1 to 12. (Aspect 16) Less than about 15 w% of the risperidone in the formulation is cumulatively released within 24 hours after administration, aspect 1 The method according to any one of aspects 1 to 15. (Aspect 17) About 7 w% to about 15 w% of the risperidone in the formulation is cumulatively released within 24 hours after administration, The method according to aspect 16. (Aspect 18) About 50 w% to about 80 w% of the risperidone in the formulation is cumulatively released within 30 days after administration, aspect The method according to any one of aspects 13 to 17. (Aspect 19) About 70 w% to about 98% w% of the risperidone in the formulation is cumulatively released within 60 days after administration, The method according to any one of aspects 13 to 18. (Aspect 20) The cumulative release is determined by the in vitro release (IVR) method disclosed herein, aspect The method according to any one of aspects 13 to 19. (Aspect 21) The psychiatric disorder or disorder is schizophrenia or bipolar disorder, any one of aspects 1 to 20 The method according to one item. (Aspect 22) The method is carried out in the absence of a loading dose or adjunctive oral risperidone The method according to any one of aspects 1 to 21. (Aspect 23) For implementation over at least 6 months, the method according to any one of aspects 1 to 22. (Aspect 24) For implementation over at least 15 months, the method according to aspect 23. (Aspect 25) The method according to any one of aspects 1 to 24, wherein the formulation is presented in a single pre-filled syringe (PFS). (Aspect 26) The method according to aspect 25, wherein the volume in the pre-filled syringe is 0.1 mL to 0.8 mL. (Aspect 27) The method according to any one of aspects 1 to 26, for subcutaneous administration to the abdomen. (Aspect 28) The method according to any one of aspects 1 to 27, for subcutaneous administration to the upper arm. (Aspect 29) The method according to any one of aspects 1 to 28, wherein the formulation is removable after administration to the subject. (Aspect 30) A pharmaceutical formulation for treating a psychiatric disorder or condition, comprising: a) risperidone or a pharmaceutically acceptable salt thereof at a concentration of about 250 to 400 mg / mL in terms of risperidone; b) a biodegradable triblock copolymer having the formula: poly(lactic acid)v - poly(ethylene glycol)w - poly(lactic acid)x (wherein v and x are the number of repeating units in the range of 24 to 682, and w is the number of repeating units in the range of 4 to 273, and v = x or v ≠ x); c) a biodegradable diblock copolymer having the formula: methoxypoly(ethylene glycol)y - poly(lactic acid)z (wherein y and z are the number of repeating units, where y is the number of repeating units in the range of 3 to 45 and z is the number of repeating units in the range of 7 to 327); and wherein the biodegradable triblock copolymer of (b) and the biodegradable diblock copolymer of (c) ​​​​​​​The ratio is 1:3 to 1:8 or 1:1 to 1:19 or 3:2 to 1:19 in the formulation that is insoluble in an aqueous environment. The pharmaceutical formulation as described above.

Claims

1. A pharmaceutical preparation for treating a psychiatric disorder or impairment, comprising: a) risperidone or a pharmaceutically acceptable salt thereof at a concentration of about 250 to 400 mg / mL in terms of risperidone; b) a biodegradable triblock copolymer having the formula: poly(lactic acid)v - poly(ethylene glycol)w - poly(lactic acid)x (wherein v and x are the number of repeating units in the range of 24 to 682, and w is the number of repeating units in the range of 4 to 273, and v = x or v ≠ x); and c) a biodegradable diblock copolymer having the formula: methoxypoly(ethylene glycol)y - poly(lactic acid)z (wherein y and z are the number of repeating units, where y is the number of repeating units in the range of 3 to 45, and z is the number of repeating units in the range of 7 to 327); wherein the ratio of the biodegradable triblock copolymer of (b) to the biodegradable diblock copolymer of (c) is 1:3 to 1:8 or 1:1 to 1:19 or 3:2 to 1:19 in the pharmaceutical preparation that is insoluble in an aqueous environment, the pharmaceutical preparation is administered to a subject in an amount of 1 mL or less, and the pharmaceutical preparation is administered subcutaneously to the subject at a frequency of once or less every 21 days.

2. The pharmaceutical preparation according to claim 1, wherein the risperidone is risperidone base.

3. The pharmaceutical preparation according to claim 1 or 2, wherein the concentration of the risperidone or the pharmaceutically acceptable salt thereof is 300 mg / mL to 400 mg / mL in terms of risperidone.

4. The pharmaceutical preparation according to any one of claims 1 to 3, wherein the triblock copolymer is present in an amount of about 3% to 20% (w / w%) of the total weight of the preparation.

5. The pharmaceutical preparation according to claim 4, wherein the triblock copolymer is present in an amount of about 5% to 15% (w / w%) of the total weight of the preparation.

6. The pharmaceutical preparation according to any one of claims 1 to 5, wherein the diblock copolymer is present in an amount of about 8% to 25% (w / w%) of the total weight of the preparation.

7. The pharmaceutical preparation according to claim 6, wherein the diblock copolymer is present in an amount of about 10% to 20% (w / w%) of the total weight of the preparation.

8. The pharmaceutical preparation according to any one of claims 1 to 7, wherein the triblock and diblock copolymers are present in a total amount of about 20% to about 50% (w / w%) of the total weight of the preparation.

9. The pharmaceutical preparation according to any one of claims 1 to 7, wherein the triblock and diblock copolymers are present in a total amount of about 20% to 30% (w / w%) of the total weight of the preparation. ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ The pharmaceutical preparation according to claim 8, present in the total amount of

10. The pharmaceutical preparation according to any one of claims 1 to 9, further comprising a water-soluble organic solvent wherein the preparation is DMSO pharmaceutical preparation.

11. The pharmaceutical preparation according to claim 10, wherein the preparation further comprises triacetin, tripropionin, or a mixture thereof pharmaceutical preparation.

12. The pharmaceutical preparation according to claim 10 or 11, wherein the organic solvent is present in an amount of about 35% to about 55% (w / w%) of the total weight of the preparation pharmaceutical preparation.

13. The pharmaceutical preparation according to any one of claims 1 to 12, wherein the administration is effective for treating the psychiatric disorder or condition of the subject for 21 days to 90 days pharmaceutical preparation.

14. The pharmaceutical preparation according to any one of claims 1 to 12, wherein the administration is effective for treating the psychiatric disorder or condition of the subject for 28 days to 90 days pharmaceutical preparation.

15. The pharmaceutical preparation according to any one of claims 1 to 12, wherein the administration is effective for treating the psychiatric disorder or condition of the subject for 28 days to 56 days pharmaceutical preparation.

16. The pharmaceutical preparation according to any one of claims 1 to 15, wherein less than about 15 w% of risperidone in the preparation is cumulatively released within 24 hours after administration pharmaceutical preparation.

17. The pharmaceutical preparation according to claim 16, wherein about 7 w% to about 15 w% of risperidone in the preparation is cumulatively released within 24 hours after administration pharmaceutical preparation.

18. The pharmaceutical preparation according to any one of claims 13 to 17, wherein about 50 w% to about 80 w% of risperidone in the preparation is cumulatively released within 30 days after administration pharmaceutical preparation.

19. The pharmaceutical preparation according to any one of claims 13 to 18, wherein about 70 w% to about 98 w% of risperidone in the preparation is cumulatively released within 60 days after administration pharmaceutical preparation.

20. The pharmaceutical preparation according to any one of claims 13 to 19, wherein the cumulative release is determined by the in vitro release (IVR) method pharmaceutical preparation.

21. The pharmaceutical preparation according to any one of claims 1 to 20, wherein the psychiatric disorder or condition is schizophrenia or bipolar disorder pharmaceutical preparation.

22. The pharmaceutical preparation according to any one of claims 1 to 21, wherein the pharmaceutical preparation is administered in the absence of a loading dose or adjunctive oral risperidone pharmaceutical preparation.

23. The pharmaceutical preparation according to any one of claims 1 to 22, administered for at least 6 months

24. The pharmaceutical preparation according to claim 23, administered for at least 15 months

25. The pharmaceutical preparation according to any one of claims 1 to 24, wherein the preparation is presented in a single pre-filled syringe (PFS). The pharmaceutical preparation as claimed in **Claim 26** The pharmaceutical preparation according to claim 25, wherein the volume in the pre-filled syringe is 0.1 mL to 0.8 mL. **Claim 27** The pharmaceutical preparation according to any one of claims 1 to 26 for subcutaneous administration to the abdomen. **Claim 28** The pharmaceutical preparation according to any one of claims 1 to 27 for subcutaneous administration to the upper arm. **Claim 29** The pharmaceutical preparation according to any one of claims 1 to 28, wherein the preparation is removable after administration to the subject. The pharmaceutical preparation as claimed in **Claim 30** A pharmaceutical preparation for treating a psychiatric disorder or condition, comprising a) risperidone or a pharmaceutically acceptable salt thereof at a concentration of about 250 to 400 mg / mL in terms of risperidone; b) a biodegradable triblock copolymer having the formula: poly(lactic acid)v - poly(ethylene glycol)w - poly(lactic acid)x (wherein v and x are the number of repeating units in the range of 24 to 682, and w is the number of repeating units in the range of 4 to 273, and v = x or v ≠ x); and c) a biodegradable diblock copolymer having the formula: methoxypoly(ethylene glycol)y - poly(lactic acid)z (wherein y and z are the number of repeating units, where y is the number of repeating units in the range of 3 to 45, and z is the number of repeating units in the range of 7 to 327), and wherein the ratio of the biodegradable triblock copolymer of (b) to the biodegradable diblock copolymer of (c) is 1:3 to 1:8 or 1:1 to 1:19 or 3:2 to 1:19 in the preparation which is insoluble in an aqueous environment. The pharmaceutical preparation as claimed in **Claim 25** ; ​ ​ ​ ​

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