Drug Delivery Formulations

Abstract

The present invention is directed to a method of treating psychiatric diseases and disorders, comprising administering to a subject in need thereof an injectable formulation comprising risperidone, a triblock, and a diblock copolymer, wherein the risperidone has a concentration of 250-400 mg / mL and an injection volume of 1 mL or less.

Description

[Technical field]

[0001] (CROSS REFERENCE TO RELATED APPLICATIONS) This application claims the benefit of U.S. Provisional Application No. 62 / 900,061, filed Sep. 13, 2019, which is incorporated by reference in its entirety.

[0002] FIELD OF THEINVENTION The present invention relates to methods of treating risperidone-responsive psychiatric diseases and disorders with high-concentration, low-dose risperidone pharmaceutical compositions comprising triblock and diblock copolymers. [Background technology]

[0003] BACKGROUND OF THE PRESENTINVENTION Risperidone is an atypical antipsychotic serotonergic (5-HT2A receptor) and dopaminergic (D2, D3, and D4 receptor) antagonist. It binds to alpha-1-adrenergic receptors, histaminergic 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®. Currently available in oral and injectable versions, risperidone is approved for several other indications, including the treatment of dementia, anxiety, some bipolar disorders, depression, and manic or psychotic episodes.

[0004] Risperidone is used in the first-line treatment of schizophrenia due to its safety profile and mid- to long-term treatment recommendations. A long-acting injectable (LAI) product has been approved by the FDA. Risperdal Consta® is an injectable risperidone product for biweekly intramuscular (IM) administration. Risperdal Consta is provided in doses of 12.5 mg, 25 mg, 37.5 mg, and 50 mg risperidone / vial with a syringe containing 2 mL of diluent. This product requires multiple reconstitution steps at the start of treatment and oral supplementation. Intramuscular injections are usually painful and anxiety-inducing, especially for the target population. Perseris®, an injectable risperidone product for monthly subcutaneous administration, is provided in two syringes that require significant mixing and resuspension prior to administration. Perseris® is provided in two dosage strengths: 90 mg (0.6 mL) and 120 mg (0.8 mL).

[0005] Drug delivery systems containing polymers such as diblock and triblock copolymers have been used to deliver a variety of drugs and are usually formulated to deliver a specific drug, whether it is a hydrophobic or hydrophilic drug. Depending on the drug solubility, these drug formulations vary in polymer concentration, type of polymer utilized, molecular weight of the polymer and solvent used in the formulation.

[0006] The type of environment in which a 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 photosensitive polymers. See, for example, K. Al-Tahami and J. 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.

[0007] U.S. Pat. No. 9,023,897 and U.S. Patent Publication No. US2019 / 160171 describe pharmaceutical formulations made of biodegradable triblock and diblock polymers that are useful for the delivery of a variety of actives.

[0008] There is a need for a long-acting risperidone formulation that aids in patient compliance, reduces patient dosing anxiety, and is easy for medical professionals to prepare and administer. Challenges in treating psychiatric diseases or disorders with risperidone include, for example, being able to subcutaneously inject a long-acting formulation with a high dose of active agent in a low injection volume with an injectable viscosity. Another challenge is developing a long-acting subcutaneous injection formulation with a low initial burst of active agent. If the long-acting formulation must be removed (due to an adverse event or other reasons), it must be removably 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 of treating a psychiatric disease or disorder in a subject, comprising administering to the subject no more than once every 21 days: a) risperidone or a pharma- ceutical acceptable salt thereof having a concentration of about 250 to 400 mg / mL in terms of risperidone; b) Formula: Poly(lactic acid) v -poly(ethylene glycol) w, -poly(lactic acid) x (In the formula, 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.) A biodegradable triblock copolymer having the formula: c) Formula: Methoxypoly(ethylene glycol) y-poly(lactic acid) z (wherein y and z are the numbers 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). A biodegradable diblock copolymer having the formula: Contains : and wherein 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 said formulation that is insoluble in an aqueous environment, and the pharmaceutical formulation is 1 mL or less. A method comprising subcutaneously administering:

[0010] In particular, the active ingredient of the injectable formulation of the present invention is risperidone present in 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 pharma- ceutically acceptable salt thereof in an amount equivalent to 250 mg / mL to 400 mg / mL of risperidone.

[0011] With respect to the injectable formulation of the present invention, the active ingredient has a release duration of 21 to 90 days (about 3 weeks to about 3 months) or 30 to 90 days (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 apparent from the description of the preferred embodiments below. [Brief description of the drawings]

[0013] BRIEF DESCRIPTION OF THE DRAWINGS [Figure 1] FIG. 1 shows the % cumulative release as a function of time for formulations F84 and F85. [Diagram 2] FIG. 2 shows the % cumulative release as a function of time for formulations F88 and F89. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

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

[0015] The term "parenteral administration" includes intramuscular, intraperitoneal, intraabdominal, subcutaneous, intravenous, and intraarterial. It also includes intradermal, intracavity, intravitreal, intracerebral, intrathecal, epidural, and intraosseous administration. In some embodiments, administration is subcutaneous.

[0016] The term "about" should be considered as disclosing a range defined by the absolute values ​​of the two endpoints. For example, the phrase "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 pharma- ceutically acceptable salts.

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

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

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

[0022] "End-capped polyethylene glycol" (cPEG) refers to PEG in which one terminal hydroxyl group has been 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 chemical functionality that is susceptible to reaction with cyclic esters or other esters, such as lactide, glycolide, caprolactone, and the like, as well as mixtures thereof. Reaction of an end-capped PEG polymer with lactide produces a diblock cPEG-PLA copolymer. 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), which terms are used interchangeably herein.

[0024] The abbreviation "PLA" refers to polylactide, polylactic acid, or poly(lactic acid), which 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] The term "diblock" as used herein refers, for example, to end-capped PEG-polyester copolymers. "mPEG" refers to methoxypolyethylene glycol. The PEG in the diblock copolymer may be capped with known capping entities other than methoxy groups. Examples of end-capped polyethylene glycols include alkoxy-capped PEGs, such as methoxy or ethoxy PEGs, urethane-capped PEGs, ester-capped PEGs, amine-capped PEGs, and amide-capped PEGs. This list of end-capped PEGs is not exhaustive, and one of skill in the art would recognize additional end-capped PEGs not listed.

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

[0028] The biodegradable drug delivery compositions used in the methods of the present invention are described in US Pat. No. 9,023,897, which is incorporated herein by reference in its entirety.

[0029] The structure of the biodegradable triblock / diblock copolymers of the present invention may also 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, also identified herein as PaRb, where "a" is the size of PEG in kDa and "b" is the molar ratio LA / EO (v+x / w) Cy-Az, which refers to diblock mPEG-PLA copolymer: methoxy-poly(ethylene glycol)y-poly(lactic acid)z, also identified herein as dPaRb, where "a" is the size of PEG in kDa and "b" is the molar ratio LA / EO(z / y). A methoxy group, or other capping group, caps one of the two hydroxyl groups of the PEG. The poly(lactic acid) chain extends only from the free hydroxyl group.

[0030] The number of y and z repeat units (degree of polymerization (DP)) in the diblock composition can vary. Thus, y can range, for example, from 7 to 43 or from 3 to 45, and z can range from 32 to 123 or from 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 capped 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. It is experimentally determined by NMR. The LA / EO molar ratio of the triblock copolymer can range from 0.5 to 3.5. 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.

[0032] 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. In another embodiment, the LA / EO ratio in the diblock can range from 0.8 to 13.

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

[0034] The method of the present invention uses a biodegradable drug composition comprising a triblock copolymer and a diblock copolymer. 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 repeat units of poly(lactic acid) and range from 24 to 682; and w is the degree of polymerization (number of repeat units) of poly(ethylene glycol) and ranges from 4 to 273, and v=x or v≠x. The degree of polymerization of DP-PEG is calculated by dividing the molecular weight of PEG by the molecular weight of an EO unit (44 Da). v+x is equal to the degree of polymerization (number of repeat units) of PLA. DP-PLA is calculated by multiplying DP-PEG by the LA / EO ratio.

[0035] The size of the PEG in the triblock copolymer can be from 194 Da to 12,000 Da.

[0036] The triblock copolymer can be combined with a biodegradable diblock copolymer having the formula: Cy-Az, where A is a polyester (i.e., PLA), C is an end-capped polyethylene glycol, and y and z are the number of repeat units ranging from 7 to 371 or 3 to 327. The combination has a ratio of triblock copolymer to diblock copolymer ranging from 1:3 to 1:8, or 1:1 to 1:19, or 3:2 to 1:19. In some embodiments, the ratio of triblock copolymer to diblock copolymer is 3:2 to 1:5. In some embodiments, the ratio of triblock copolymer to diblock copolymer is 3:2 to 1:4. In some embodiments, the ratio of triblock copolymer to diblock copolymer is 3:2 to 1:3.5. In some embodiments, the ratio of triblock copolymer to diblock copolymer is 3:2 to 1:3. In some embodiments, the ratio of triblock copolymer to diblock copolymer is 3:2 to 1:2.5. In some embodiments, the ratio of triblock copolymer to diblock copolymer is 3:2 to 1:2. In some embodiments, the ratio of triblock copolymer to diblock copolymer is 3:2 to 1:1.5. In some embodiments, the ratio of triblock copolymer to diblock copolymer is 3:2 to 1:1.

[0037] In some embodiments, the psychiatric disease or disorder is schizophrenia, schizoaffective disorder, or bipolar disorder. In other embodiments, the psychiatric disease or disorder is schizophrenia or bipolar disorder. In other embodiments, the psychiatric disease or disorder is schizophrenia. In other embodiments, the psychiatric disease or disorder is schizoaffective disorder. In still other embodiments, the psychiatric disease or disorder is bipolar disorder. In some embodiments, the psychiatric disease is dementia. In some embodiments, the psychiatric disease is bipolar disorder. In some embodiments, the psychiatric disease is depression. In some embodiments, the psychiatric disease is manic disorder. In some embodiments, the psychiatric disease is a psychotic episode. As used herein, a method of treatment refers to alleviating the symptoms of a psychiatric disease or disorder. In some embodiments, the method of treatment includes a delay in time to relapse compared to a subject not receiving the pharmaceutical formulation. In some embodiments, the method of treatment includes a reduction in the rate of imminent relapse estimated using the Kaplan-Meier method. In some embodiments, the method of treatment includes a reduction in the observed rate of imminent relapse. In some embodiments, the treatment method includes maintaining stability, which includes meeting all of the following criteria for at least 4 consecutive weeks: outpatient status; PANSS total score ≦80; minimal presence of specific psychotic symptoms on PANSS, as measured by a score of ≦4 for each of the following items: conceptual integration disorder, suspiciousness, hallucinatory behavior, and unnatural thought content; Clinical Global Impression of Severity (CGI-S) score ≦4 (moderate illness); and Clinical Global Impression-Suicidality Severity (CGI-SS) score ≦2 (mild suicidal ideation) in part 1 and ≦5 (minimal deterioration) in part 2. The percentage is calculated as the number of patients who maintain stability at the endpoint divided by the number of patients in a given treatment group. In some embodiments, the treatment method includes achieving remission. All remission criteria can be obtained from PANSS items.

[0038] In some embodiments, the present invention is directed to a subcutaneous administration method for treating a psychiatric disease or disorder 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.

[0039] The method of the present invention comprises 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.

[0040] Subcutaneous administration of the risperidone formulation of the present invention can result in the in situ formation of a solid or semi-solid implant.In these embodiments, the solid or semi-solid formulation can be excised (i.e., removed from the subject) after administration to the subject.A medical professional skilled in the art can determine the preferred method and time to excise.

[0041] In some embodiments of the methods of the present invention, administration is no more frequent than once every 21 days. In these embodiments, administration results in treatment of the psychiatric disease or disorder for at least 21 days. In some embodiments, administration is no more frequent than once every 28 days. In these embodiments, administration results in treatment of the psychiatric disease or disorder for at least 28 days. In some embodiments, administration is no more frequent than once every 30 days. In these embodiments, administration results in treatment of the psychiatric disease or disorder for at least 30 days. In other embodiments, administration is no more frequent than once every 45 days. In these embodiments, administration results in treatment of the psychiatric disease or disorder for at least 45 days. In other embodiments, administration is no more frequent than once every 56 days. In these embodiments, administration results in treatment of the psychiatric disease or disorder for at least 56 days. In other embodiments, administration is no more frequent than once every 60 days. In these embodiments, administration results in treatment of the psychiatric disease or disorder for at least 60 days.

[0042] According to the methods of the present invention, the subject is administered 1 mL or less of the pharmaceutical formulation as described herein. In some embodiments, the subject is administered 1 mL of the pharmaceutical formulation. In other embodiments, the subject is administered 0.9 mL or less of the pharmaceutical formulation. In other embodiments, the subject is administered 0.8 mL or less of the pharmaceutical formulation. In other embodiments, the subject is administered 0.7 mL or less of the pharmaceutical formulation. In other embodiments, the subject is administered 0.6 mL or less of the pharmaceutical formulation. In other embodiments, the subject is administered 0.5 mL or less of the pharmaceutical formulation. In other embodiments, the subject is administered 0.4 mL or less of the pharmaceutical formulation. In other embodiments, the subject is administered 0.3 mL or less of the pharmaceutical formulation. In other embodiments, the subject is administered 0.2 mL or less of the pharmaceutical formulation. In other embodiments, the subject is administered 0.1 mL or less of the pharmaceutical formulation. In some embodiments, the subject is administered 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, or 1 mL of the pharmaceutical formulation. In some embodiments, the subject is administered 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, 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 formulation is administered. In some embodiments, the pharmaceutical formulation contains risperidone or a salt thereof in an amount of 250 mg / mL to 400 mg / mL in terms of risperidone.

[0043] According to the method of the present invention, the pharmaceutical formulation administered comprises risperidone or a pharma- ceutically acceptable salt thereof. In some embodiments, the pharmaceutical formulation comprises risperidone as risperidone base. In other embodiments, the pharmaceutical formulation comprises risperidone as a pharma- ceutically acceptable salt of risperidone. In yet other embodiments, the pharmaceutical formulation comprises risperidone as a mixture of risperidone base and a pharma- ceutically acceptable salt of risperidone.

[0044] The medicamentously effective amount of risperidone may 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 directed to a formulation having a concentration of at least 250mg / mL of risperidone (or its salt) with a delivery volume of 1mL or less.Although there is no strict upper limit for the amount of risperidone (or its salt), the formulation should be of suitable viscosity for injection through a syringe needle so that it can effectively treat psychiatric disease or disorder without exposing the subject to the risk of risperidone overdose.

[0045] The concentration of risperidone or a pharma- ceutically acceptable salt thereof used in the biodegradable drug delivery composition of the present invention is at least 250 mg / mL in risperidone equivalent, preferably at least 300 mg / mL in risperidone equivalent. In some embodiments, the concentration of risperidone or a pharma-ceutically acceptable salt thereof used in the biodegradable drug delivery composition of the present invention is 250-300 mg / mL in risperidone equivalent. In other embodiments, the concentration of risperidone or a pharma-ceutically acceptable salt thereof used in the biodegradable drug delivery composition of the present invention is 300-400 mg / mL in risperidone equivalent. In other embodiments, the concentration of risperidone or a pharma-ceutically acceptable salt thereof used in the biodegradable drug delivery composition of the present invention is 300-350 mg / mL in risperidone equivalent. In other embodiments, the concentration of risperidone or a pharma-ceutically acceptable salt thereof used in the biodegradable drug delivery composition of the present invention is 350-400 mg / mL in risperidone equivalent.

[0046] The concentration of risperidone or an equivalent amount of risperidone salt in the formulation is about 250mg / mL to 400mg / mL, 260mg / mL to 400mg / mL, 270mg / mL to 400mg / mL, 280mg / mL to 400mg / mL, 290mg / mL to 400mg / mL, 300mg / mL to 400mg / mL, 310mg / mL to 440mg / mL, 315mg / mL to 440mg / mL, 320mg / mL to 400mg / mL, The concentration can be in the range of 330mg / mL to 400mg / mL, 340mg / mL to 400mg / mL, 350mg / mL to 400mg / mL, 360mg / mL to 400mg / mL, 370mg / mL to 400mg / mL, 380mg / mL to 400mg / mL, 390mg / mL to 400mg / mL, 260mg / mL to 340mg / mL, 270mg / mL to 340mg / mL, or 280mg / mL to 340mg / mL.In various embodiments, the concentration of risperidone or an equivalent amount of risperidone salt in the formulation is 250, 251, 252, 253, 254, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275, 276, 277, 278, 279, 280, 281, 282, 283, 284, 285, 286, 287, 288, 289, 290, 291, 292, 293, 294, 295, 296, 297, 298, 299, 300, 301, 302, 303, 304, 305, 306, 307, 308, 309, 310, 311, 312, 313, 314, 315, 316, 317, 318, 319, 320, 321, 322, 323, 324, 325, 326, 327, 328, 329, 330, 331, 332, 333, 334, 335, 336, 337, 338, 339, 340, 341, 342, 343, 344, 345, 346 81, 282, 283, 284, 285, 286, 287, 288, 289, 290, 291, 292, 293, 294, 295, 296, 297, 298, 299, 300, 301, 302, 303, 304, 305, 306, 307, 308, 309, 310, 311, 312, 313, 314, 315, 316, 317, 318, 319, 320, 321, 322 , 323, 324, 325, 326, 327, 328, 329, 330, 331, 332, 333, 334, 335, 336, 337, 338, 339, 340, 341, 342, 343, 344, 345, 346, 347, 348, 349, 350, 351, 352, 353, 354, 355, 356, 357, 358, 359, 360, 361, 362, 363, 364, 365, 366, 367, 368, 369, 370, 371, 372, 373, 374, 375, 376, 377, 378, 379, 380, 381, 382, ​​383, 384, 385, 386, 387, 388, 389, 390, 391, 392, 393, 394, 395, 396, 397, 398, 399, 399, 400, 401, 402, 403, 404, 405, 406, 407, 408, 409, 410, 411, 412, 413, 414, 415, 416, 417, 418, 419, 420, 421, 422, 423 63, 364, 365, 366, 367, 368, 369, 370, 371, 372, 373, 374, 375, 376, 377, 378, 379, 380, 381, 382, ​​383, 384, 385, 386, 387, 388, 389, 390, 391, 392, 393, 394, 395, 396, 397, 398, 399, or 400 (units are 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 (in mg / mL).

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

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

[0050] The size of the polyethylene glycol chain ranges from 200 Da to 12 kDa in the biodegradable drug delivery composition, or it can range from 400 Da to 12 kDa or from 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. 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 copolymer is present in an amount of 5% to 17% (w / w%) of the total weight of the formulation. In another embodiment, the triblock 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. In yet another embodiment, the triblock copolymer is present in an amount of 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 the biodegradable drug composition in an amount of 8% to 50% (w / w%) of the total weight of the 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 the biodegradable drug formulation in an amount of 6% to 30% (w / w%) of the total weight of the formulation. In another embodiment, the diblock copolymer is present in an amount of 8% to 30% (w / w%) of the total weight of the formulation. In some embodiments 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 embodiment, the diblock copolymer is present in an amount of 10% to 25% (w / w%) of the total weight of the formulation. In some embodiments of the methods 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, hi other embodiments, the diblock copolymer is present in an amount of about 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. Present in amounts of 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%, and 30% (w / w%).

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

[0054] In a preferred embodiment, the total amount of triblock and diblock copolymers is present in an amount of 20% to 45% (w / w%) of the total weight of the formulation. In another preferred embodiment, the total amount of triblock and diblock copolymers present in the pharmaceutical formulation 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. In yet another embodiment, the polymer is present in the biodegradable drug formulation in an amount of 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% or 32% of the total weight of the formulation. 0.5%, 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%).

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

[0056] In one embodiment, the ratio of the biodegradable triblock copolymer to the biodegradable diblock copolymer is selected from 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 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 yet other embodiments, the ratio of the biodegradable triblock copolymer to the biodegradable CA diblock copolymer is 2:3.

[0058] The pharmaceutical preparation used in the method of the present disclosure may further comprise a pharma- ceutical acceptable carrier, adjuvant, or vehicle. The acceptable carrier may be saline, buffered saline, etc. The adjuvant may be formulated at the same time when the drug is mixed. In this regard, the adjuvants that may be used are alum, aluminum phosphate, calcium phosphate, MPL™, CpG motifs, modified toxins, saponins, intrinsic stimulatory adjuvants, such as cytokines, Freund's complete and incomplete adjuvants, ISCOM-type adjuvants, muramyl peptides, etc.

[0059] The pharmaceutical preparation used in the method of the present invention also includes an organic solvent. In a preferred embodiment, the organic solvent is a water-soluble organic solvent. The organic solvent that can be used in the method described herein is selected from the group: 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, tetraglycol, triacetin, tributyrin, tripropionin (tripro), or triethylene glycol dimethyl ether (triglyme), and mixtures thereof. The preferred organic solvent is the water-soluble organic solvent DMSO.

[0060] The organic solvent is present in an amount of 40% to 74% (w / w%) of the total composition. In another embodiment, the organic solvent used in the preparation of the biodegradable drug delivery composition is present in an amount of 50% to 60% (w / w%) of the total composition. In yet another embodiment, the solvent used in the preparation of the biodegradable drug delivery composition is present in an amount of 60% to 70% (w / w%) of the total composition. The organic solvent can be present in an amount of 15% to 45% or 40% to 74% (w / w%) of the total formulation. In another embodiment, the organic solvent used in the preparation of the pharmaceutical formulation is present in an amount of 40% to 50% (w / w%) of the total formulation.

[0061] 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% to 55% (w / w%), preferably 35% to 45% (w / w%). In one embodiment, DMSO can include an amount of 10% to 15% (w / w%) of triglycerides, such as triacetin, tripropionin, or a mixture thereof.

[0062] In the biodegradable drug delivery composition of the present invention, also referred to as pharmaceutical formulation herein, 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 triblock and diblock copolymers. Thus, the greater the lactic acid content of 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 active ingredient or drug. That is, the greater the LA / EO molar ratio and the greater the weight percentage of triblock and diblock copolymers, the longer it takes for the active ingredient to be released from the drug composition. Volume can also affect the release, with the active ingredient being released for a longer period of time from a larger volume than from a smaller volume [see data in Example 2 below].

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

[0064] In the methods of the invention, the administration results in an effective amount of risperidone being released from the formulation to treat the subject's psychiatric disease or disorder for an extended period of time. In some embodiments, the administration is effective to treat the subject's psychiatric disease or disorder for 21 to 90 days. In some embodiments, the administration is effective to treat the subject's psychiatric disease or disorder for 28 to 90 days. In other embodiments, the administration is effective to treat the subject's psychiatric disease or disorder for 28 or 30 to 56 or 60 days. In some embodiments, the administration is effective to treat the subject's psychiatric disease or disorder for 28 or 30 days. In other embodiments, the administration is effective to treat the subject's psychiatric disease or disorder for 45 days. In other embodiments, the administration is effective to treat the subject's psychiatric disease or disorder for 56 or 60 days. In other embodiments, the administration is effective to treat the subject's psychiatric disease or disorder for 84 or 90 days. The administration may be repeated after each period of, for example, 28 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 therapeutically effective levels of risperidone are achieved within 24 hours of subcutaneous administration.If therapeutically effective levels of risperidone are achieved within 24 hours of subcutaneous administration, an alternative immediate release risperidone formulation (e.g., immediate release oral formulation or immediate release injectable formulation) is not required to ensure sufficient risperidone levels in the subject.That is, a "loading dose" or supplemental oral dose of risperidone is not required in the method of the present invention.Thus, in some embodiments, the method is carried out in the absence of a loading dose or supplemental oral risperidone.

[0066] Using the method of the present invention, a therapeutically effective amount of risperidone will be released by the target date. Thus, in the amount of "30-day formulation", about 50 w% or about 50 w% to about 80 w%, e.g., 50, 55, 60, 65, 70, 75, or 80 w% of risperidone (or its salt) will be cumulatively released by 30 days after administration, preferably with a near-linear release profile. 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 in vitro release (IVR) methods known in the art and described herein. Thus, in the amount of the "60-day formulation," about 75 w% or about 75 w% to about 98 w%, e.g., 75, 70, 85, 90, 91, 92, 93, 94, 95, 96, 97, or about 98 w% of the risperidone (or salt thereof) is cumulatively released by 60 days after administration, preferably in a near-linear release profile. Thus, the present invention provides sustained and uniform release of risperidone over a desired period of time.

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

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

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

[0070] The pharmaceutical formulations used in the methods of the present disclosure are injectable at room temperature and can be injected via a syringe without undue force. The compositions are also in situ formed, biodegradable, and become solid or semi-solid implants when injected into an animal.

[0071] In some embodiments of the method of the present invention, the pharmaceutical preparation is administered from a pre-filled syringe (PFS). A PFS is a syringe that contains an appropriate amount of pharmaceutical preparation and is preferably prepared for subcutaneous administration by a medical professional. In some embodiments of the method of the present invention, the pharmaceutical preparation is administered from a single pre-filled syringe. In other embodiments, the pharmaceutical preparation is administered from multiple pre-filled syringes, for example, from two, three, four, five, or six or more pre-filled syringes.

[0072] According to the present disclosure, the volume of the pharmaceutical formulation in the prefilled syringe is 1 mL or less. In some embodiments, the volume of the pharmaceutical formulation in the prefilled syringe is 0.1 mL to 0.9 mL. In some embodiments, the volume of the pharmaceutical formulation in the prefilled syringe is 0.1 mL to 0.8 mL. In some embodiments, the volume of the pharmaceutical formulation in the prefilled syringe is 0.1 mL to 0.5 mL. In some embodiments, the volume of the pharmaceutical formulation in the prefilled syringe is about 0.1 mL. In some embodiments, the volume of the pharmaceutical formulation in the prefilled syringe is about 0.2 mL. In some embodiments, the volume of the pharmaceutical formulation in the prefilled syringe is about 0.3 mL. In some embodiments, the volume of the pharmaceutical formulation in the prefilled syringe is about 0.4 mL. In some embodiments, the volume of the pharmaceutical formulation in the prefilled syringe is about 0.5 mL. In some embodiments, the volume of the pharmaceutical formulation in the prefilled syringe is about 0.6 mL. In some embodiments, the volume of the pharmaceutical formulation in the prefilled syringe is about 0.7 mL. In some embodiments, the volume of the pharmaceutical formulation in the prefilled syringe is about 0.8 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 50 mg in a volume of about 0.14 mL. In some embodiments, the amount of risperidone in the pharmaceutical formulation is 100 mg in a volume of about 0.28 mL. 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 amount of risperidone in the pharmaceutical formulation is 200 mg in a volume of about 0.56 mL. In some embodiments, the amount of risperidone in the pharmaceutical formulation is 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 psychiatric disorders are chronic diseases that require continuous treatment to suppress symptoms and prevent relapse. Therefore, the method of the present invention can be carried out over a long period of time. In some embodiments, the method is carried out for at least 6 months. In other embodiments, the method is carried out for at least 12 months. In other embodiments, the method is carried out for at least 15 months. In other embodiments, the method is carried out for at least 24 months.

[0074] Further provided is a pharmaceutical composition comprising 1 mL or less of: a) risperidone or a pharma- ceutical acceptable salt thereof having a concentration of about 250 to 400 mg / mL in terms of risperidone; b) Formula: Poly(lactic acid) v -poly(ethylene glycol) w, -poly(lactic acid) x (In the formula, 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.) : A biodegradable triblock copolymer having the following structure; c) Formula: Methoxypoly(ethylene glycol) y-poly(lactic acid) z (wherein y and z are the numbers 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). A biodegradable diblock copolymer having: and wherein 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 said formulation that is insoluble in an aqueous environment.

[0075] Methods for preparing pharmaceutical formulations used in the methods of the present invention are disclosed, for example, in US Pat. No. 9,023,897, incorporated herein by reference.

[0076] Some mPEG-OH is contaminated with small amounts of OH-PEG-OH. By using contaminated mPEG-OH according to the methods of the present invention, the final product is mPEG-PLA contaminated with small amounts of PLA-PEG-PLA, which is encompassed by the present invention.

[0077] With respect to the foregoing embodiments, each embodiment disclosed herein is believed to be applicable to each of the other disclosed embodiments, for example, elements recited in the method embodiments can be used in the pharmaceutical composition or formulation embodiments described herein, and vice versa.

[0078] The following examples are intended to be illustrative and not limiting. Those of skill in the art will readily recognize various features that can be changed or modified to yield essentially the same results. EXAMPLES

[0079] (Example) Example 1. In Vitro Release (IVR) Model The in vitro model setup was based on the USP II dissolution test technique. In this technique, the in vitro release of the drug formulation is followed in a tube containing an aqueous buffer maintained at +37°C under constant stirring. Approximately 100 or 170 mg of the formulation was injected inside a Falcon® tube prefilled with 50 mL of Krebs-Ringer-Tris buffer (KRT, pH 7.4) using a 0.5-mL syringe fitted with a 23G needle and immediately incubated at +37°C under constant orbital stirring speed (180 rpm). As the copolymer is not soluble in water, the depot was formed freely immediately after contact with the buffer. This is intended to mimic the implant formation in the subcutaneous tissue in vivo.

[0080] In vitro release of each formulation was performed in duplicate. At pre-determined time points, the release buffer was sampled and freshly replaced. Special attention was paid to not lose any fraction of the depot (if any) during the buffer exchange. When the IVR was finished, the amount of active agent in the remaining depot was determined by HPLC to assess the mass balance and ensure that the amount of active agent remaining in the depot correlated with the cumulative release. Briefly, the remaining depot was dissolved in 10 mL of acetonitrile. The solution was mixed using a vortex mixer until completely dissolved, after which 10 mL of ultrapure water was added. The mixture was shaken once more before HPLC analysis.

[0081] Preparation of stock solutions, standards, and quality control samples To obtain a 200 μg / mL risperidone solution, risperidone was dissolved in acetonitrile / H 2 A stock solution was prepared by dissolving 1,2-dichlorophenyl ether in a 1:1 O mixture (50 / 50 v / v). This "mother solution" was stored at +2-8°C and was stable for a minimum of 5 months. Starting from this mother solution, calibration standards were prepared by dilution into the same sample solvent mixture as above. Six dilutions were performed to obtain calibration standards of 1, 5, 10, 25, 50, 100, and 200 μg / mL.

[0082] Additional working solutions containing 0.10, 0.25, 0.50, and 0.75 μg / mL were similarly prepared by further diluting the 10 μg / mL standard. These more diluted samples were specifically used to investigate the limits of detection (LOD) and quantitation (LOQ) of the chromatographic method.

[0083] A series of three precision 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. These standards were used to assess the level of precision of the developed method.

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

[0085] According to the above conditions, the retention time of risperidone was 5.5 min. Linearity was evaluated throughout the analysis of standards (1, 5, 10, 25, 50, 100, and 200 μg / mL). Calibration was established based on each standard peak area. Linear regression analysis was used to determine the best-fit curve, r 2 A 100% confidence interval (CI) of >0.9999 was given. Precision was determined by calculating the relative standard deviation (RSD) between the mean measured concentrations of three precision standards, i.e., 10, 100, and 200 μg / mL. The RSD was <0.1% for all precision standards, and the recoveries ranged from 99.7 to 101.9% of the target concentrations. The LOD was calculated to be 0.1 μg / mL (corresponding to three times the average baseline noise). The LOQ was assessed as the lowest concentration allowing 90% recovery of the target drug concentration. The LOQ was found to be 0.5 μg / mL.

[0086] Injectability was measured according to standard operating procedures (SOP, Texturometer Use (LA-PR-EQ-6-1-EN)). The method was inspired from a previous study by F. Cilurzo et al. The equipment used for injectability measurements was a Friction Tester FTPlus (Lloyd Instruments) connected with Nexygen Plus software. Briefly, injectability tests were 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. The dynamic glide force (DGF) (i.e., the average force in Newtons (N) required to sustain the movement of the plunger to expel the formulation from the syringe) was then measured for each test. F. Cilurzo et al. showed that "this parameter is representative of manual syringe delivery to the patient" (Cilurzo, F et al., Injectability Evaluation: An Open Issue. AAPS PharmSciTech. 2011 2: 604-609).

[0087] Example 2. Risperidone Formulations Formulations of risperidone having an amount of risperidone of at least 250 mg / mL, such as at least 300 mg / mL, and up to about 400 mg / mL, for an injection volume of ≦1 mL.

[0088] Preparation of Risperidone Particles Particles of risperidone can be prepared using micronization, micronization, or milled sourcing.

[0089] (Dose adjustment by bolus injection) A two-fold increase in injection volume resulted in a non-proportional increase in release rate, as evidenced by the change in 75% cumulative release between the 125 mg and 250 mg depots. The 250 mg depot released its risperidone cargo over a longer period than the 125 mg depot.

[0090] Exemplary formulations are shown in Table 2. The percentages shown are weight percentages from the total formulation composition. Table 2 [Table 2] * PaRb represents the TB copolymer, where a is the size of the PEG chain in kDa and b is the lactic acid / ethylene oxide (LA / EO) molar ratio.

[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 [Table 4]

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

[0093] The compositions were injected subcutaneously in the interscapular and flank areas of rats, dogs, minipigs, and pigs.

[0094] One study examined the feasibility of locating and excising sc injected implants for long-acting release of risperidone by the clinically relevant imaging techniques ultrasound and MRI in minipigs. Two Yucatan minipigs (Sus scrofa) were injected sc into the flank of the animals with 50 and 150 mg of risperidone formulation, corresponding to volumes of 140 and 420 μL, respectively. Additionally, these animals were injected sc with three vehicle formulations (non-API control formulations) with volumes ranging from 70 to 840 μL, for a total of five implants per animal (two risperidone, three vehicle).

[0095] MRI (Magnetom Sonata Syngo 1.5 T; Siemens), ultrasound (FujiFilm Vevo MD instrument for frequencies of 15, 30, and 50 MHz), and Siemens Acuson SC2000 Apparel (for a frequency of 9 MHz) imaging modalities were used to localize the implants at 4 hours and at days 1, 3, 6, 14, 20, 27, and 35 after injection. Implant excision was performed on day 14 after injection, and PK samples were collected before and after 72 hours to confirm complete removal.

[0096] MRI provided a useful visual aid for implant depth and size throughout the study. Ultrasound imaging 4 hours after administration was challenging, and implants with volumes of 70-140 μL were difficult to locate. On days 1-6, the echogenicity of the depot was variable but visible using lower frequencies (9 and 15 MHz). On days 14-35, ultrasound images were clear with both the 9 and 15 MHz probes and aided in locating the smaller injection volumes. Higher frequency probes (30 and 50 MHz) did not aid in locating the implant. Risperidone implants were surgically removed 14 days after injection, after imaging and palpation at the injection site. No trace of the implant could be imaged, and risperidone plasma levels dropped soon after removal. The removal site healed within a few days after surgery, and animals monitored for up to 2 weeks after removal recovered well. Overall, localization of sc implants by clinically relevant imaging techniques such as ultrasound with 9 MHz and 15 MHz probes and MRI proved feasible. Ablation was good and complete, allowing removal of risperidone from the systemic circulation when necessary.

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

[0098] The study was conducted on 53 healthy volunteers and 6 other patients receiving injections of the formulation vehicle without risperidone.

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

[0100] Example 5 SAD / MAD Test Sequential single ascending dose and multiple ascending dose studies were conducted to evaluate the safety, tolerability, and pharmacokinetics of the risperidone extended release injectable suspension disclosed herein for subcutaneous use in patients with schizophrenia or schizoaffective disorder.

[0101] The study population was 99 patients with schizophrenia, with 88 patients included in the safety component of the study.

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

[0103] The studies of Examples 3 and 4 taken together demonstrated several points: · the safety profile of the formulations disclosed herein was consistent with other risperidone formulations; -There have been no serious adverse reactions associated with the formulations disclosed herein Treatment options demonstrated a favorable risk / benefit profile No significant changes in pharmacokinetic parameters were observed during the change in injection area. Validation of dose and target duration: 1 month (Q1M) and 2 month (Q2M) products

[0104] The results of the clinical trials in Examples 4 and 5 show that formulations disclosed herein with 1-month and 2-month release profiles at various doses provide rapid establishment of clinically relevant risperidone plasma concentrations that peak in the first 24 hours, avoiding the need for oral supplementation after initiation of treatment, and then slowly decline over 1-2 months, respectively. Doses were selected based on comparability of plasma concentrations to those observed with oral risperidone over a 24-hour dosing interval, with the goal of ensuring adequate exposure throughout the dosing period.

[0105] Safety, including local tolerability at the injection site, was examined in two clinical trials in Examples 4 and 5. The results of the two trials, with a total of 147 patients, showed a safety profile consistent with the known safety profile of risperidone, along with good local tolerability at the injection site. Two serious adverse events were reported from cohort 8 of the study in Example 5, both of which were evaluated by both investigators and funders not involved in the risperidone formulation. There were no other serious adverse events in patients who received the risperidone formulation in this study.

[0106] The safety analysis of the Example 5 study is presented in Table 5. Table 5 [Table 5] Abd=abdominal sc injection

[0107] Example 6: Phase 3 clinical trial using risperidone formulation (Purpose of the test:) The objective of the study is to evaluate the efficacy, safety, and tolerability of various dose regimens of subcutaneously administered risperidone formulations described herein compared to placebo during the maintenance treatment phase in adult and adolescent patients with schizophrenia.

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

[0109] (Test population:) Male and female patients aged 13-65 years with a confirmed diagnosis of schizophrenia, who are clinically stable and eligible for risperidone treatment.

[0110] (Test Drug:) 250-400 mg / mL risperidone in the formulation disclosed herein. The investigational product will be presented in a glass vial containing a fixed amount of the risperidone formulation or a prefilled syringe (PFS) containing a fixed amount of the risperidone formulation. The investigational product will be tested for comparability of risperidone exposure when administered subcutaneously once every 28-30 days (Q1M) or once every 56-60 days (Q2M) to oral risperidone tablets.

[0111] (Primary and secondary endpoints:) (Primary endpoint:) 1. Time to threatened recurrence [time frame: 15 months] Calculated as the earliest date on which a patient meets ≥1 threatened recurrence criterion

[0112] (Secondary endpoints:) 1. Time to threatened recurrence [time frame: 15 months] As defined under the primary objective in the total population (adults and adolescents) 2. Time to threatened relapse in adolescents with schizophrenia 3. Threatened recurrence rate [time frame: 24 weeks] This rate is estimated using the Kaplan-Meier method. 4. Observed rate of imminent relapse [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 remaining stable [Time frame: 15 months] Stable disease is defined as meeting all of the following criteria for at least 4 consecutive weeks: Outpatient setting; PANSS total score ≦80; minimal presence of specific psychotic symptoms on the PANSS as measured by a score of ≦4 for each of the following items: conceptual integration disorder, suspiciousness, hallucinatory behavior, and unnatural thought content; Clinical Global Impression of Severity (CGI-S) score ≦4 (moderate illness); and Clinical Global Impression-Suicidality Severity (CGI-SS) score ≦2 in part 1 (mild suicidal ideation) and ≦5 in part 2 (minimal deterioration). Percentages are calculated as the number of patients who remained stable at the endpoint divided by the number of patients in a given treatment group. 6. Percentage of patients achieving remission [Time frame: 15 months] Positive symptoms, negative symptoms, and overall symptom remission will be examined and will include criteria for severity and duration as defined by Andreasen et al. (2005). All remission criteria will be derived 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 herein can be made and executed without undue experimentation in light of the present disclosure. While the compositions and methods of the present invention have been described in terms of preferred embodiments, it will be apparent to those skilled in the art that modifications can be applied without departing from the spirit and scope of the invention.

[0114] All patents, patent applications, and publications disclosed herein are incorporated by reference to the same extent as if each individual publication was specifically and individually indicated to be incorporated by reference. Although the present invention has been specifically disclosed by preferred embodiments and optional features, it should be understood that modifications and variations of the concepts disclosed herein may be employed by those skilled in the art, and that such modifications and variations are believed to be within the scope of the present invention as defined by the appended claims. The present application provides the following aspects of the invention. (Aspect 1) 1. A method of treating a psychiatric disease or disorder in a subject, comprising administering to the subject no more than once every 21 days: a) risperidone or a pharma- ceutical acceptable salt thereof having a concentration of about 250 to 400 mg / mL in terms of risperidone; b) Formula: Poly(lactic acid) v -poly(ethylene glycol) w, -poly(lactic acid) x (In the formula, 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.) A biodegradable triblock copolymer having the formula: c) Formula: Methoxypoly(ethylene glycol) y-poly(lactic acid) z (wherein y and z are the numbers 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). A biodegradable diblock copolymer having the formula: Contains : and wherein 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 said formulation that is insoluble in an aqueous environment, and the pharmaceutical formulation is 1 mL or less. The method comprises subcutaneously administering: (Aspect 2) The method of embodiment 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 pharma- ceutical acceptable salt thereof is 300 mg / mL to 400 mg / mL in terms of risperidone. (Aspect 4) The method of any one of embodiments 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 method of embodiment 4, wherein the triblock copolymer is present in an amount of about 5% to 15% (w / w%) of the total weight of the formulation. (Aspect 6) The method of any one of embodiments 1-5, wherein the diblock copolymer is present in an amount of about 8%-25% (w / w%) of the total weight of the formulation. (Aspect 7) The method of embodiment 6, wherein the diblock copolymer is present in an amount of about 10% to 20% (w / w%) of the total weight of the formulation. (Aspect 8) The method of any one of embodiments 1-7, 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 formulation. (Aspect 9) The method of embodiment 8, wherein the triblock and diblock copolymers are present in a total amount of about 20%-30% (w / w%) of the total weight of the formulation. (Aspect 10) The method of any one of aspects 1-9, wherein the formulation further comprises a water soluble organic solvent, which is DMSO. (Aspect 11) The method of embodiment 10, wherein the formulation further comprises triacetin, tripropionin, or a mixture thereof. (Aspect 12) 12. The method of 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 formulation. (Aspect 13) The method of any one of embodiments 1-12, wherein said administration is effective to treat the psychiatric disease or disorder in the subject for 21 to 90 days. (Aspect 14) The method of any one of embodiments 1-12, wherein said administration is effective to treat the psychiatric disease or disorder in the subject for between 28 and 90 days. (Aspect 15) The method of any one of embodiments 1-12, wherein said administration is effective to treat the psychiatric disease or disorder in the subject for between 28 and 56 days. (Aspect 16) The method of any one of embodiments 1-15, wherein less than about 15 w% of the risperidone in the formulation is cumulatively released 24 hours after administration. (Aspect 17) The method of embodiment 16, wherein about 7 wt.% to about 15 wt.% of the risperidone in the formulation is cumulatively released over 24 hours after administration. (Aspect 18) The method according to any one of aspects 13 to 17, wherein about 50 w% to about 80 w% of the risperidone in the formulation is cumulatively released 30 days after administration. (Aspect 19) The method of any one of aspects 13-18, wherein about 70 w% to about 98% w% of the risperidone in the formulation is cumulatively released 60 days after administration. (Aspect 20) The method of any one of embodiments 13-19, wherein said cumulative release is determined by an in vitro release (IVR) method disclosed herein. (Aspect 21) 21. The method of any one of aspects 1-20, wherein said psychiatric disease or disorder is schizophrenia or bipolar disorder. (Aspect 22) The method of any one of embodiments 1-21, wherein said method is performed in the absence of a loading dose or adjunctive oral risperidone. (Aspect 23) The method according to any one of embodiments 1 to 22, for implementation over a period of at least six months. (Aspect 24) 24. The method of embodiment 23, for implementation for at least 15 months. (Aspect 25) The method of any one of embodiments 1 to 24, wherein said formulation is presented in a single pre-filled syringe (PFS). (Aspect 26) The method of embodiment 25, wherein the volume in the prefilled syringe is between 0.1 mL and 0.8 mL. (Aspect 27) The method according to any one of embodiments 1 to 26, for subcutaneous administration to the abdomen. (Aspect 28) The method according to any one of embodiments 1 to 27, for subcutaneous administration to the upper arm. (Aspect 29) The method of any one of embodiments 1-28, wherein said formulation is resectable following administration to said subject. (Aspect 30) 1. A pharmaceutical formulation for treating a psychiatric disease or disorder, comprising 1 mL or less of: a) risperidone or a pharma- ceutical acceptable salt thereof having a concentration of about 250 to 400 mg / mL in terms of risperidone; b) Formula: Poly(lactic acid) v -poly(ethylene glycol) w, -poly(lactic acid) x (In the formula, 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.) A biodegradable triblock copolymer having the formula: c) Formula: Methoxypoly(ethylene glycol) y-poly(lactic acid) z (wherein y and z are the numbers 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). A biodegradable diblock copolymer having the formula: and wherein 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 formulation that is insoluble in an aqueous environment.

Claims

1. 1. A pharmaceutical formulation for treating a psychiatric disease or disorder, comprising: a) risperidone or a pharma- ceutical acceptable salt thereof at a concentration of about 250 to 400 mg / mL in terms of risperidone; b) Formula: poly(lactic acid) v -poly(ethylene glycol) w, -poly(lactic acid) x where v and x are the number of repeating units ranging from 24 to 682, and w is the number of repeating units ranging from 4 to 273, and v=x or v≠x; and c) Formula: methoxypoly(ethylene glycol) y-poly(lactic acid) z where y and z are numbers of repeating units, where y is a number of repeating units ranging from 3 to 45 and z is a number of repeating units ranging from 7 to 327; 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 formulation that is insoluble in an aqueous environment; The pharmaceutical formulation is administered to a subject in an amount of 1 mL or less; and The pharmaceutical formulation is administered subcutaneously to the subject no more than once every 21 days.

2. 2. The pharmaceutical formulation of claim 1, wherein the risperidone is risperidone base.

3. 3. The pharmaceutical formulation according to claim 1, wherein the concentration of the risperidone or the pharma- ceutical acceptable salt thereof is 300 mg / mL to 400 mg / mL in terms of risperidone.

4. 4. The pharmaceutical formulation of 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 formulation.

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

6. 6. The pharmaceutical formulation of 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 formulation.

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

8. 8. The pharmaceutical formulation of 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 formulation.

9. 9. The pharmaceutical formulation of claim 8, 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 formulation.

10. 10. The pharmaceutical formulation of any one of claims 1 to 9, wherein the formulation further comprises a water-soluble organic solvent, which is DMSO.

11. 11. The pharmaceutical formulation of claim 10, wherein the formulation further comprises triacetin, tripropionin, or a mixture thereof.

12. 12. The pharmaceutical formulation of 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 formulation.

13. 13. The pharmaceutical formulation of any one of claims 1 to 12, wherein said administration is effective to treat the psychiatric disease or disorder in the subject for 21 to 90 days.

14. 13. The pharmaceutical formulation of any one of claims 1 to 12, wherein said administration is effective to treat the psychiatric disease or disorder in the subject for 28 to 90 days.

15. 13. The pharmaceutical formulation of any one of claims 1 to 12, wherein said administration is effective to treat the psychiatric disease or disorder in the subject for between 28 and 56 days.

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

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

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

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

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

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

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

23. 23. The pharmaceutical formulation of any one of claims 1 to 22, which is administered for at least 6 months.

24. 24. The pharmaceutical formulation of claim 23, which is administered for at least 15 months.

25. The pharmaceutical formulation according to any one of claims 1 to 24, wherein said formulation is presented in a single pre-filled syringe (PFS).

26. 26. The pharmaceutical formulation of claim 25, wherein the volume in the prefilled syringe is between 0.1 mL and 0.8 mL.

27. 27. The pharmaceutical formulation according to any one of claims 1 to 26, for subcutaneous administration to the abdomen.

28. 28. The pharmaceutical formulation according to any one of claims 1 to 27, for subcutaneous administration to the upper arm.

29. The pharmaceutical preparation of any one of claims 1 to 28, wherein the preparation is excisable after administration to the subject.

30. 1. A pharmaceutical formulation for treating a psychiatric disease or disorder, comprising: a) risperidone or a pharma- ceutical acceptable salt thereof at a concentration of about 250 to 400 mg / mL in terms of risperidone; b) Formula: poly(lactic acid) v -poly(ethylene glycol) w, -poly(lactic acid) x where v and x are the number of repeating units ranging from 24 to 682, and w is the number of repeating units ranging from 4 to 273, and v=x or v≠x; and c) Formula: methoxypoly(ethylene glycol) y-poly(lactic acid) z where y and z are numbers of repeating units, where y is the number of repeating units ranging from 3 to 45, and z is the number of repeating units ranging from 7 to 327; and wherein 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 said formulation that is insoluble in an aqueous environment.

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