Long-acting injectable formulations containing risperidone and biodegradable polymers

Abstract

The present invention relates to a method for treating psychiatric diseases and disorders, comprising administering to a subject in need thereof no more than once every 28 days an injectable formulation comprising risperidone, a triblock and a diblock copolymer, wherein the concentration of risperidone is 250-400 mg / mL and the injection volume is 1 mL or less.

Description

[Technical field]

[0001] (Related Applications) This application claims the benefit of U.S. Provisional Application Nos. 63 / 162,272, filed March 17, 2021, 63 / 208,860, filed June 9, 2021, and 63 / 270,174, filed October 21, 2021, which are incorporated by reference in their entireties herein, and International Application No. PCT / IB2021 / 052248, filed March 17, 2021.

[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 THEINVENTION Schizophrenia is a debilitating psychotic disorder with a complex etiology. It is characterized by positive symptoms (e.g., delusions, hallucinations, and severely disorganized or catatonic behavior) and negative symptoms (e.g., flat affect, aphasia, and amotivation). Cognitive impairments, including impairments in executive function and attention, and short-term and long-term memory difficulties, are common.

[0004] Risperidone is an atypical antipsychotic serotonergic (5-HT2A receptor) and dopaminergic (D2, D3, and D4 receptor) antagonist. It also 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, bipolar disorder, autism spectrum disorder (ASD), and manic or psychotic episodes.

[0005] Risperidone is used in the first-line treatment of schizophrenia due to its safety profile and mid- to long-term treatment recommendations. Premature discontinuation of antipsychotic therapy is a common phenomenon. Even among patients who do not explicitly discontinue pharmacotherapy, non-adherence to long-term oral drug regimens is one of the most significant therapeutic problems in the treatment of schizophrenia and related disorders. As a result, many of these patients do not fully benefit from antipsychotic therapy and suffer frequent relapses or exacerbations that often require readmission in the setting of a psychiatric emergency (Rainer MK, 2008. Risperidone long-acting injection: a review of its long term safety and efficacy. Neuropsychiatr Dis Treat 4(5):919-27). Therefore, the use of long-acting injectable (LAI) antipsychotics may improve prognosis and increase acceptance by healthcare professionals (HCPs) as well as compliance in patients with schizophrenia.

[0006] LAI antipsychotic products are approved by the FDA. Risperdal Consta® is an injectable risperidone product for biweekly intramuscular (IM) administration. Risperdal Consta® is a microparticle formulation 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. The product requires multiple reconstitution steps at the start of treatment and oral supplementation. Intramuscular injections are typically painful and anxiety-inducing, especially for the target population.

[0007] Perseris®, an injectable risperidone product for monthly subcutaneous administration, is provided in two syringes: one containing a PLGA polymer (liquid syringe) and a second containing risperidone (powder syringe), which 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), which correspond to 3 mg / day and 4 mg / day, respectively.

[0008] U.S. Pat. No. 9,023,897 and U.S. Patent Publication No. US2019 / 160171 describe pharmaceutical formulations comprising biodegradable triblock and diblock copolymers that are useful for the delivery of a variety of actives.

[0009] Challenges in treating psychiatric diseases or disorders with risperidone include, for example, being able to subcutaneously inject long-acting formulations with high doses of active agent in low injection volumes and with injectable viscosity. Another challenge is the development of long-acting subcutaneous injectable formulations with active agent that have no or a low initial burst.

[0010] There is a need for a long-acting risperidone formulation that improves patient outcomes, improves patient quality of life, increases patient and HCP acceptance and patient compliance, reduces patient anxiety upon administration, potentially delays relapse, and gives patients and HCPs flexibility in choosing dose strength, dosing regimen, and ease of administration. Furthermore, a formulation that improves the likelihood that patients with schizophrenia will remain stable and improve after stabilization would be of considerable benefit to patients and the healthcare system. The compositions and methods disclosed herein meet these and other needs. Summary of the Invention

[0011] (Summary of the invention) Provided herein are compositions and methods for treating a psychiatric disease or disorder in a subject, the compositions and methods providing to the subject improved patient outcomes and having the following characteristics: · Achieve therapeutic levels within 24 hours, thereby eliminating the need for oral or parenteral supplementation or loading or boosting doses; · Extend time to recurrence; · Reduce recurrence rates; ·Long-term reduction in Total Positive and Negative Syndrome Scale (PANSS) scores; · Maintaining patient stability and increasing the chances of improvement after stabilization; · A ready-to-use (RTU) flowable formulation in a prefilled syringe with a short (5 / 8 inch, 16 mm), low gauge (21 G) needle; Allows dosing directly from oral risperidone up to once a month (Q1M) or once every two months (Q2M); · Flexibility for patients and HCPs to adjust doses (i.e., switch between doses, i.e., from 50 mg to 75 mg or from 75 mg to 100 mg, etc.) as needed; · Flexibility for patients and HCPs to switch dosing regimens (i.e., from Q1M to Q2M or between Q2M and Q1M) if necessary; · Flexibility for patients and HCPs to switch patients from an orally administered antipsychotic, i.e., risperidone, to the risperidone formulations disclosed herein (Q1M or Q2M) the day after the last dose of oral therapy; · flexibility for patients and HCPs to switch patients from parenterally administered antipsychotics to the risperidone formulations disclosed herein (Q1M or Q2M) at the time of their next dose; Flexibility to choose administration site (abdomen or upper arm) independently for each administration for optimal compliance and comfort The present invention relates to compositions and methods comprising subcutaneously administering a risperidone formulation for once-monthly or once-every-two-months administration, the formulation exhibiting one or more of:

[0012] Moreover, the offer of a once every two months (Q2M) dose is specifically intended to address the unmet medical need of convenience and improved compliance, one of the biggest obstacles to pharmacological success in the treatment of schizophrenia. The treatment also increased the proportion of patients who remained stable, e.g., remained stable for up to 6 months, remained stable for up to 9 months, remained stable for up to 12 months, remained stable for up to 15 months, and longer. Surprisingly, patients continue to improve after stabilization, e.g., for up to 6 months after stabilization, for up to 9 months after stabilization, for up to 12 months after stabilization, for up to 15 months after stabilization, and longer, as assessed by the PANSS (i.e., score decline).

[0013] The methods disclosed herein eliminate the need for supplemental or loading doses of risperidone therapy (e.g., oral or parenteral) to reach a therapeutic dose. An aspect of the invention is a method of switching a subject from daily oral risperidone therapy to a long-acting injectable risperidone formulation, comprising: i. orally administering the final dose of daily oral risperidone therapy (after which no further oral risperidone therapy is administered); and ii. The next day, the subject (a) risperidone or a pharma- ceutical acceptable salt thereof having a concentration of about 250 to 400 mg / mL in terms of risperidone; Formula (b): 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: Methoxy-poly(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 50, and z is the number of 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, which is insoluble in an aqueous environment; thereby switching the subject from daily oral risperidone therapy to a long-acting injectable risperidone formulation. A method is provided, including:

[0014] A further aspect of the invention is a method of switching a subject from a long-acting injectable antipsychotic to a long-acting injectable risperidone formulation without the need for adjunctive oral risperidone therapy, comprising: i. administering the final dose of a long-acting injectable antipsychotic; and ii. The next dose will be administered subcutaneously using a long-acting injectable risperidone formulation; Including, wherein the long-acting injectable risperidone formulation is 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 where v and x are numbers of repeating units ranging from 24 to 682, and w is a number of repeating units ranging from 4 to 273, and v=x or v≠x; c. Formula: Methoxy-poly(ethylene glycol) y -Poly(lactic acid) z where y and z are the number of repeating units, where y is the number of repeating units in the range of 3 to 50, and z is the number of units in the range of 7 to 327; Contains : and wherein the ratio of the (b) biodegradable triblock copolymer to the (c) biodegradable diblock copolymer 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; and Provided herein are methods, wherein the method is performed without administering adjunctive oral risperidone therapy to the subject.

[0015] In a further embodiment, a subject can be switched between monthly and bimonthly dosing of a long-acting injectable risperidone formulation by administering the first dose of the new dosing regimen on the next scheduled dosing date of the original dosing regimen. The dose administration schedule can be modified to reflect the change. Thus, the present invention provides a method of switching a subject from a monthly to a bimonthly (i.e., bimonthly) long-acting injectable risperidone formulation without the need for supplemental oral risperidone therapy, comprising: i. administering the final dose of a long-acting injectable risperidone formulation subcutaneously once a month; and ii. one month later, a long-acting injectable risperidone formulation administered subcutaneously once every other month (i.e., once every two months); Contains: wherein each of the monthly and bimonthly (i.e., once every two months) long-acting injectable risperidone formulations is (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 where v and x are numbers of repeating units ranging from 24 to 682, and w is a number of repeating units ranging from 4 to 273, and v=x or v≠x; (c) Formula: Methoxy-poly(ethylene glycol) y -Poly(lactic acid) z where y and z are the number of repeating units, where y is the number of repeating units in the range of 3 to 50, and z is the number of units in the range of 7 to 327; and wherein the ratio of the (b) biodegradable triblock copolymer to the (c) biodegradable diblock copolymer 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; and Provided herein are methods, wherein the method is performed without administering adjunctive oral risperidone therapy to the subject.

[0016] In a further aspect, the present invention provides a method of switching a subject from a once every other month (i.e., once every two months) long-acting injectable risperidone formulation to a once every month long-acting injectable risperidone formulation without the need for adjunctive oral risperidone therapy, comprising: i. administering the final dose of a long-acting injectable risperidone formulation subcutaneously once every other month (i.e., once every two months); and ii. After 2 months, a long-acting injectable risperidone formulation administered subcutaneously once a month; Contains: Wherein monthly and bimonthly (i.e., once every two months) long-acting injectable risperidone formulations are (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 where v and x are numbers of repeating units ranging from 24 to 682, and w is a number of repeating units ranging from 4 to 273, and v=x or v≠x; (c) Formula: Methoxypoly(ethylene glycol) y -Poly(lactic acid) z where y and z are the number of repeating units, where y is the number of repeating units in the range of 3 to 50, and z is the number of units in the range of 7 to 327; and wherein the ratio of the (b) biodegradable triblock copolymer to the (c) biodegradable diblock copolymer 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; and Methods are provided herein, wherein the method is performed without administering adjunctive oral risperidone therapy to the subject.

[0017] In another aspect, the present invention provides a method of treating a psychiatric disease or disorder in a subject, comprising subcutaneously administering to the subject a long-acting injectable risperidone-polymer formulation, wherein the administration is once every two months, and wherein the administration results in a mean exposure (AUC0-tau) of TAM equivalent to that of oral risperidone (2 mg / day to 5 mg / day) administered over a comparable administration period.

[0018] In another aspect, the present invention provides a method of treating a psychiatric disease or disorder in a subject, comprising subcutaneously administering to the subject a long-acting injectable risperidone-polymer formulation, wherein the risperidone formulation comprises risperidone and a polymer, and administration is selected from the upper arm and / or abdomen of the subject.

[0019] A further aspect of the invention is a method of switching risperidone dosage in a subject administered a monthly or bimonthly (i.e., once every two months) long-acting injectable risperidone formulation from a first dose of a long-acting injectable risperidone formulation to a subsequent dose of a long-acting injectable risperidone formulation without the need for adjunctive oral risperidone therapy, comprising: i. administering the final dose of the initial dose of a long-acting injectable risperidone formulation subcutaneously; and ii. Administer a subsequent dose of a long-acting injectable risperidone formulation subcutaneously at the next dose; Including, wherein the initial dose and the subsequent doses of a long-acting injectable risperidone formulation are (a) risperidone or a pharma- ceutical acceptable salt thereof having a concentration of about 250 to 400 mg / mL in terms of risperidone; Formula (b): Poly(lactic acid) v -Poly(ethylene glycol) w -Poly(lactic acid) x where v and x are numbers of repeating units ranging from 24 to 682, and w is a number of repeating units ranging from 4 to 273, and v=x or v≠x; (c) Formula: Methoxy-poly(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 50, and z is the number of units in the range of 7 to 327; wherein the ratio of the (b) biodegradable triblock copolymer to the (c) biodegradable diblock copolymer 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; and Provided herein are methods, wherein said method is performed without administering any adjunctive oral risperidone therapy to said patient.

[0020] Yet a further embodiment is a method of administering risperidone to a subject receiving long-acting injectable risperidone therapy, where the subject has a history of missing a dose of the long-acting injectable risperidone formulation, comprising subcutaneously administering a monthly or bimonthly (i.e., once every two months) dose of the long-acting injectable risperidone formulation; wherein the long-acting injectable risperidone formulation is (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 where v and x are numbers of repeating units ranging from 24 to 682, and w is a number of repeating units ranging from 4 to 273, and v=x or v≠x; (c) Formula: Methoxy-poly(ethylene glycol) y -Poly(lactic acid) z where y and z are the number of repeating units, where y is the number of repeating units in the range of 3 to 50, and z is the number of units in the range of 7 to 327; and wherein the ratio of the (b) biodegradable triblock copolymer to the (c) biodegradable diblock copolymer 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; and Provided herein are methods, wherein said method is performed without administering any adjunctive oral risperidone therapy to said patient.

[0021] A further aspect of the invention is a pre-filled syringe (PFS) for subcutaneous administration of a long-acting injectable risperidone formulation, comprising: A long-acting injectable risperidone formulation, wherein the formulation comprises: (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 where v and x are numbers of repeating units ranging from 24 to 682, and w is a number of repeating units ranging from 4 to 273, and v=x or v≠x; (c) Formula: Methoxy-poly(ethylene glycol) y -Poly(lactic acid) z where y and z are the number of repeating units, where y is the number of repeating units in the range of 3 to 50, and z is the number of units in the range of 7 to 327; and wherein the ratio of (b) the biodegradable triblock copolymer to (c) the biodegradable diblock copolymer 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; and Needles with a gauge of 21 or greater and / or a length of 5 / 8 inch or less The present invention provides a prefilled syringe comprising:

[0022] A further aspect of the present invention is Prefilled syringes as defined above; a needle having a gauge of 21 or greater and / or a length of 5 / 8 inch or less; and, optionally, User manual A kit is provided, comprising:

[0023] A further aspect of the present invention provides a method of treating a psychiatric disease or disorder in a subject, comprising subcutaneously administering to the subject a long-acting injectable risperidone-polymer formulation, wherein the administration is once every two months, and wherein the administration results in a mean exposure (AUC0-tau) of TAM equivalent to that of oral risperidone (2 mg / day to 5 mg / day) administered over a comparable administration period.

[0024] A further aspect of the present invention provides a method of treating a psychiatric disease or disorder in a subject comprising subcutaneously administering to the subject a long-acting injectable risperidone-polymer formulation, wherein the risperidone formulation comprises risperidone and a polymer, and wherein the administration is selected from the upper arm and / or abdomen of the subject.

[0025] In some embodiments, the disclosure provides a method of treating a psychiatric disease or disorder in a subject, comprising administering to the subject no more than once every 28 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: Methoxy-poly(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 50, and z is the number of repeating units in the range of 7 to 327). A biodegradable diblock copolymer having the formula: Contains: 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, comprising subcutaneously administering 1 mL or less of a long-acting injectable risperidone formulation; Herein, the risperidone formulation provides a therapeutically effective amount of risperidone for at least 28 days.

[0026] In some embodiments, the formulation is administered subcutaneously to a subject once a month (Q1M), wherein the formulation provides a therapeutically effective amount of risperidone for at least one month. In some embodiments, the formulation is administered subcutaneously to a subject once every two months (Q2M), wherein the formulation provides a therapeutically effective amount of risperidone for at least two months.

[0027] In some embodiments, the formulation is administered subcutaneously to a subject for a period intermediate between Q1M and Q2M, e.g., once every six weeks (Q6W), wherein the formulation provides a therapeutically effective amount of risperidone for about six weeks.

[0028] In particular, the active ingredient of the injectable formulation disclosed herein is risperidone present at a concentration of 250 mg / mL or more, e.g., 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. In some embodiments, risperidone is present at a concentration of 360 mg / mL, or a pharma-ceutically acceptable salt thereof in an amount equivalent to about 360 mg / mL of risperidone. 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 62 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).

[0029] In some embodiments, administration of a long-acting injectable risperidone formulation provides plasma levels of total active moieties (TAM) equivalent to a daily oral dose of 2-5 mg (2 mg, 3 mg, 4 mg, or 5 mg).

[0030] In some embodiments, the long-acting injectable risperidone formulation is administered to the subject no more than once every 28 days. In some embodiments, the long-acting injectable risperidone formulation is administered once a month, the formulation comprises about 50 mg to about 125 mg of risperidone, for example, 50, 75, 100, or 125 mg of risperidone. In some embodiments, the monthly dose comprises 50 mg of risperidone. In some embodiments, the monthly dose comprises 75 mg of risperidone. In some embodiments, the monthly dose comprises 100 mg of risperidone. In some embodiments, the monthly dose comprises 125 mg of risperidone. In some embodiments, the volume of the risperidone formulation for a Q1M dose of up to 125 mg is 0.5 mL or less, specifically, about 0.1 mL to about 0.5 mL or about 0.14 mL to about 0.35 mL. In some embodiments, the volume of the risperidone formulation for a 50 mg dose is about 0.1 mL, for a 75 mg dose it is about 0.2 mL, for a 100 mg dose it is about 0.3 mL, and for a 125 mg dose it is about 0.4 mL. In some embodiments, the volume of the risperidone formulation for a 50 mg dose is about 0.14 mL, for a 75 mg dose it is about 0.21 mL, for a 100 mg dose it is about 0.28 mL, and for a 125 mg dose it is about 0.35 mL.

[0031] In some embodiments where the long-acting injectable risperidone formulation is administered bimonthly, the formulation comprises about 100 mg to about 250 mg of risperidone, e.g., 100, 150, 200, or 250 mg of risperidone. In some embodiments, the bimonthly dose comprises 100 mg of risperidone. In some embodiments, the bimonthly dose comprises 150 mg of risperidone. In some embodiments, the bimonthly dose comprises 200 mg of risperidone. In some embodiments, the bimonthly dose comprises 250 mg of risperidone. In some embodiments, the volume of the risperidone formulation for a Q2M dose of up to 250 mg is 1.0 mL or less, in particular, about 0.2 mL to about 1.0 mL, or about 0.2 mL to a maximum of about 0.7 mL. In some embodiments, the volume of the risperidone formulation for a 100 mg dose is about 0.3 mL, for a 150 mg dose it is about 0.4 mL, for a 200 mg dose it is about 0.6 mL, and for a 250 mg dose it is about 0.7 mL. In some embodiments, the volume of the risperidone formulation for a 100 mg dose is about 0.28 mL, for a 150 mg dose it is about 0.42 mL, for a 200 mg dose it is about 0.56 mL, and for a 250 mg dose it is about 0.70 mL.

[0032] In some embodiments where the long-acting injectable risperidone formulation is administered once every six weeks (Q6W), each dose contains from about 75 mg to about 200 mg of risperidone.

[0033] 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]

[0034] BRIEF DESCRIPTION OF THE DRAWINGS [Figure 1]Figure 1: Results of the primary efficacy endpoint, time to impending relapse (ITT analysis set), shown as Kaplan-Meier survival curves. Risperidone formulations reduced the risk of relapse by 80.0% and 62.5% for Q1M (short dashed line) and Q2M (long dashed line), respectively, compared to placebo (solid line), over the entire study period. [Diagram 2] Figure 2: Reduction in total PANSS scores after stabilization, Q1M (short dashed line with triangles) and Q2M (long dashed line with squares) respectively compared to placebo (solid line with circles). [Diagram 3]3A and 3B: Absorption profile of subcutaneously (sc) administered risperidone formulations disclosed herein compared to that of subcutaneously (sc) administered PERSERIS®. Following a single sc injection of the risperidone formulations described herein, a single absorption peak of risperidone and its metabolite, 9-OH risperidone, was observed (3A. Upper panel of Q1M (50 mg, 75 mg, 100 mg, 125 mg) and lower panel of Q2M (100 mg, 150 mg, 200 mg, 250 mg)). Following a single sc injection, PERSERIS® shows two absorption peaks for risperidone in plasma. The first peak of risperidone occurs with a Tmax of 4-6 hours, which is due to the initial release of drug during the depot formation process. The second peak of risperidone is observed 10-14 days after administration, which is associated with a slow release of risperidone from the subcutaneous depot. The primary and secondary peaks of risperidone are of similar magnitude. For both 9-hydroxyrisperidone and total active moiety, the median Tmax of the primary peak ranges from 4 to 48 hours, and the secondary peak ranges from 7 to 11 days. (3B) (Ivaturi et al., Exposure-response analysis after subcutaneous administration of RBP-7000, a once-a-month long-acting Atrigel formulation of risperidone. Br J Clin Pharmacol. 2017 Jul; 83(7): 1476-1498; PERSERIS PI 07 / 2018. https: / / www.accessdata.fda.gov / drugsatfda_docs / label / 2018 / 210655s000lbl.pdf) DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0035] (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.

[0036] The term "parenteral administration" includes intramuscular, intraperitoneal, intraabdominal, subcutaneous, intravenous, and intraarterial. It also includes intradermal, intracavitary, intravitreal, intracerebral, intrathecal, epidural, and intraosseous administration. In some embodiments, the formulations disclosed herein are administered subcutaneously. In a specific embodiment, the risperidone formulations disclosed herein are administered by a medical professional as a subcutaneous injection into the abdomen or upper arm.

[0037] 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.

[0038] The term "subject" encompasses all members of the Kingdom Animalia, with humans being preferred.

[0039] The active ingredient, i.e., active pharmaceutical ingredient API, according to the present invention is risperidone and its pharma- ceutical acceptable salts.

[0040] As used herein, "psychiatric disease or disorder" refers to mental illness regardless of etiology.Specific psychiatric diseases and disorders that are known to be responsive to risperidone include, for example, schizophrenia, schizoaffective disorder, schizophreniform disorder, bipolar disorder, for example, bipolar 1 disorder, and autism-associated irritability (IAA), for example, adult or childhood irritability associated with autism spectrum.

[0041] As used herein, "risperidone formulation", "long-acting injectable risperidone formulation", "extended release injectable suspension", "pharmaceutical composition", "pharmaceutical formulation", "biodegradable drug formulation", and "biodegradable drug delivery composition" refer to risperidone formulations described herein that provide therapeutic concentrations of risperidone in plasma to a patient in need thereof over a one or two month period, and may be used interchangeably. "Long-acting injectable risperidone therapy" refers to treatment of a subject with a risperidone formulation disclosed herein.

[0042] As used herein, "long-acting injectable antipsychotic" refers to a long-acting injectable product containing an antipsychotic substance that is approved (by a regulatory authority, e.g., FDA and / or EMA) for parenteral administration (e.g., intramuscular, subcutaneous). Non-limiting examples include PERSERIS®, Risperdal®, Consta®, and Abilify Maintena®.

[0043] As used herein, "administered no more frequently than once every 28 days" refers to administration of a long-acting injectable risperidone formulation once every 28 days and up to once every two months.

[0044] As used herein, the term "monthly" or "q1m" or "Q1M" or "monthly" means once a month, and they can be used interchangeably. In some embodiments, "monthly" or "q1m" or "Q1M" or "monthly" means once every 4 weeks (Q4W), once every 28-31 days, such as once every 28 days, once every 29 days, once every 30 days, or once every 31 days. The "monthly", "q1m", "Q1M", or "monthly" administration may be performed on any day of the month, such as, for example, the 1st, 2nd, 3rd, etc. Thereafter, a subsequent administration of the "monthly", "q1m", "Q1M", or "monthly" formulation is performed one month later, such as, for example, 28 days or 28-31 days.

[0045] As used herein, the term "every other month" or "q2m" or "Q2M" or "every two months" means once every two months, and they can be used interchangeably. In some embodiments, "every other month" or "q2m" or "Q2M" or "every two months" means once every 8 weeks (Q8W), or once every 56-62 days, such as once every 56 days, once every 57 days, once every 58 days, once every 59 days, once every 60 days, once every 61 days, or once every 62 days. "Every other month" or "q2m" or "Q2M" or "every two months" administration may be performed on any day of the month, such as, for example, the 1st, 2nd, 3rd, etc. Thereafter, a subsequent administration of the "every other month" or "q2m" or "Q2M" or "every two months" formulation is performed two months later, such as 56 days or 56-62 days.

[0046] "Once every 6 weeks" or "Q6W" administration can be used interchangeably and means once every 42 days or about once every 42 days, e.g., once every 41 days, once every 42 days, or once every 43 days, etc. "Once every 6 weeks" or "Q6W" administration may occur on any day of the month, e.g., day 1, day 2, day 3, etc. Subsequent administration of the "Once every 6 weeks" or "Q6W" formulation is then administered 6 weeks later, e.g., at or about 42 days later.

[0047] In one embodiment of the methods disclosed herein, the dosing regimen may be maintained (e.g., Q1M, then Q1M) or may be switched between doses (e.g., Q1M to Q2M or Q2M to Q1M).

[0048] 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 as described herein (i.e., subcutaneously) without undue force.

[0049] 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).

[0050] "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. As an example, mPEG-PLA refers to a methoxy-capped PEG-polylactide diblock copolymer.

[0051] The abbreviation "PEG" refers to poly(ethylene glycol), poly(ethylene oxide), or poly(oxyethylene), which terms are used interchangeably herein. PEG polymers contain repeating units of ethylene glycol, also known as ethylene oxide (EO).

[0052] The abbreviation "PLA" refers to polylactide, polylactic acid, or poly(lactic acid), which terms are used interchangeably herein. PLA polymers contain repeating units of lactic acid (LA).

[0053] The abbreviations "T" or "TB" refer to triblock copolymers, while the abbreviations "D" or "DB" refer to diblock copolymers.

[0054] The term "diblock" as used herein refers, for example, to end-capped PEG-polyester copolymers, preferably end-capped PEG-poly(lactic acid) 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.

[0055] This list of end-capped PEGs is not exhaustive, and one of skill in the art will recognize additional end-capped PEGs that are not listed.

[0056] The term "triblock" refers, for example, to a polyester-PEG-polyester copolymer, preferably a poly(lactic acid)-PEG-poly(lactic acid) copolymer.

[0057] In some embodiments of the risperidone formulation, the diblock copolymer comprises methoxy-capped PEG and poly(D,L-lactic acid) and can be referred to as "mPEG-PDL" or "mPEG-PDLLA" and the triblock copolymer comprises poly(D,L-lactic acid)-PEG-poly(D,L-lactic acid) and can be referred to as "PDL-PEG-PDL" or "PDLLA-PEG-PDLLA."

[0058] Biodegradable drug delivery compositions used in the methods of the present disclosure are described in US Pat. No. 9,023,897, which is incorporated herein by reference in its entirety.

[0059] The structure of the biodegradable triblock / diblock copolymers of the present invention may also be represented as follows: A v -B w -A x (This is the triblock copolymer poly(lactic acid)v -Poly(ethylene oxide) w -Poly(lactic acid) x and is 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). C y -A z (This is a diblock mPEG-PLA copolymer: methoxy-poly(ethylene glycol) y -Poly(lactic acid) z and is 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 PEG. Poly(lactic acid) chains extend only from the free hydroxyl groups.

[0060] The letters v, w, x, y, and z represent the number of repeat units. 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 3 to 50, 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 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.

[0061] 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 8. 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.

[0062] 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.

[0063] 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 3-50, while for PLA, it can be about 84-327, or it can be 24-682 or 7-327.

[0064] The methods disclosed herein use biodegradable drug compositions comprising triblock and diblock copolymers. The biodegradable triblock copolymers have the formula: v -B w -A x(wherein A is poly(lactic acid), B is poly(ethylene glycol), v and x are the number of repeating units of poly(lactic acid) ranging from 24 to 682; and w is the degree of polymerization (number of repeating units) of poly(ethylene glycol) ranging 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 repeating units) of PLA. DP-PLA is calculated by multiplying DP-PEG by the LA / EO ratio.

[0065] The size of the PEG in the triblock copolymer can be from 194 Da to 12,000 Da. The triblock copolymer has the formula: y -A zwhere 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 1:4. 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. In some embodiments, the ratio of triblock copolymer to diblock copolymer is 3:2, 3:1, 2:1, 1:1, 1:1.5, 1:2, 1:2.5, 1:3, 1:3.5, 1:4, 1:4.5, or 1:5. In some embodiments, the ratio of triblock copolymer to diblock copolymer is about 1:1.5.

[0066] In various embodiments of the methods, compositions, and kits disclosed herein, a compound of formula A v -B w -A xwherein each of v and x is independently a number of repeat units ranging from about 24 to 682, or from about 25 to 420, or from about 25 to 400, or from about 30 to 200, 35 to 120, or from about 40 to 100, and w is a number of repeat units ranging from 4 to 273, or from about 4 to 115, or from about 20 to 75; and a triblock copolymer having formula C y -A z wherein y is 3 to 50, or about 8 to 50, and z is 7 to 327, or about 25 to 300, or about 50 to 200. Thus, in specific embodiments of the methods, compositions, and kits disclosed herein, a diblock copolymer having formula A v -B w -A x wherein each of v and x is independently a number of repeat units ranging from about 40 to 100, and w is a number of repeat units ranging from about 20 to 75; and a triblock copolymer having formula C y -A z wherein y is about 8 to 50, and z is about 50 to 200.

[0067] In some embodiments, the psychiatric disease or disorder is schizophrenia, schizoaffective disorder, autism-associated irritability, 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 yet other embodiments, the psychiatric disease or disorder is bipolar disorder, e.g., bipolar 1 disorder. In some embodiments, the psychiatric disease or disorder is childhood or adolescent and / or adult irritability associated with autism spectrum, also known as autism-associated irritability (IAA).

[0068] In some embodiments, the psychiatric illness is dementia. In some embodiments, the psychiatric illness is bipolar disorder. In some embodiments, the psychiatric illness is depression. In some embodiments, the psychiatric illness is manic disorder. In some embodiments, the psychiatric illness is a psychotic episode.

[0069] As used herein, a "treatment method" refers to alleviating symptoms of a psychiatric disease or disorder. In certain preferred embodiments, the psychiatric disease or disorder is schizophrenia. In some embodiments, the treatment method includes a delay in time to relapse compared to subjects not receiving the pharmaceutical preparation, e.g., compared to subjects receiving a placebo. In some embodiments, the treatment method includes a reduction in the rate of impending relapse estimated using the Kaplan-Meier method. In some embodiments, the treatment method includes a reduction in the observed rate of impending relapse. In some embodiments, the treatment method includes an improvement after stabilization, as assessed by PANSS. In some embodiments, the treatment method includes a reduction in the risk of relapse. In some embodiments, the treatment method includes maintenance of stabilization. In some embodiments, the treatment method includes an improvement in quality of life, as measured, for example, by SQLS score.

[0070] In some embodiments, the method of treating schizophrenia 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 disorganization, 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, part 1 ≦2 (mild suicidal ideation) and part 2 ≦5 (minimal deterioration). Percentages are 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 method of treatment includes achieving remission. All remission criteria can be obtained from PANSS items.

[0071] In some embodiments, the disclosed methods result in a reduced risk of relapse in subjects with schizophrenia compared to placebo. In some embodiments, the risk of relapse is reduced by at least 50% in subjects with schizophrenia compared to placebo.

[0072] In some embodiments where the long-acting injectable risperidone formulation is administered monthly, the risk of relapse is reduced by 60-80% in subjects with schizophrenia compared to placebo. In some embodiments where the long-acting injectable risperidone formulation is administered monthly, the risk of relapse is reduced by 80% in subjects with schizophrenia compared to placebo.

[0073] In some embodiments where the long-acting injectable risperidone formulation is administered bimonthly, the risk of relapse is reduced by 50-65% in subjects with schizophrenia compared to placebo. In some embodiments where the long-acting injectable risperidone formulation is administered bimonthly, the risk of relapse is reduced by 62.5% in subjects with schizophrenia compared to placebo.

[0074] In other embodiments, the disclosed methods result in a reduced relapse rate in subjects with schizophrenia, as compared to placebo.

[0075] In yet another embodiment, the disclosed method extends the time to relapse in a subject with schizophrenia compared to placebo.In some embodiments, the time to relapse is extended by at least 2-fold in a subject with schizophrenia compared to placebo.

[0076] In some embodiments where the long-acting injectable risperidone formulation is administered monthly, the time to relapse is increased by at least 2.5 to 5 times compared to placebo in subjects with schizophrenia. In some embodiments where the long-acting injectable risperidone formulation is administered monthly, the time to relapse is increased by 5 times compared to placebo in subjects with schizophrenia.

[0077] In some embodiments where the long-acting injectable risperidone formulation is administered bimonthly, the time to relapse is increased by at least 2.5 to 5 times compared to placebo in subjects with schizophrenia. In some embodiments where the long-acting injectable risperidone formulation is administered bimonthly, the time to relapse is increased by 2.7 times compared to placebo in subjects with schizophrenia.

[0078] In some embodiments, the present disclosure relates to a method for treating a psychiatric disease or disorder in a subject by subcutaneous administration of a long-acting injectable risperidone formulation. In a particularly preferred embodiment, the subject is a human. In some embodiments, the subject is an adult aged 18 years or older or between 18 and 65 years. In some embodiments, the subject is a human adolescent between 13 and 17 years.

[0079] The methods disclosed herein include subcutaneous administration of a high concentration, low volume formulation of risperidone to a subject in need thereof, for example, a subject suffering from a psychiatric disease or disorder. In some embodiments, the subcutaneous administration is to the subject's upper arm or the subject's abdomen. In some embodiments, the subcutaneous administration is to the subject's abdomen. In other embodiments, the subcutaneous administration is to the subject's upper arm, particularly the back of the upper arm. The administration site (abdomen or upper arm) can be switched, i.e., alternated from administration to administration, without affecting the efficacy or safety of any of the methods disclosed herein. Thus, in some embodiments of the disclosed methods, subcutaneous administration of a long-acting injectable risperidone formulation to the upper arm is followed by subcutaneous administration of a long-acting injectable risperidone formulation to the abdomen at the next administration. In some embodiments, subcutaneous administration of a long-acting injectable risperidone formulation to the abdomen is followed by subcutaneous administration of a long-acting injectable risperidone formulation to the upper arm at the next administration. As used herein, the phrase "at the next dose" refers to the next dosing event at which a long-acting injectable risperidone formulation is administered.

[0080] Subcutaneous administration of the risperidone formulation of the present invention usually results 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., can be removed from the subject) after administration to the subject.A medical practitioner (HCP) skilled in the art can decide whether to excise, and the preferred method and time of excision.

[0081] In some embodiments of the methods of the 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 42 days. In these embodiments, administration results in treatment of the psychiatric disease or disorder for at least 42 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.

[0082] 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 comprises 250 mg / mL to 400 mg / mL risperidone or a salt thereof equivalent to 250 mg / mL to 400 mg / mL risperidone. In some embodiments, the pharmaceutical formulation comprises 300 mg / mL to 400 mg / mL or 300 mg / mL, 310 mg / mL, 320 mg / mL, 330 mg / mL, 340 mg / mL, 350 mg / mL, 360 mg / mL, 370 mg / mL, 380 mg / mL, 390 mg / mL, or 400 mg / mL risperidone or a salt thereof equivalent to 300 mg / mL, 310 mg / mL, 320 mg / mL, 330 mg / mL, 340 mg / mL, 350 mg / mL, 360 mg / mL, 370 mg / mL, 380 mg / mL, 390 mg / mL, or 400 mg / mL risperidone.

[0083] In some embodiments, the disclosure provides a method of administering a therapeutically effective dose of risperidone to a subject for a period of at least 28 days and up to 2 months, comprising administering to the subject: (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 where v and x are numbers of repeating units ranging from 24 to 682, and w is a number of repeating units ranging from 4 to 273, and v=x or v≠x; (c) Formula: Methoxy-poly(ethylene glycol) y -Poly(lactic acid) z where y and z are the number of repeating units, where y is the number of repeating units in the range of 3 to 50, and z is the number of units in the range of 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 the formulation that is insoluble in an aqueous environment, comprising subcutaneously administering 1 mL or less of a long-acting injectable risperidone formulation; wherein said frequency of administration is at least once every 28 days and up to 2 months; and wherein said administration results in systemic administration of said risperidone over said period.

[0084] In some embodiments of such methods, the frequency of administration is no more than once every 28 days, or once a month or once every two months. In some embodiments of such methods, the period is one month. In other embodiments, the period is two months.

[0085] In some embodiments, provided herein is a method of treating a risperidone-naive patient with a long-acting injectable risperidone formulation disclosed herein, comprising: a) Establish patient tolerability with daily oral risperidone; b) administering to the patient a monthly or bimonthly long-acting injectable risperidone formulation subcutaneously the day after the last dose of oral therapy; Including, c) wherein the long-acting injectable risperidone formulation is i) risperidone or a pharma- ceutical acceptable salt thereof having a concentration of about 250 to 400 mg / mL in terms of risperidone; ii) 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: iii) Formula: methoxy-poly(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 50, and z is the number of repeating units in the range of 7 to 327). A biodegradable diblock copolymer having the formula: Contains: wherein the ratio of the (b) biodegradable triblock copolymer to the (c) biodegradable diblock copolymer 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; This provides a method for treating patients who have not been administered risperidone.

[0086] Risperidone-naive patients are those who have never received risperidone before.

[0087] In some embodiments, the disclosure relates to a method of switching a subject from daily oral risperidone therapy to a long-acting injectable risperidone formulation, e.g., switching from oral daily risperidone to a monthly injection or a bimonthly injection the day after the last dose of oral therapy. In some embodiments, such a method comprises: i. orally administering the final dose of daily oral risperidone therapy (after which no further oral risperidone therapy is administered); and ii. The next day, the subject (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 where v and x are numbers of repeating units ranging from 24 to 682, and w is a number of repeating units ranging from 4 to 273, and v=x or v≠x; (c) Formula: Methoxy-poly(ethylene glycol) y -Poly(lactic acid) zwhere y and z are the number of repeating units, where y is the number of repeating units in the range of 3 to 50, and z is the number of units in the range of 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 the formulation, which is insoluble in an aqueous environment; thereby switching the subject from daily oral risperidone therapy to a long-acting injectable risperidone formulation. Contains :.

[0088] As used herein, a daily oral risperidone therapy refers to risperidone (e.g., a pharmaceutical composition containing a risperidone active ingredient) orally administered to a subject once a day. In some embodiments, the daily oral risperidone therapy is 2 mg / day to 6 mg / day, or 2 mg / day to 5 mg / day, or 2 mg / day, 3 mg / day, 4 mg / day, 5 mg / day, or 6 mg / day.

[0089] In some embodiments of the method of switching a subject from daily oral risperidone therapy to a long-acting injectable risperidone formulation, the method comprises monthly administration of the long-acting injectable risperidone formulation. In some embodiments, the long-acting injectable risperidone formulation comprises about 50 mg to about 125 mg of risperidone.

[0090] In other embodiments of the method of switching a subject from daily oral risperidone therapy to a long-acting injectable risperidone formulation, the method comprises administering the long-acting injectable risperidone formulation once every two months. In some embodiments, the long-acting injectable risperidone formulation comprises about 100 mg to about 250 mg of risperidone.

[0091] For example, long-acting injectable risperidone formulations can be initiated as follows: a patient treated with a 2 mg / day oral dose of risperidone can be switched to an LAI risperidone formulation disclosed herein at a dose of 50 mg once a month or 100 mg once every two months, a patient treated with a 3 mg / day oral dose of risperidone can be switched to an LAI risperidone formulation disclosed herein at a dose of 75 mg once a month or 150 mg once every two months, a patient treated with a 4 mg / day oral dose of risperidone can be switched to an LAI risperidone formulation disclosed herein at a dose of 100 mg once a month or 200 mg once every two months, and a patient treated with a 5 mg / day oral dose of risperidone can be switched to an LAI risperidone formulation disclosed herein at a dose of 125 mg once a month or 250 mg once every two months.

[0092] In some aspects, the present disclosure relates to a method for switching a subject from a parenteral, i.e., intramuscular or subcutaneous, long-acting injectable antipsychotic product to a long-acting injectable risperidone formulation disclosed herein. Advantageously, such switching can be achieved without the need for supplemental risperidone therapy, i.e., oral or parenteral. For example, the method of the present disclosure allows a subject to switch to a long-acting injectable risperidone formulation disclosed herein without the need for a loading dose of risperidone. In some embodiments, provided herein is a method for switching a patient from an intramuscular or subcutaneous long-acting injectable antipsychotic to a long-acting injectable risperidone formulation disclosed herein without the need for a loading dose of oral or parenteral risperidone.

[0093] In some embodiments, the present disclosure is a method of switching a subject from a long-acting injectable antipsychotic to a long-acting injectable risperidone formulation without the need for adjunctive risperidone therapy. In some embodiments, such a method comprises: i. administering the final dose of a long-acting injectable antipsychotic; and ii. The next dose will be administered subcutaneously using a long-acting injectable risperidone formulation; Contains: wherein the long-acting injectable risperidone formulation is 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: Methoxy-poly(ethylene glycol) y -Poly(lactic acid) z where y and z are the number of repeating units, where y is the number of repeating units in the range of 3 to 50, and z is the number of units in the range of 7 to 327; and wherein the ratio of the (b) biodegradable triblock copolymer to the (c) biodegradable diblock copolymer 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; and Here, the method is performed without administering adjunctive oral risperidone therapy to the subject.

[0094] As used in this context, the phrase "at the next dose" refers to a dosing event at which the next dose of the long-acting injectable antipsychotic would be administered unless the long-acting injectable antipsychotic were to be discontinued. In some embodiments, the long-acting injectable antipsychotic is an intramuscular long-acting injectable product (e.g., Risperdal®, Consta®, Abilify Maintena®). In some embodiments, the long-acting injectable antipsychotic is a subcutaneous long-acting injectable product (e.g., PERSERIS®). In some embodiments, the long-acting injectable antipsychotic comprises an approved antipsychotic, e.g., risperidone, 9-OH-risperidone (paliperidone), or aripiprazole. In some embodiments where the long-acting injectable antipsychotic is not risperidone, a salt thereof, or a metabolite thereof, the subject has been evaluated for risperidone tolerability.

[0095] In some embodiments, the present disclosure relates to a method of switching a subject from a monthly long-acting injectable risperidone formulation to a bimonthly (i.e., once every two months) long-acting injectable risperidone formulation without the need for supplemental oral or parenteral risperidone therapy. In some embodiments, such a method comprises: i. administering the final dose of a long-acting injectable risperidone formulation subcutaneously once a month; and ii. After 1 month (i.e., 28-31 days), a long-acting injectable risperidone formulation administered subcutaneously once every 2 months; Contains: wherein each of the monthly and bimonthly long-acting injectable risperidone formulations is (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) xwhere v and x are numbers of repeating units ranging from 24 to 682, and w is a number of repeating units ranging from 4 to 273, and v=x or v≠x; (c) Formula: Methoxy-poly(ethylene glycol) y -Poly(lactic acid) z where y and z are the number of repeating units, where y is the number of repeating units in the range of 3 to 50, and z is the number of units in the range of 7 to 327; and wherein the ratio of the (b) biodegradable triblock copolymer to the (c) biodegradable diblock copolymer 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; and Here, the method is performed without administering adjunctive oral risperidone therapy to the subject.

[0096] In other aspects, the disclosure relates to methods of switching a subject from a once every other month (i.e., once every two months) long-acting injectable risperidone formulation to a once every month long-acting injectable risperidone formulation without the need for supplemental oral or parenteral risperidone therapy. In some embodiments, such methods include: i. administering the final dose of a long-acting injectable risperidone formulation subcutaneously once every other month (i.e., once every two months); and ii. After 2 months, a long-acting injectable risperidone formulation administered subcutaneously once a month; Including, wherein each of the monthly long-acting injectable risperidone formulation and the bimonthly (i.e., once every two months) long-acting injectable risperidone formulation is (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) xwhere v and x are numbers of repeating units ranging from 24 to 682, and w is a number of repeating units ranging from 4 to 273, and v=x or v≠x; (c) Formula: Methoxy-poly(ethylene glycol) y -Poly(lactic acid) z where y and z are the number of repeating units, where y is the number of repeating units in the range of 3 to 50, and z is the number of units in the range of 7 to 327; and wherein the ratio of the (b) biodegradable triblock copolymer to the (c) biodegradable diblock copolymer 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; and Here, the method is performed without administering adjunctive oral risperidone therapy to the subject.

[0097] For the methods disclosed above, administration schedules should be adjusted accordingly, if necessary.

[0098] In other aspects, the disclosure provides methods for changing the risperidone dose administered to a subject receiving a monthly or bimonthly (i.e., once every two months) long-acting injectable risperidone formulation from an initial dose to a subsequent dose without the need for adjunctive risperidone therapy, such as a loading dose of oral or parenteral risperidone.

[0099] In some embodiments, the present disclosure provides a method of switching a risperidone dose administered to a subject from an initial dose to a subsequent dose without the need for adjunctive oral risperidone therapy, comprising: i. administering the final dose of the initial dose of a long-acting injectable risperidone formulation subcutaneously; and ii. Administer a subsequent dose of a long-acting injectable risperidone formulation subcutaneously at the next dose; Contains: wherein the initial dose and the subsequent doses of a long-acting injectable risperidone formulation are (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 where v and x are numbers of repeating units ranging from 24 to 682, and w is a number of repeating units ranging from 4 to 273, and v=x or v≠x; (c) Formula: Methoxy-poly(ethylene glycol) y -Poly(lactic acid) z where y and z are the number of repeating units, where y is the number of repeating units in the range of 3 to 50, and z is the number of units in the range of 7 to 327; and wherein the ratio of the (b) biodegradable triblock copolymer to the (c) biodegradable diblock copolymer is 1:3 to 1:8, or 1:1 to 1:19, or 3:2 to 1:19 in said formulations that are insoluble in an aqueous environment; and Provided herein are methods, wherein said method is performed without administering any adjunctive oral risperidone therapy to said patient.

[0100] In some embodiments, when using a monthly formulation, the first dose of the long-acting injectable risperidone formulation contains a higher dose of risperidone than the subsequent dose of the long-acting injectable risperidone formulation.In some embodiments, the first dose of the long-acting injectable risperidone formulation contains about 125mg, and the subsequent dose of the long-acting injectable risperidone formulation contains about 50mg, 75mg, or about 100mg of risperidone.In some embodiments, the first dose of the long-acting injectable risperidone formulation contains about 100mg of risperidone, and the subsequent dose of the long-acting injectable risperidone formulation contains about 50mg or 75mg of risperidone.In another example, when using a bimonthly formulation, the first dose of the long-acting injectable risperidone formulation contains about 250mg, and the subsequent dose of the long-acting injectable risperidone formulation contains about 100mg, 150mg, or about 200mg of risperidone. In some embodiments, the first dose of the long-acting injectable risperidone formulation comprises about 200 mg of risperidone and the subsequent doses of the long-acting injectable risperidone formulation comprise about 100 mg or 150 mg of risperidone.

[0101] In other embodiments, when using a monthly formulation, the first dose of the long-acting injectable risperidone formulation contains a lower dose of risperidone than the subsequent dose of the long-acting injectable risperidone formulation.In some embodiments, the first dose of the long-acting injectable risperidone formulation contains about 50mg of risperidone, and the subsequent dose of the long-acting injectable risperidone formulation contains about 75mg, 100mg, or 125mg of risperidone.In some embodiments, the first dose of the long-acting injectable risperidone formulation contains about 75mg of risperidone, and the subsequent dose of the long-acting injectable risperidone formulation contains about 100mg or 125mg of risperidone.In another example, when using a bimonthly formulation, the first dose of the long-acting injectable risperidone formulation contains about 100mg, and the subsequent dose of the long-acting injectable risperidone formulation contains about 150mg, 200mg, or about 250mg of risperidone. In some embodiments, the first dose of the long-acting injectable risperidone formulation comprises about 150 mg of risperidone and the subsequent doses of the long-acting injectable risperidone formulation comprise about 200 mg or 250 mg of risperidone.

[0102] Depending on the administration regimen of the first dose, the subsequent dose of the long-acting injectable risperidone formulation is administered one month (i.e., 28-31 days) after administration of the first dose of the long-acting injectable risperidone formulation. In other embodiments, the subsequent dose of the long-acting injectable risperidone formulation is administered two months (i.e., 56-62 days) after administration of the first dose of the long-acting injectable risperidone formulation. Optionally, the administration regimen may be changed at the same time (from a bimonthly (i.e., every two months) long-acting injectable risperidone formulation to a monthly long-acting injectable risperidone formulation, or vice versa).

[0103] In some embodiments, the disclosure provides a method of administering risperidone to a subject receiving long-acting injectable risperidone therapy, where the subject has missed a dose of the long-acting injectable risperidone formulation.

[0104] As used herein, the term "missed dose" means that a subject does not receive a dose of a long-acting injectable risperidone formulation within the period recommended for a particular long-acting injectable risperidone therapy.For example, a subject receiving a monthly long-acting injectable risperidone therapy, a missed dose occurs when more than one month has passed since the last administration of a monthly long-acting injectable risperidone formulation.For a subject receiving a bimonthly regimen, i.e., a bimonthly long-acting injectable risperidone formulation, a missed dose occurs when more than two months have passed since the last administration of a bimonthly long-acting injectable risperidone formulation.

[0105] In some embodiments, such methods comprise subcutaneously administering a monthly or bimonthly (i.e., once every two months) dose of a long-acting injectable risperidone formulation; wherein the long-acting injectable risperidone formulation is (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 where v and x are numbers of repeating units ranging from 24 to 682, and w is a number of repeating units ranging from 4 to 273, and v=x or v≠x; (c) Formula: Methoxy-poly(ethylene glycol) y -Poly(lactic acid) z where y and z are the number of repeating units, where y is the number of repeating units in the range of 3 to 50, and z is the number of units in the range of 7 to 327; and wherein the ratio of the (b) biodegradable triblock copolymer to the (c) biodegradable diblock copolymer 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; and wherein the method is performed without administering to the subject any adjunctive oral risperidone therapy.

[0106] In the methods of the present disclosure, administration of the long-acting injectable risperidone formulation can be resumed without administering to the subject any adjunctive oral risperidone therapy, such as, for example, a loading dose of oral risperidone.

[0107] 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.

[0108] 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 risperidone (or a salt thereof) of at least 250 mg / mL of risperidone equivalent with a delivery volume of 1 mL or less. Although there is no strict upper limit on the amount of risperidone (or a salt thereof), the formulation should be of a suitable viscosity for injection through a syringe needle so that it can effectively treat a psychiatric disease or disorder without exposing the subject to the risk of risperidone overdose. In some embodiments, the method includes administration of a risperidone formulation from a prefilled syringe. In some embodiments, the prefilled syringe is a single-dose prefilled syringe. The single-dose prefilled syringe may contain 25 mg to about 500 mg of risperidone or a pharma- ceutical acceptable salt equivalent, or about 50 mg to about 250 mg of risperidone or a pharma- ceutical acceptable salt equivalent. In some embodiments, the needle used to administer the formulation of the present invention is 21 gauge or larger. In some embodiments, the needle used to administer the formulation is 21-23 gauge, or 21 gauge, or 23 gauge. In some embodiments, the needle used to administer the formulation of the present invention is 5 / 8 inch or less in length. In some embodiments, the needle used to administer the formulation of the present invention is 12 mm to 20 mm long, or about 12.7 mm (1 / 2 inch), 13 mm, 14 mm, 15 mm, 16 mm (5 / 8 inch), 17 mm, 18 mm, 19 mm, or 20 mm. In some embodiments, the needle used to administer the formulation of the present invention is 21 gauge and 16 mm (5 / 8 inch) long.

[0109] Thus, in some embodiments of the method of the present invention, the long-acting injectable risperidone formulation is administered from a pre-filled syringe equipped with a needle having a gauge of 21 or more and / or a length of 5 / 8 inches or less. In some embodiments, the long-acting injectable risperidone formulation is administered from a pre-filled syringe equipped with a needle having a gauge of 21 or more, such as 21 gauge, 22 gauge, 23 gauge, etc. In other embodiments, the long-acting injectable risperidone formulation is administered from a pre-filled syringe equipped with a needle having a length of 5 / 8 inches (i.e., 16 mm) or less, such as 16 mm, 15 mm, 14 mm, 13 mm, 12 mm, etc. In some embodiments of the method of the present invention, the long-acting injectable risperidone formulation is administered from a pre-filled syringe equipped with a safety needle having a gauge of 21 or more and a length of 5 / 8 inches or less.

[0110] A "therapeutically effective amount of risperidone" is an amount having the following formula that is effective to alleviate at least some of the symptoms of a psychiatric disease or disorder in an affected subject: [Active moiety](ng / mL)=[Risperidone](ng / mL)+[9-OH-Risperidone](ng / mL) 410 / 426) The plasma concentration of risperidone is the sum of the plasma concentrations of risperidone and 9-OH-risperidone, corrected for molecular weight according to: A therapeutically effective amount of risperidone can be, for example, a plasma level of >10 ng / mL within about 6 hours of administration (Eerdekens et al., Pharmacokinetics and tolerability of long-acting risperidone in schizophrenia. Schizophr Res 70(1):91. 2004).

[0111] 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. 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 range can be from 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. In some embodiments, the formulation comprises about 25% to about 35% risperidone by total weight percentage of the formulation, or about 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, or 35%, or an equivalent amount of a risperidone salt.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, 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, 347, 348 2, 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, 38 23, 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, or 400 (units are mg / mL).

[0112] 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).

[0113] The polyester chain length is defined by its polyester to ethylene oxide molar ratio, which for triblock copolymers is 0.5 to 8 or 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. In some embodiments, the polyester chains are defined by their polyester to ethylene oxide molar ratio in the triblock, which may be 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.1, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.1 ... 5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, or 10.

[0114] In some embodiments, the polyester chains are defined by their polyester to ethylene oxide molar ratio in the diblock, which is 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, or 10.

[0115] The mass of the end-capped polyethylene glycol in the diblock copolymer can range from 164 Da to 2,000 Da, or 100 Da to 2 kDa, or 100 Da to about 2,200 Da. It can be in the lower range of 100 to 300 Da, or in the range of 1 kDa to 2 kDa. In some embodiments, the size of the end-capped polyethylene glycol chain is in the range of 200, 300, 400, 500, 600, 700, 800, 900, 1000, 1100, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, 2000, 2100, or 2200 (Da).

[0116] The size of the end-capped polyethylene glycol chain in the triblock copolymer can range from 200 Da to 12 kDa, or it can range from 400 Da to 12 kDa or 194 Da to 12 kDa in the biodegradable drug delivery composition. In some embodiments, the size of the polyethylene glycol chain can range from 200, 300, 400, 500, 600, 700, 800, 900, 1000, 1100, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, 2000, 2100, 2200, 2300, 2400, 2500, 2600, 2700, 2800, 2900, 3000, 3100, 3200, 3300, 3400, 3500, 3600, 3700, 3800, 3900, 4000, 4100, 4200, 4300, 4400, 4500, 4600, 4700, 4800, 4900, 5000, 5100, 5200, 5300, 5400, 5500, 5600, 5700, 5800, 5900, 6000, 6100, 6200, 6300, 6400, 6500, 6600, 6700, 6800, 6900, 7000, 7100, 7200, 7300, 00, 26900, 2700, 2800, 2900, 3000, 3100, 3200, 3300, 3400, 3500, 3600, 3700, 3800, 3900, 4000, 4100, 4200, 4300, 4400, 4500, 4600, 4700, 4800, 4900, or 5000 (Da).

[0117] The triblock copolymer is present in the risperidone formulation in an amount of 3.0% to 45% (w / w%) of the total weight of the formulation. In another embodiment, the triblock copolymer is present in the risperidone formulation in an amount of 6% to 10% (w / w%) of the total weight of the formulation. In yet another embodiment, the triblock copolymer is present in the risperidone formulation in an amount of 20% to 40% (w / w%) of the total weight of the formulation. In some embodiments, the triblock copolymer is present in the risperidone formulation 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 the risperidone formulation 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 the risperidone formulation 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 the risperidone formulation 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 the risperidone formulation 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. In some embodiments, the triblock copolymer is present in the risperidone formulation in an amount of about 10% (w / w%) of the total weight of the formulation. In some embodiments, the triblock copolymer is poly(D,L-lactide)-co-poly(ethylene glycol)-co-poly(D,L-lactide).

[0118] The diblock copolymer can be present in the risperidone formulation (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 the risperidone formulation in an amount of 10% to 20% (w / w%) of the total weight of the formulation. In yet another embodiment, the diblock copolymer is present in the risperidone formulation in an amount of 20% to 40% (w / w%) of the total weight of the formulation. In some embodiments, the diblock copolymer can be present in the risperidone 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 the risperidone formulation 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. In yet another embodiment, 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. The diblock copolymer is present in an amount 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%, 30% (w / w%). In some embodiments, the diblock copolymer is present in the risperidone formulation in an amount of about 15% (w / w) of the total weight of the formulation. In some embodiments, the diblock copolymer is methoxy-poly(ethylene glycol)-co-poly(D,L-lactide).

[0119] The copolymer is present in the pharmaceutical risperidone formulation in an amount of 20%-50% (w / w%) of the total weight of the composition. In another embodiment, the total weight of the copolymer present in the biodegradable drug composition is 30%-50% (w / w%) of the total weight of the composition. In yet another embodiment, the copolymer is present in the biodegradable drug composition in an amount of 40%-50% (w / w%) of the total weight of the composition.

[0120] In a preferred embodiment, the total amount of triblock and diblock copolymers, i.e., poly(D,L-lactide)-co-poly(ethylene glycol)-co-poly(D,L-lactide) and methoxy-poly(ethylene glycol)-co-poly(D,L-lactide), is dissolved in a solvent, i.e., DMSO, and is present in the risperidone formulation (biodegradable drug composition or pharmaceutical formulation) in an amount of 20%-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 risperidone formulation used herein is 20%-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 copolymer is present in the biodegradable drug formulation at 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%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 100%, 101%, 102%, 103%, 104%, 105%, 106%, 107%, 108%, 109%, 109.5%, 109%, 108.5%, 109%, 109.5%, 109.5%, 109.5%, 109.5%, 109 In another embodiment, the copolymers, i.e., poly(D,L-lactide)-co-poly(ethylene glycol)-co-poly(D,L-lactide) and methoxy-poly(ethylene glycol)-co-poly(D,L-lactide), are present in the biodegradable drug formulation at about 25% (w / w%) of the total weight of the formulation.

[0121] The ratio of the biodegradable triblock copolymer (b) to the biodegradable diblock copolymer (c) in the risperidone formulation is 1:3 to 1:8, or 1:1 to 1:19, or 3:2 to 1:19 in the pharmaceutical formulation of the present invention.

[0122] In one embodiment, the ratio of the biodegradable triblock copolymer to the biodegradable diblock copolymer in the risperidone formulation 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. In some embodiments, the ratio of the biodegradable triblock copolymer to the biodegradable diblock copolymer in the risperidone formulation is about 1:1.5.

[0123] 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 diblock copolymer is 2:3.

[0124] 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.

[0125] The pharmaceutical preparation used in the method of the present invention comprises 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.

[0126] 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 weight of the total formulation.

[0127] 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 formulations and methods disclosed herein can be 35%-55% (w / w%), preferably 35%-45% (w / w%). In another embodiment, the organic solvent is dimethyl sulfoxide (DMSO) and is present in an amount of about 45% (w / w%) by weight of the total formulation. In one aspect, the solvent, i.e., DMSO, can further include triglycerides, such as triacetin, tripropionin, or mixtures thereof, in an amount of 10%-15% (w / w%) by weight of the total formulation.

[0128] In the biodegradable drug delivery composition of the present disclosure, particularly also referred to herein as 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 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 the 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 over a longer period of time from a larger volume than from a smaller volume. See the data in Example 2 below.

[0129] In one embodiment, the biodegradable drug delivery composition delivers, i.e., releases, risperidone, i.e., therapeutic levels, to a subject for at least 21 days, and in specific embodiments, for at least 28 days or at least 56 days. In one embodiment, the biodegradable drug delivery composition can deliver risperidone for 21 days up to about 90 days. In another embodiment, the biodegradable drug delivery composition can deliver risperidone for about 21-30 days or about 28-31 days. In another embodiment, the biodegradable drug delivery composition can deliver risperidone for at least 28, 29, or 30 days. In another embodiment, the biodegradable drug delivery composition can deliver risperidone for about 56-63 days. In another embodiment, the biodegradable drug delivery composition can deliver risperidone for at least 56, 57, 58, 59, or 60 days. In one embodiment, the biodegradable drug delivery composition can deliver risperidone for at least 90 days.

[0130] In the methods disclosed herein, 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 31 to 56 or 62 days. In some embodiments, the administration is effective to treat the subject's psychiatric disease or disorder for 28 or 31 days. In other embodiments, the administration is effective to treat the subject's psychiatric disease or disorder for 42 days. In other embodiments, the administration is effective to treat the subject's psychiatric disease or disorder for 56 or 62 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, for example, after each period of 28 or 56 days.

[0131] 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, an alternative immediate release risperidone formulation (e.g., an immediate release oral formulation or an 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 or supplemental parenteral dose of risperidone is not required in the method of the present invention. Thus, in some embodiments, the method is performed in the absence of a loading dose or supplemental oral risperidone or supplemental parenteral risperidone or other antipsychotic drug. One such embodiment is the administration of the pharmaceutical formulation disclosed herein to a subject after a missed dose. Because a loading dose is not required, a patient who misses a dose (i.e., a Q1M or Q2M dose, depending on the individual regimen) can receive the pharmaceutical formulation as soon as possible after the missed dose event.

[0132] 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 "once a month 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 28 days or 29, 30, or 31 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, for example, in a "bimonthly formulation" amount, 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) will have been cumulatively released by 56 days or 57, 58, 59, 60, 61, or 62 days after administration, preferably with a near linear release profile. Thus, provided herein is sustained release of risperidone over a desired period of time, i.e., at least 28 days and up to 2 months.

[0133] 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.

[0134] In some embodiments, about 50 w% to about 80 w% of the risperidone (or salt thereof) in the formulation, e.g., 50, 55, 60, 65, 70, 75, or 80 w% is cumulatively released after 28 days or 28 to 31 days after administration. In some embodiments, about 50 w% to about 80 w% of the risperidone (or salt thereof) in the formulation, e.g., 50, 55, 60, 65, 70, 75, or 80 w% is cumulatively released after 28 days after administration.

[0135] In some embodiments, about 70 w% to about 98 w% of the risperidone (or salt thereof) in the formulation, e.g., 75, 70, 85, 90, 91, 92, 93, 94, 95, 96, 97, or about 98 w% is cumulatively released after 56 days or 56 to 62 days after administration. In some embodiments, about 70 w% to about 98 w% of the risperidone (or salt thereof) in the formulation, e.g., 75, 70, 85, 90, 91, 92, 93, 94, 95, 96, 97, or about 98 w% is cumulatively released after 56 days after administration.

[0136] 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 and biodegradable, becoming solid or semi-solid implants when injected into an animal, allowing for the release of risperidone over an extended period of time.

[0137] In some embodiments of the method of the present invention, the pharmaceutical formulation is administered from a pre-filled syringe (PFS). The PFS is a syringe that contains an appropriate amount of pharmaceutical formulation and is preferably ready for subcutaneous administration by a medical professional. The ready-to-use PFS disclosed herein represents a major advance in the field of subcutaneous LAI in that it does not require laborious or time-consuming reconstitution before administration. 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, from two, three, four, five, or six or more pre-filled syringes.

[0138] 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 delivery dose of the risperidone formulation in the prefilled syringe is 0.14 mL to 0.7 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 0.5mL. In some embodiments, the volume of the pharmaceutical formulation in the prefilled syringe is about 0.6mL. In some embodiments, the volume of the pharmaceutical formulation in the prefilled syringe is about 0.7mL. In some embodiments, the volume of the pharmaceutical formulation in the prefilled syringe is about 0.8mL. In some embodiments, the volume of the pharmaceutical formulation in the prefilled syringe is about 0.9mL. In some embodiments, the volume of the pharmaceutical formulation in the prefilled syringe is about 1.0mL. The volume during PFS refers to the delivery volume, i.e., the volume administered to the subject, and extra volume may be required during PFS to cover the dead volume of the syringe connected to the needle.

[0139] 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 125 mg in a volume of about 0.35 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. In some embodiments, the amount of risperidone in the pharmaceutical formulation is 50 mg in a volume of about 0.1 mL. In some embodiments, the amount of risperidone in the pharmaceutical formulation is 100mg in a volume of about 0.2mL. In some embodiments, the amount of risperidone in the pharmaceutical formulation is 125mg in a volume of about 0.3mL. In some embodiments, the amount of risperidone in the pharmaceutical formulation is 150mg in a volume of about 0.4mL. In some embodiments, the amount of risperidone in the pharmaceutical formulation is 200mg in a volume of about 0.6mL. In some embodiments, the amount of risperidone in the pharmaceutical formulation is 250mg in a volume of about 0.7mL. These doses provide therapeutic levels of risperidone equivalent to 2 mg / day (50 mg once a month or 100 mg once every two months), 3 mg / day (75 mg once a month or 150 mg once every two months), 4 mg / day (100 mg once a month or 200 mg once every two months), and 5 mg / day (125 mg once a month or 250 mg once every two months) oral risperidone.

[0140] In some embodiments of the methods and compositions, PFS and kits disclosed herein, the long-acting injectable risperidone formulation comprises 30% risperidone, 45% (w / w) DMSO, 10% (w / w) triblock copolymer, 15% (w / w) diblock copolymer, 25% (w / w) total copolymer. In some embodiments, the ratio of triblock copolymer to diblock copolymer can be 3:2 to 2:3.

[0141] In some embodiments of the methods and compositions, PFS and kits disclosed herein, the risperidone formulations disclosed herein are sustained release injectable suspensions.

[0142] In some embodiments of the methods and compositions, PFS and kits disclosed herein, the long-acting injectable risperidone formulation comprises 25% (w / w) of triblock copolymer and diblock copolymer by weight percentage of the total weight of the formulation.

[0143] In some embodiments of the methods and compositions, PFS and kits disclosed herein, the long-acting injectable risperidone formulation comprises 45% DMSO by total weight percentage of the formulation.

[0144] In other embodiments of the methods and compositions, PFS and kits disclosed herein, the long-acting injectable risperidone formulation comprises about 30% risperidone or its pharma- ceutical acceptable salt equivalent by weight percentage of the total formulation.

[0145] Many psychiatric disorders are chronic diseases that require continuous treatment to suppress symptoms and prevent relapse. Therefore, the methods disclosed herein can be carried out over a long period of time. In some embodiments, the methods are carried out for at least 6 months. In other embodiments, the methods are carried out for at least 12 months. In other embodiments, the methods are carried out for at least 15 months. In other embodiments, the methods are carried out for at least 24 months.

[0146] In some patients with renal or hepatic impairment, the method can be practiced by titrating oral risperidone to at least 2 mg once daily before initiating treatment with the long-acting injectable risperidone formulation disclosed herein. If tolerated, the patient can be switched to a long-acting injectable risperidone formulation at a dose of 50 mg once monthly.

[0147] Also provided is a pre-filled syringe for subcutaneous administration of a long-acting injectable risperidone formulation, comprising: i. A long-acting injectable risperidone formulation, wherein the formulation is 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: Methoxy-poly(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 50, and z is the number of units in the range of 7 to 327). A biodegradable diblock copolymer having the formula: wherein the ratio of the (b) biodegradable triblock copolymer to the (c) biodegradable diblock copolymer 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 ii. Needles having a gauge of 21 or greater and / or a length of 5 / 8 inch or less; A prefilled syringe comprising:

[0148] In addition, the following is provided: i. A pre-filled syringe containing a long-acting injectable risperidone formulation, wherein the formulation is 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: Methoxy-poly(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 50, and z is the number of units in the range of 7 to 327). A biodegradable diblock copolymer having the formula: Including, wherein the ratio of (b) the biodegradable triblock copolymer to (c) the biodegradable diblock copolymer 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; ii. Needles having a gauge of 21 or greater and / or a length of 5 / 8 inch or less; and iii. Instructions for use A kit comprising a prefilled syringe containing:

[0149] In some embodiments, the kit is a single-use kit, i.e., contains a single-dose prefilled syringe and a 21 gauge, 5 / 8 inch needle. In some embodiments, the kit is provided in a tray, which may be a blister tray. In some embodiments, further provided is a means for physically protecting the prefilled syringe from light, including, for example, ambient light. In non-limiting embodiments, the means is a carton, box, bag, or aluminum foil wrap. In some embodiments, the means is a carton. In some embodiments, the needle is a safety needle. The safety needle may include a safety shield and / or needle sheath and may be packaged in an individual sterile pouch. The PFS may be any syringe suitable for administering the drug-polymer suspension. In some embodiments, the syringe is a glass syringe or a polymer syringe. In some embodiments, the syringe contains a white to off-white opaque suspension. In a specific embodiment, each prefilled syringe contains a sterile white to off-white opaque viscous suspension for subcutaneous use, and 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 200 mg, or 250 mg of risperidone. In some embodiments, the PFS is a glass syringe that includes a cap with a collar that covers the needle hub. The syringe can further include a syringe barrel label that includes the dosage and expiration date. In various embodiments, the risperidone solution is viscous, and the instructions for use include holding the syringe at or near the collar and flicking the syringe forcefully, for example, in a downward whip motion, about three times to move (air) bubbles from the syringe to the cap area of ​​the syringe. Such bubbles may appear partially opaque. If bubbles are in the cap, the cap can be removed from the vertically held syringe by bending and breaking the cap. The needle can be attached to the needle hub inside the collar. Further provided is a kit containing the risperidone formulation in a vial and a syringe for administration.

[0150] In some embodiments of the methods disclosed herein, the long-acting injectable risperidone formulation in the prefilled syringe of the present invention is stable at room temperature (20-25° C.) for up to 30 days. In some embodiments, the formulation is stable at room temperature for at least 90 days. In other embodiments, the long-acting injectable risperidone formulation in the prefilled syringe of the present invention is stable at 25° C. / 60% RH for up to 6 months. The long-acting injectable risperidone formulation can be returned to refrigerated storage (2-8° C.) within 90 days unless opened. In other embodiments, the long-acting injectable risperidone formulation in the prefilled syringe of the present invention is stable and can be stored at 2-8° C. for at least 12 months, at least 24 months, at least 30 months, or at least 36 months. In some embodiments, the risperidone formulation is solid at refrigerated temperatures (2-8° C.) and liquid at room temperature (20-25° C.). In another embodiment, the long-acting injectable risperidone formulation in the prefilled syringe of the present invention is stable after 3 cycles of 2 days at -20°C, followed by 2 days at 25°C / 60%RH. In another embodiment, the long-acting injectable risperidone formulation in the prefilled syringe of the present invention is stable after 2 weeks at -20°C, followed by 2 weeks at 2-8°C. In another embodiment, the long-acting injectable risperidone formulation in the prefilled syringe of the present invention is stable after at least 30 days at 20-25°C, followed by up to 36 months at 2-8°C and up to 30 days at 20-25°C.

[0151] In some embodiments, provided are methods of treating a psychiatric disease or disorder in a subject, comprising administering to the subject no more than once every 28 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 where v and x are numbers of repeating units ranging from 24 to 682, and w is a number of repeating units ranging from 4 to 273, and v=x or v≠x; c) Formula: methoxy-poly(ethylene glycol) y-poly(lactic acid) z where y and z are the number of repeating units, where y is the number of repeating units in the range of 3 to 50, and z is the number of repeating units in the range of 7 to 327; Including, wherein the ratio of the (b) biodegradable triblock copolymer to the (c) biodegradable diblock copolymer 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; wherein the method comprises subcutaneously administering 1 mL or less of a long-acting injectable risperidone formulation, wherein the long-acting injectable risperidone formulation is stored unopened at room temperature (20° C.-25° C.) for up to 90 days prior to administration, or stored unopened and refrigerated (2° C.-8° C.) for up to 36 months prior to administration.

[0152] In some embodiments, the long-acting injectable risperidone formulation is allowed to come to room temperature for at least 30 minutes prior to administration.

[0153] 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.

[0154] Some mPEG-OH may contain small amounts of OH-PEG-OH. By following the methods disclosed herein, the final product may be mPEG-PLA with small amounts of PLA-PEG-PLA.

[0155] Regarding the above-mentioned embodiments, each embodiment disclosed herein is considered to be applicable to each of the other disclosed embodiments.For example, the elements listed in the embodiment of the method can be used in the embodiment of the pre-filled syringe or kit described herein, and vice versa.

[0156] Disclosures of publications cited throughout are hereby incorporated by reference in their entireties into this application in order to more fully describe the state of the art as of the date of the invention described herein.

[0157] 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

[0158] (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.

[0159] In vitro release of each formulation was performed in duplicate. At the designated time points, the release buffer was sampled and freshly replenished. Special care was taken not to lose any depot fragments (if any) during buffer exchange. When the IVR was finished, the amount of active agent in the remaining depot was determined by HPLC to assess 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.

[0160] Preparation of stock solutions, standards, and quality control samples A stock solution was prepared by dissolving risperidone in an acetonitrile / HO mixture (50 / 50 v / v) to obtain a 200 μg / mL risperidone solution. This "mother solution" was stored at +2-8°C and showed stability 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.

[0161] 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.

[0162] 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.

[0163] (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]

[0164] According to the above conditions, the retention time of risperidone is 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, and R 2 >0.9999 was obtained. 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 evaluated as the lowest concentration allowing 90% recovery of the target drug concentration. The LOQ was found to be 0.5 μg / mL.

[0165] Injectability was measured according to a standardized operating procedure. The method was inspired by a previous study by Cilurzo et al. The device used to measure injectability was a Friction Tester FTPlus (Lloyd Instruments) connected to 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. Cilurzo et al. indicated 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).

[0166] Example 2. Risperidone Formulations Long-acting injectable risperidone formulations contain risperidone in an amount 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.

[0167] Preparation of Risperidone Particles Particles of risperidone can be prepared using ultra-micronization, micronization, or milled sourcing. The particle size distribution (PSD) of the risperidone particles in the formulation may be as follows: D10 20μm or less (NMT); D50 NMT 40μm; D90 NMT 70μm.

[0168] D50 refers to the median diameter of the particles, e.g., 50% of the particles have a diameter greater than 40 um and 50% of the particles have a diameter less than or equal to 40 um. The particle size distribution of the microparticles is determined by conventional methods, e.g., dynamic or static light scattering of an aqueous dispersion.

[0169] (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 75% change in cumulative release between the 125 mg and 250 mg depots: the 250 mg depot will release its risperidone cargo over a longer period than the 125 mg depot.

[0170] Exemplary formulations are shown in Table 2. The percentages shown are weight percentages from the total formulation composition. Table 2 [Table 2] RSP=Risperidone * PaRb represents triblock (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; **dPaRb represents a diblock (DB) copolymer, where a is the size of the mPEG chain in kDa and b is the lactic acid / ethylene oxide (LA / EO) molar ratio.

[0171] 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]

[0172] Example 3 In vivo ablation test The possibility of removing the composition from the subcutaneous (sc) space was examined. Without wishing to be bound by any particular theory, medical professionals may consider removing the implant after administration in case of an adverse event.

[0173] The compositions were injected subcutaneously in the interscapular and flank areas of rats, dogs, minipigs, and pigs.

[0174] 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).

[0175] 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 at day 14 after injection, and PK samples were collected up front and up to 72 hours later to confirm complete removal.

[0176] MRI provided a useful visual aid for implant depth and size throughout the study. Ultrasound imaging 4 hours after administration was challenging, with implants with volumes of 70-140 μL difficult to locate. On days 1-6, 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, it was proven feasible to locate the sc implants by clinically relevant imaging techniques such as ultrasound with 9 and 15 MHz probes and MRI. The ablation was good and complete, allowing removal of risperidone from the systemic circulation when necessary.

[0177] Examples 4-8 below provide details of human clinical trials evaluating risperidone formulations. All subjects were administered the formulations using a sterile 1 mL syringe and a 21G x 5 / 8 inch (16 mm) sterile stainless steel safety needle. The PFS was used in a Phase 1 BA and Phase 3 safety study. The risperidone formulation in the PFS is a ready-to-use, white to off-white, opaque, injectable suspension of 30% (w / w) risperidone in a dimethyl sulfoxide (DMSO) solution of two copolymers (a triblock copolymer and a diblock copolymer). In some embodiments, the copolymer mixture is dissolved in DMSO.

[0178] Example 4: Phase 1 Preliminary Pharmacokinetic Study A two-part clinical trial was conducted to evaluate (Part 1) the safety, tolerability, and pharmacokinetics of the risperidone extended release suspension (risperidone formulation) disclosed herein for subcutaneous injection, and (Part 2) the effect of injection and administration site manipulation on the pharmacokinetics (PK) of risperidone, its metabolite 9-hydroxy-risperidone (9-OH-risperidone, paliperidone), and total active moieties (TAM).

[0179] The study was conducted on 59 healthy volunteers, 53 of whom received the risperidone formulation and 6 received vehicle (formulation vehicle without risperidone) injections.

[0180] 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).

[0181] This study demonstrated that the risperidone formulation was safe and that the injection sites (upper arm / abdomen) were interchangeable.

[0182] Example 5 Phase 1 SAD / MAD Study 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.

[0183] The study population consisted of 99 patients with schizophrenia, with 88 patients aged 18-55 years included in the safety component of the study. The study design was an open-label single ascending dose (SAD) study (6 cohorts) and multiple ascending dose (MAD) study (2 cohorts), with a total of 8 cohorts.

[0184] The studies of Examples 4 and 5 taken together demonstrated several points: · the safety profile of the formulations disclosed herein was consistent with known risperidone formulations; Friction did not affect the properties of the risperidone formulation; -There have been no serious adverse reactions associated with the formulations disclosed herein; The treatment approach demonstrated a favorable risk / benefit profile; · No significant changes in pharmacokinetic parameters were observed during the change of injection site; · Validation of dose and target duration: 1-month (once a month; Q1M) and 2-month (once every 2 months; Q2M) products.

[0185] The results of the studies in Examples 4 and 5 show that the formulations disclosed herein have one-month and two-month release profiles at various doses and achieve therapeutic levels during the first 24 hours and remain in the therapeutic range throughout the entire dosing interval, thereby avoiding the need for oral supplementation after treatment initiation, and resulting in rapid establishment of clinically relevant risperidone plasma concentrations that then slowly decline over one to two months, respectively. Doses were selected based on the equivalence of plasma concentrations to those obtained with oral risperidone over a 24-hour dosing interval at steady state, with the goal of ensuring adequate exposure throughout the dosing period. Similar exposures were detected for arm and abdominal dosing.

[0186] Furthermore, model-based analyses intended to support dosing rationale (dose and regimen) in Phase 3 efficacy studies suggested that median TAM exposure for risperidone formulations following dosing of 50 mg to 250 mg Q1M and Q2M throughout the dosing interval was within the range of 2 mg to 5 mg daily doses of daily oral risperidone.

[0187] Safety, including local tolerability at the injection site, was examined in two clinical trials in Examples 4 and 5. Results from the two trials, totaling 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. The safety analysis for the study described in Example 5 is shown in Table 5. Table 5 [Table 5] Abd = abdominal sc injection, UA = upper arm (dorsal of the upper arm) sc injection

[0188] The interchangeability of the two injection sites, the abdomen and the back of the upper arm, was demonstrated in two clinical trials described in Examples 4 and 5. In Example 4, the interchangeability of the injection sites was investigated at a subtherapeutic dose (25 mg in cohorts F and D). There was no significant difference in TAM exposure between the injection sites, and max and AUC 0-t In the study described in Example 5 (225 mg in cohorts 5 (abd) and 8 (UA)), the optimal exposure parameters for single dose injections were AUC 0-t and AUC 0-∞ , which resulted in similar values. Table 6 provides a comparison of TAM PK parameters from the two studies by subcutaneous injection site. Table 6 [Table 6]

[0189] Example 6: Phase 1 Relative Bioavailability (BA) Study (test:) The objective of this Phase 1 study was to evaluate the relative bioavailability of a subcutaneous formulation of risperidone during PFS compared with vial in patients with schizophrenia or schizoaffective disorder.

[0190] (Test Design:) An open-label, parallel-design, single-dose study comparing 100 mg from a vial and 1-mL plastic syringe, sterile 21-gauge, 16-mm needle with 100 mg from a single-use 1-mL, Luer-lock, glass, clear PFS and sterile 21-gauge, 16-mm needle.

[0191] The 100 mg dose was considered representative of the dose intended for clinical practice. Noncompartmental pharmacokinetic analysis showed that a single dose of 100 mg resulted in exposures similar to those of 4 mg oral risperidone daily over a one-month period. Specifically, similar exposures were shown following administration of 100 mg of the risperidone formulation Q1M and 4 mg oral risperidone daily. Based on the above, and because 4 mg is the therapeutic dose for most patients with schizophrenia (Stroup and Marder, 2017), a dose of 100 mg Q1M, equivalent to a 4 mg oral risperidone dose, was considered the most appropriate dose to efficiently conduct this pharmacokinetic study.

[0192] One hundred twenty (120) patients were randomized into the BA study (10148). After enrollment, patients received oral risperidone 4 mg daily (qd) for 7 days, followed by a washout period of at least 7 days. Patients were then randomly assigned to one of the following groups: Group 1: Single dose of risperidone formulation 100 mg administered sc from a vial (n=60) Arm 2: A single dose of risperidone formulation 100 mg administered sc from PFS (n=60)

[0193] (result) The mean plasma concentration-time profiles of TAM after treatment with the vial and PFS presentations of risperidone formulations were qualitatively comparable. After sc administration, TAM plasma concentrations increased immediately, with each treatment group reaching therapeutic levels (≥10 ng / mL; Eerdekens et al., 2004) within 24 hours after dosing. Observed concentration values ​​(geometric mean) 24 hours after dosing [C24h] were 12.1 ng / mL (vial) and 13.4 ng / mL (PFS). The primary PK parameter used for comparison between the two presentations was AUC0-84d (area under the plasma concentration-time curve from time 0 to the end of the 84-day dosing interval).

[0194] In the ad hoc analysis, oral exposure covariate (AUC0-tau,ss) was included in the analysis of covariance (ANCOVA) of the primary endpoint for both data sets because of the inherent heterogeneity identified as indicated by a clear trend towards higher TAM exposure with oral risperidone in patients randomized to the PFS treatment group compared with those randomized to the vial treatment group. When oral risperidone exposure was normalized in the primary and ad hoc data sets, bioavailability was similar between the vial and PFS presentations of risperidone formulations. The exposure (AUC0-84) of PFS compared with vial when oral risperidone AUC0-tau,ss was used as a covariate was 24,295 ng / mL. * h / mL(PFS) and 22,411ng * h / mL (vial).

[0195] Furthermore, the safety and tolerability of the PFS presentation was comparable to that of the vial presentation with respect to pain intensity, local reactions (pruritus, nodules, rash, and swelling), incidence of AEs, change from baseline in ECG parameters, selected laboratory values ​​(including prolactin), vital signs, Columbia Suicide Severity Scale (C SSRS), and Positive and Negative Syndrome Scale (PANSS): indicating that the safety and tolerability of PFS in patients with schizophrenia was comparable to that of the vial presentation.

[0196] Data including primary analysis results, baseline-adjusted results, and safety results indicate that both formulations provide equivalent exposure and result in similar clinical profiles.

[0197] Example 7: Phase 3 pivotal efficacy clinical trial with risperidone formulation (30072) (test:) The objective of this study was to evaluate the efficacy, safety, and tolerability of various dose regimens of subcutaneously administered risperidone formulations described herein compared to placebo during the treatment phase in adult and adolescent patients with schizophrenia.

[0198] (Test Design:) A double-blind, randomized, relapse prevention study comparing therapeutic doses of the disclosed once-monthly (Q1M) and once-every-other-monthly (Q2M) risperidone formulations (50 mg to 250 mg) with placebo SC (once-monthly, Q1M) in a 1:1:1 ratio.

[0199] (Test population:) Male and female patients aged 13-65 years with a confirmed diagnosis of schizophrenia were clinically stable and eligible for risperidone treatment. In total, 1267 patients were screened, 863 were enrolled, and 544 patients were aged 16-65 years (inclusive) and randomized (eITT population); 363 patients of that group were randomized to receive either the Q1M(183) or Q2M(180) dosing regimen (the remainder received placebo), and all 363 patients were evaluable for pharmacokinetics.

[0200] (Test Drug:) Risperidone at 360 mg / mL in the formulation disclosed herein. Study drug was presented in a glass vial containing a fixed amount of the risperidone formulation. Study drug was tested for risperidone exposure when administered subcutaneously (sc) once a month (Q4W), once a month or once every 28-31 days (Q1M), or once every two months (Q8W, every 56-62 days) (Q2M). Participants received sc injections in the upper arm or abdomen depending on the study site.

[0201] (Placebo group:) Participants received sc injections of a placebo (polymer vehicle) matching the risperidone formulation at baseline and every 4 weeks (Q4W) thereafter. Participants continued treatment until they experienced a relapse event; met one or more of the study discontinuation or withdrawal criteria; or remained relapse-free during the double-blind period until the end of the study.

[0202] (Q1M group:) Participants received sc injections of the risperidone formulation at baseline and Q4W thereafter. The maximum dose administered to adult participants was equivalent to a 5 mg / day oral risperidone dose, and the maximum dose administered to adolescents (13-17 years) was equivalent to a 4 mg / day oral risperidone dose. Participants continued treatment until they experienced a relapse event; met one or more of the study discontinuation or withdrawal criteria; or remained relapse-free during the double-blind period until the end of the study.

[0203] (Q2M group:) Participants received sc injections of a risperidone formulation at baseline and every 8 weeks (Q8W) thereafter, and sc injections of placebo 4 weeks after baseline and Q8W thereafter. The maximum dose in both groups corresponded to the same daily oral dose. Participants continued treatment until they experienced a relapse event; met one or more of the study discontinuation or withdrawal criteria; or remained relapse-free during the double-blind period until the end of the study.

[0204] Table 7 shows the dosage selection of risperidone formulations (extended release injectable suspension) compared to oral doses of risperidone. Table 8 shows the dose composition. Table 7. Dosage Selection Guidelines [Table 7] Table 8. Composition of risperidone formulations [Table 8]

[0205] (Primary and secondary outcome measures:) (Primary outcome measures:) 1. Time to imminent recurrence [Time frame: 15 months] Calculated as the earliest date on which a patient meets ≥1 imminent recurrence criterion Final analysis with 90 recurrent events

[0206] (Secondary outcome measures:) 1. Time to imminent relapse [time frame: 15 months] as defined under the primary objective in the total population (adults and adolescents) 2. Time to impending relapse in adolescent patients with schizophrenia 3. Rate of imminent recurrence [time frame: 24 weeks] This rate will be estimated using the Kaplan-Meier method. 4. Observed rate of impending relapse [time frame: 15 months] Calculated as the number of patients who relapsed by the endpoint divided by the number of patients in each treatment group 5. Percentage of Patients Remaining Stable [Time Frame: 15 months] Stable 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 and will be defined as per Andreasen et al. (Remission in Schizophrenia: Proposed Criteria and Rationale for Consensus, Am J Psychiatry, 162(3): 441. 2005). All remission criteria will be derived from the PANSS items. 7. Percentage of Participants with Adverse Events [Time Frame: 15 months]

[0207] Recurrence was defined as one or more of the following: Clinical Global Impression-Improvement (CGI-I) ≥ 5 and An increase in any of the following PANSS items: conceptual disorganization, hallucinatory behavior, suspiciousness, and unnatural thought content to a score >4 with an absolute increase of ≥2 for that particular item since randomization, or An increase in any of the following four PANSS items: conceptual integration disorder, hallucinatory behavior, suspiciousness, and unnatural thought content to a score >4, with an absolute increase of ≥4 in the combined score of the four PANSS items since randomization; Hospitalization due to worsening psychiatric symptoms Clinical Global Impression-Suicidality Severity Scale (CGI-SS), 4 or 5 in Part 1 and / or 6 or 7 in Part 2 · Clinically significant violent behaviour resulting in self-harm, injury to others or damage to property.

[0208] (result) Study 30072 was a double-blind randomized study comparing therapeutic doses of risperidone formulations administered subcutaneously (sc) Q1M and Q2M with placebo sc Q1M for the treatment of schizophrenia after oral transition and stabilization stage (Stage 1). The study was intended to provide extensive and pertinent safety and efficacy information for the risperidone formulations Q1M and Q2M dosing regimens. PK data collected during the course of the study were further analyzed with Population PK (PopPK) modeling (Example 9 below). A final analysis was performed on 90 relapse events.

[0209] During the randomized portion of the study (Stage 2), patients received their assigned treatment until they experienced a relapse event or met one or more of the study withdrawal criteria. The mean (median) duration of exposure in Stage 2 was 30.9 weeks (24.3 weeks) for patients in the placebo group, 41.9 weeks (40.0 weeks) for patients in the risperidone Q1M group, and 42.1 weeks (38.1 weeks) for patients in the risperidone Q2M group. For at least 6 months, 26 (15%) patients received placebo, 29 (16%) patients received risperidone Q1M, and 25 (14%) patients received risperidone Q2M. For at least 12 months, 36 (20%) patients received placebo, 64 (35%) patients received risperidone Q1M, and 65 (36%) patients received risperidone Q2M.

[0210] Patient population characteristics were balanced across treatment arms. Ninety patients discontinued the study due to recurrence, and 250 patients were recurrence-free at study end. Subpopulation analyses by sex, age, and race did not suggest clear evidence of differential response to treatment. All data were processed and summarized using SAS® version 9.4. Time to events methodologies were used for the primary and several key secondary endpoints. For other continuous endpoints, least squares (LS) means and SAS type III sums of squares for statistical inference were used for mixed model repeated measures (MMRM). For categorical endpoints, the Cochran-Mantel-Haenszel (CMH) test was used. All statistical tests were two-sided with a significance level of 0.05.

[0211] (Summary of results) Long-acting injectable risperidone formulations administered once monthly (Q1M) or twice monthly (Q2M) demonstrated statistically significant treatment benefit compared with placebo. Treatment with risperidone resulted in a statistically significant increase / delay in time to impending relapse compared to placebo, overall and for the Q1M and Q2M regimens. Compared to placebo, risperidone significantly increased the time to impending relapse by 3.5-fold overall, 5-fold for the Q1M regimen, and 2.7-fold for the Q2M regimen. Risperidone significantly reduced the risk of relapse by 80.0% (Q1M) and 62.5% (Q2M) compared with placebo over the entire study period. The proportion of patients with impending relapse at week 24 was significantly lower in the risperidone-treated groups (overall: 9%; Q1M: 7%; Q2M: 11%) compared with the placebo-treated group (28%; P<0.0001, P<0.0001, P=0.0001, respectively). A significantly higher proportion of patients maintained stable disease (overall: 83%, Q1M: 87%, Q2M: 80%; compared with placebo 61%, P<0.0001, P<0.0001, P=0.0001, respectively).

[0212] The primary endpoint of number of participants with impending relapse at week 108 (in the intention-to-treat [ITT] analysis set) is provided in Table 9. Data are presented as distribution of participants with impending relapse (number of participants with impending relapse): ITT analysis set: adult participants randomized to double-blind maintenance treatment, whether or not they received treatment. Table 9 [Table 9]

[0213] Clinical importance was further demonstrated by key secondary endpoints in a pooled analysis of risperidone Q1M and Q2M dosing regimens compared with placebo.

[0214] The number of participants with impending relapse at week 108 (in the expanded intention-to-treat [eITT] analysis set, which included adolescent subjects) is provided in Table 10. Data are presented as the distribution of participants with impending relapse (number of participants with impending relapse). The eITT analysis set included participants randomized to double-blind maintenance treatment, whether or not they received treatment. Table 10 [Table 10]

[0215] Impending relapse at week 24 was estimated using Kaplan-Meier product estimation. The ITT analysis set included adult participants randomized to double-blind maintenance treatment, whether or not they received treatment. Impending relapse at week 24 was statistically significantly lower in patients treated with risperidone formulations (9% overall [7% Q1M and 11% Q2M]) compared to placebo (28%). The results are provided in Figure 1 and Table 11 below: Table 11 [Table 11]

[0216] Furthermore, the percentage of patients remaining stable at the endpoint was statistically significantly higher in patients treated with risperidone formulations (83% overall [87% Q1M and 80% Q2M]) compared to placebo treatment (61%). Stable was defined as 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 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 CGI-SS scores ≦2 in part 1 (mild suicidal ideation) and ≦5 in part 2 (minimal deterioration). The last valid participant assessment was used as the outcome measure. Table 12 shows the number of patients stabilized with each treatment: Table 12 [Table 12]

[0217] The number of patients achieving remission at endpoint (up to 108 weeks) is shown in Table 13. Although it did not reach statistical significance, this result was not unexpected given the relatively long mean disease duration of the patients in this study (>18 years) combined with the strict criteria used to define remission in this study (i.e., a score of ≦3 must be maintained on each of eight specific PANSS items: P1 [delusions], G9 [unnatural thought content], P3 [hallucinatory behavior], P2 [impaired conceptual integration], G5 [pedantic / unnatural posture], N1 [blunted affect], N4 [social withdrawal], and N6 [lack of spontaneity]) without relapse during the study period and for at least 6 months prior to the endpoint). Table 13 [Table 13]

[0218] Changes in severity of psychopathological symptoms in subjects treated with risperidone formulations compared with placebo Positive and Negative Syndrome Scale (PANSS), Clinical Global Impression-Severity (CGI-S), and Clinical Global Impression-Improvement (CGI-I) was used for evaluation.

[0219] Changes in CGI-S did not reach statistical significance at the end of treatment. However, PANSS scores decreased by the end of treatment (EoT) for subjects treated with risperidone formulations, but increased for the placebo group (least squares mean (LSM) change (standard error, SE): Q1M, -3.46 (0.69); Q2M, -4.88 (0.73); placebo, 1.11 (0.86); both P<0.0001 vs placebo). Greater symptom improvement was observed from week 12 / randomization (study baseline) to the end of treatment with risperidone formulations compared with placebo, as assessed by CGI-I (LSM (SE): Q1M, 3.30 (0.08); Q2M, 3.15 (0.08); placebo, 3.85 (0.10); both P<0.0001 vs placebo).

[0220] Patient-centered outcomes assessed throughout the study included: Drug Attitudes Inventory 10-item version (DAI-10); the DAI-10 scale correlates with medication compliance and treatment outcome -Schizophrenia Quality of Life Scale (SQLS), EuroQol's - 5-point European Quality of Life EQ-5D (EQ-5D-5L) visual analogue scale (VAS) and descriptors · Personal and Social Functioning Scale (PSP).

[0221] After significant improvement during the oral stabilization phase: SQLS and EQ-5D-5L VAS scores continued to improve significantly from randomization to end of treatment (EOT, 108 weeks) for all risperidone treatment groups, while the scores remained similar in the placebo group. Improvements in quality of life (QoL) were expressed as decreases in SQLS scores and increases in EQ-5D-5L scores.

[0222] The key secondary efficacy variable, change from baseline in SQLS total score, showed a small difference from placebo in favor of the investigational drug (Q1M and Q2M) at ET (LS mean [SE]: -3.99 [1.74] and -1.58 [1.78], respectively, compared with 3.20 [1.58] for placebo) and EoT (LS mean [SE]: -5.40 [1.12] and -4.54 [1.16], respectively, compared with 1.14 [1.32] for placebo). The exploratory efficacy variable, change from baseline in EQ-5D-5L score, showed differences from placebo in favor of the investigational drug (pooled Q1M and Q2M) at ET (LS mean [SE]: -0.99 [1.41] compared with -4.74 [1.76] for placebo) and at EoT (LS mean [SE]: 2.28 [0.83] compared with -2.46 [1.32] for placebo).

[0223] Higher PSP total scores represent better personal and social functioning. Mean PSP scores did not continue to improve significantly from randomization in any treatment group. However, the exploratory efficacy variable of change in PSP total score from baseline showed differences in favor of the study drug (pooled Q1M and Q2M) over placebo for investigator-assessed personal and social functioning at ET (LS mean [SE]: −2.65 [0.82] for pooled Q1M and Q2M groups compared with −5.29 [0.97] for placebo) and at EoT (LS mean [SE]: 1.56 [0.52] for pooled Q1M and Q2M groups compared with 0.11 [0.84] for placebo).

[0224] Efficacy study data showed a high correlation between medication compliance and treatment outcome as measured by the DAI-10 scale. Mean DAI-10 scores improved significantly (P<0.01) from randomization in the overall and Q1M treatment groups treated with risperidone formulations. A positive total score indicates a positive attitude toward psychosis medication and thus corresponds to a compliant response, and vice versa. The key secondary efficacy variable, change from baseline in DAI-10 total score, showed small differences from placebo in favor of the investigational drugs (Q1M and Q2M) with respect to patient attitudes toward taking their medication at ET (LS mean [SE]: 0.25 [0.42] and -0.40 [0.41], respectively, compared with -0.55 [0.38] for placebo) and EoT (LS mean [SE]: 0.57 [0.28] and 0.10 [0.29], respectively, compared with -0.59 [0.31] for placebo).

[0225] After little improvement during the oral stabilization phase, EQ-5D-5L descriptor scores improved significantly between randomization and EOT for mobility (overall and Q1M only), pain / discomfort, and anxiety / depression (all risperidone-treated groups) (P<0.05).

[0226] Patients receiving risperidone formulations showed continued improvement with continued treatment compared with placebo in terms of their attitude toward their medication (DAI-10 total score) and investigator-assessed psychopathology (PANSS total score).

[0227] PANSS total scores were assessed over time. Unexpectedly, a decrease in PANSS scores after stabilization was observed over time, at least until week 64 (Figure 2). This was surprising given that study participants were clinically stable at enrollment and had a long disease history (mean 10 years). The proportion of patients who remained stable and / or showed improvement after stabilization was significant in the risperidone formulation treatment group.

[0228] (Conclusion) The study met its primary efficacy endpoint for the long-acting injectable risperidone formulation Q1M compared with placebo (p<0.0001).

[0229] The study achieved its primary endpoint of favoring the risperidone formulation Q2M compared with placebo (p<0.0001).

[0230] Risperidone formulations reduced the risk of relapse by 80.0% and 62.5% for Q1M and Q2M, respectively, compared with placebo throughout the study period.

[0231] Risperidone formulations prolonged the time to relapse by 5-fold and 2.7-fold compared with placebo in Q1M and Q2M, respectively. The proportion of patients with imminent relapse was lower in the treatment groups (13 [7%] patients in the Q1M group and 23 [13%] patients in the Q2M group) compared with placebo (53 [29%] patients).

[0232] Patients taking risperidone preparations demonstrated beneficial and sustained post-stabilization reductions in PANSS scores over time.

[0233] Sensitivity analyses showed that statistical significance was maintained even with extremely conservative assumptions regarding early termination.

[0234] The safety profile was favorable, with no unexpected findings.

[0235] Safety, PK parameters, and efficacy of both brachial and abdominal injection sites are similar and can be used interchangeably to administer risperidone formulations.

[0236] Mean exposure values ​​over the dosing period (Cavg,ss) were comparable for monthly and bimonthly risperidone formulations at corresponding doses. After both monthly (50 mg-125 mg) and bimonthly (100 mg-250 mg) dosing, mean exposure to TAM (AUC0-tau) was comparable to that of daily oral risperidone (2 mg-5 mg / day) administered over comparable dosing periods.

[0237] The efficacy and safety results of this study support the benefit of risperidone formulations Q1M and Q2M for the treatment of patients with schizophrenia. Treatment with risperidone formulations significantly shortened the time to imminent relapse and significantly reduced the risk of relapse compared to placebo, and the reduction in relapse risk was sustained throughout the study period. Compared to placebo, risperidone formulations extended the time to relapse by 5-fold with Q1M administration and 2.7-fold with Q2M administration.

[0238] The safety profile of the active ingredient, risperidone, administered orally or as a long-acting parenteral formulation, has been well characterized. Data from this study demonstrated that risperidone formulations administered subcutaneously once monthly (Q1M) and once every two months (Q2M) exhibited a safety profile, including common adverse events, consistent with other formulations of risperidone and patient populations.

[0239] The availability of both Q1M and Q2M dosing regimens, with several dosing options (equivalent to 2-5 mg / day oral therapy), has the potential to improve patient outcomes by delaying relapse, shortening time to relapse, and sustaining reduction in PANSS total scores. These features may also improve compliance and acceptance, both of which are crucial for patients to maintain their required therapeutic dose and thereby improve disease outcomes. These dose options provide longer dosing intervals, as well as greater flexibility for clinicians to vary the dose (50 mg-250 mg, equivalent to 2-5 mg / day oral) and dosing interval between monthly and bimonthly regimens based on clinical need and suitability.

[0240] One of skill in the art can determine the appropriate dosage and administration regimen for a particular subject.

[0241] Example 8: Phase 3 safety clinical trial with risperidone formulations (test:) The primary objective of this study was to evaluate the long-term safety and tolerability of the risperidone formulation. All subjects were treated with the risperidone formulation in a prefilled syringe (PFS). The prefilled syringe was a 1 ml glass syringe with a 5 / 8 inch (16 mm) long, 21-gauge sterile safety needle. The primary safety and tolerability endpoint was the frequency of all adverse events (AEs), including serious adverse events (SAEs). For new patients, the total duration of patient participation in the study was up to 80 weeks (including up to 4 weeks of screening, 12 weeks of oral transition / stabilization phase [Phase 1], 56 weeks of double-blind phase [Phase 2], and follow-up period [8 weeks]). For rollover patients (Efficacy Study 30072, Example 7), the total duration of patient participation in the study was planned to be up to 64 weeks (including up to 56 weeks of Phase 2 and follow-up period [8 weeks]). Patients who started Phase 2, relapsed, or met one or more withdrawal criteria were invited to an early termination visit as soon as possible within 4 weeks of their last injection. Patients who withdrew from the study before completing the 56-week Phase 2 underwent follow-up procedures and evaluations at the follow-up visit. During follow-up, patients were treated according to the investigator's discretion.

[0242] (Test Design:) Allocation: Randomized Intervention model: Parallel allocation Masking: quadruple (participant, healthcare provider, investigator, outcome assessor) Primary purpose: treatment

[0243] (Test evaluation items) Primary outcome measures: 1. Number of AEs including SAEs [time frame: 56 weeks] Other outcome measures: 1. Number of participants who withdrew due to AEs [time frame: 56 weeks]

[0244] Age: 13-65 years old (Young people (13-17 years old); Adults (18-65 years old)

[0245] (Inclusion criteria:) (Patients rolling over from pivotal efficacy study 30072:) 1. Patients had to participate in Study 30072 without experiencing a recurrent event and without major protocol deviations. 2. If a patient was taking antidepressants or mood stabilizers in Study 30072, dose changes or initiation of treatment with these medications will not be permitted. 3. Patient requires chronic treatment with an antipsychotic as determined by the investigator.

[0246] (New patients (not rolling over from study 30072):) 1. Patient has a diagnosis of schizophrenia. 2. Patient has responded to antipsychotic treatment (other than clozapine) within the past year based on the investigator's judgment (and discussion with family, caregiver, or healthcare professional, if applicable). 3. Patient requires chronic treatment with an antipsychotic as determined by the investigator.

[0247] (Exclusion criteria:) (Rollover patients from study 30072:) 1. Patients have baseline 12-lead ECG findings that are considered clinically significant in the investigator's judgment. 2. Poor compliance with study procedures during the primary efficacy study period (in the opinion of the investigator or sponsor). This should be discussed on a case-by-case basis.

[0248] (New patients (not rolling over from Study 30072) and rollover patients:) 1. Patients were currently taking clozapine or had received electroconvulsive therapy within the past 12 months. 2. Patient has a history of epilepsy or seizures, neuroleptic malignant syndrome, tardive dyskinesia, or other medical condition that places the patient at undue risk. 3. Patient has positive serology for human immunodeficiency virus (HIV)-1, HIV-2, hepatitis B surface antigen, and / or hepatitis C. 4. Patient has current or history of known hypersensitivity to risperidone or any of the excipients in the risperidone formulation or to the oral formulation of risperidone used in the stabilization phase. 5. The patient has a substance use disorder, including alcohol and benzodiazepines, but excluding nicotine and caffeine. 6. The patient is a pregnant or breastfeeding woman. 7. Patients have used any investigational drug other than risperidone within 3 months prior to screening or participated in a non-drug clinical trial within 30 days prior to screening. 8. Vulnerable patients (e.g., people in confinement).

[0249] Example 9: Population Pharmacokinetic (PopPK) Modeling The five clinical trials disclosed above contributed to the characterization of the pharmacokinetic (PK) and exposure-response (ER) relationships of risperidone formulations following subcutaneous administration.

[0250] A PopPK validation model was developed using the data from the Phase 1 and Phase 3 efficacy and safety studies disclosed above: PopPK of the parent molecule (risperidone), its major active metabolite (9-hydroxyrisperidone, 9-OH-risperidone), and the total active moiety (TAM). The TAM of risperidone has the following formula: [Active moiety](ng / mL)=[Risperidone](ng / mL)+[9-OH-Risperidone](ng / mL) 410 / 426) The plasma concentrations were calculated as the sum of risperidone and 9-OH-risperidone, corrected for molecular weight, according to

[0251] The Phase 1 study included extensive PK sampling and the Phase 3 study included plasma samples for PK measurements, both collected at each clinical visit during the oral risperidone stabilization and treatment periods.

[0252] The general steps followed for the development of the PopPK model are outlined below: 1. Exploratory Data Analysis 2. Development of the basic structure model 3. Assessment of covariate effects 4. Model Improvement 5. Evaluating the Model

[0253] An initial PK model was developed based on data from two Phase 1 studies (Examples 4 and 5). The model was able to adequately capture the complex release and absorption of risperidone and was used to aid in determining the in-study dose escalation during the Phase 1 SAD / MAD study (Example 5) in patients with schizophrenia or schizoaffective disorder, and to aid in the design of subsequent studies (Examples 6, 7, and 8).

[0254] The second PK model was a sequential parent-metabolite model: First, a model was developed to describe the PK of risperidone (parent) based on the data from all clinical trials (Examples 4-8), which was a one-compartment model with first-order and through-compartment absorption pathways and first-order excretion.

[0255] Next, a sequential model was developed to describe the PK of 9-OH-risperidone (the metabolite). The PK of 9-OH-risperidone was described by a one-compartment model with first-order input from the risperidone compartment and first-order elimination. Predicted risperidone concentrations from the parent model were used as input to the metabolite-centered compartment. No covariates were identified that were deemed statistically significant and clinically relevant.

[0256] Finally, model-estimated parent and metabolite levels were used to calculate TAM exposure, which was used for PK assessment and simulation as well as exposure-response assessment of safety and efficacy.

[0257] PopPK simulations performed with the final model suggested that TAM exposure during treatment with risperidone formulations at various dosing regimens was generally sustained over time and comparable to established oral risperidone regimens.

[0258] PopPK simulations showed that the selected doses and dosing regimens provided adequate TAM exposure equivalent to that of the corresponding daily oral doses (2 mg, 3 mg, 4 mg, 5 mg) throughout the dosing interval (at least 28 days and up to 2 months).

[0259] Risperidone formulations showed dual absorption with a rapid initial absorption phase and a slow secondary absorption phase. After single dose sc administration, median Tmax ranged from 8 to 14 days, and for multiple dose administration, it ranged from 9 to 15 days. Therapeutic plasma risperidone concentrations were rapidly reached within 6 to 24 hours after sc injection, depending on the dose. Therefore, neither a loading dose of oral risperidone nor supplemental oral risperidone is required. Similarly, the PopPK of risperidone (parent) was best described by two absorption rate processes (one fast and one slow) to account for the rapid initial appearance of risperidone into the systemic circulation and sustained plasma concentrations governed by the slow release of risperidone from the depot.

[0260] The median AUC accumulation ratios at steady state were approximately 2.0 and 1.5 for the Q1M and Q2M regimens, respectively; max The median accumulation ratios of C at steady state were approximately 1.9 and 1.4 for the Q1M and Q2M regimens, respectively; trough The median accumulation ratios were approximately 2.4 and 1.5 for the Q1M and Q2M regimens, respectively.

[0261] For all doses, steady-state plasma levels of risperidone and 9-OH-risperidone were reached within 2 months of initiation of both the Q1M and Q2M dosing regimens. Steady-state plasma exposure values ​​of risperidone, 9-OH-risperidone, and TAM after monthly dosing were approximately 2-2.5-fold higher than the single-dose exposures, while values ​​for the risperidone formulations administered every two months were approximately 1.5-fold higher than the respective single-dose exposures. After dosing, plasma levels (AUC0-tau and Cmax) of risperidone, 9-OH-risperidone, and TAM increased in a dose-proportional manner.

[0262] Risperidone formulations administered in the abdomen or upper arm produced similar pharmacokinetic profiles for all doses, and either injection site could be used interchangeably. In the Phase 3 study, the risperidone formulation was administered by sc injection to the abdomen of most patients. Approximately 20% of the centers injected the formulation into the dorsum of the upper arm of patients. In Study 30072, 32% of patients received the risperidone formulation in the upper arm, and in Study 30078, 11% of patients received the risperidone formulation in the upper arm. Comparability of the two injection sites was also evaluated in the final PopPK model, which included pooled pharmacokinetic data from Phase 1 and Phase 3 clinical trials. This dataset included injection data for 2251 and 1035 injections administered in the abdomen and arm, respectively. Simulations showed similar exposure following administration to the different injection sites. The overall exposure (AUC,ss; and Cmax,ss) for both injection sites and the 90% prediction intervals for each exposure metric overlapped.

[0263] Covariate analysis based on the PopPK model suggested that age and weight did not affect the exposure of risperidone formulations in adolescent populations (13-17 years), which was considered to be similar to that in adults.

[0264] The final PopPK model estimated clearance (CL) of risperidone and 9-OH-risperidone was 14.3 L / h and 5.78 L / h, respectively. The final PopPK model revealed that poor CYP2D6 metabolizer status was associated with relatively lower risperidone clearance, and the clearance of metabolites of 9-OH-risperidone (CLMO) was generally higher in poor CYP2D6 metabolizers. These findings are consistent with a mechanism of CYP2D6-mediated 9-hydroxylation of risperidone. In poor CYP2D6 metabolizers, risperidone clearance is lower than in subjects with normal CYP2D6 metabolism, resulting in a lower percentage of risperidone metabolized to 9-OH-risperidone and a higher apparent CLMO. Because the overall pharmacological activity of risperidone is governed by TAM, the effects of the above demographic factors on the CL of risperidone and the CLMO of 9-OH-risperidone are not expected to be clinically meaningful, and therefore, dose adjustments based on CYP2D6 metabolic activity status are not required.

[0265] (Exposure-Response (ER) Analysis) Data from Phase 3 studies in patients with schizophrenia (Examples 7 and 8) were pooled to develop an ER model describing the relationship between exposure (TAM) of risperidone formulations and measures of efficacy and safety. Endpoints evaluated in the ER analysis were: Efficacy endpoints: time to relapse (defined by CGI-I, PANSS, and CGI-SS scores, hospitalization for worsening psychotic symptoms, violent behavior). Criteria for imminent relapse are disclosed in Example 7 above. -Occurrence of specific adverse events (AEs)

[0266] Exposure parameters used in the exposure-efficacy analysis were obtained from the final PopPK dataset and included the following: Cavg,ss, Cmax,ss, and Ctrough,ss.

[0267] The combined exposure parameters (Cavg,ss, Cmax,ss, and Ctrough,ss) for all doses and dosing regimens of TV 46000 were divided into four equally sized quartiles using bin calculations based on the distribution of the parameters to allow better visualization in Kaplan-Meier plots.

[0268] The quartiles were defined as follows: Q1=lowest 25th percentile, N=107 Q2=25th percentile 50th percentile, N=106 Q3=50th percentile 75th percentile, N=106 Q4=75th percentile maximum), N=106

[0269] Time-to-event analysis of impending recurrence was examined by Kaplan-Meier assessment. Kaplan-Meier curves of impending recurrence were stratified by group based on dosing frequency, cohort, and TAM exposure. Kaplan-Meier assessment was also performed for systemic AEs and stratified by TAM exposure. Logistic regression was performed for AEs.

[0270] (result:) The exposure metrics were divided into four equally sized quartiles based on the distribution of the metrics. Table 14 provides predicted TAM PK values ​​for Cavg, Cmax, and Ctrough at steady state (ss). [Table 14]

[0271] Exposure-response analyses for impending relapse showed no trends, suggesting similar treatment effects for the Q1M and Q2M regimens across all dose and exposure groups in the Phase 3 study. Lower TAM Ctrough,ss concentrations were not associated with an increased risk of impending relapse.

[0272] (Safety analysis:) An exposure-response relationship was found between TAM levels and the occurrence of extrapyramidal symptom (EPS) adverse events (AEs), which was further explored using logistic regression and Kaplan-Meier plots. The incidence of EPS was higher in the subpopulation of patients with higher TAM Cmax,ss concentrations. However, all EPS events occurring in the Phase 3 study after risperidone formulations for all doses and dose regimens were mild or moderate in severity, and no severe EPS events were observed. When stratifying EPS AEs based on moderate severity only, no significant differences were observed between placebo and treatment (for Cmax,ss, p=0.26), suggesting that there is no clear ER relationship between TAM Cmax,ss range and moderate EPS AEs.

[0273] Example 10: Storage and stability test of risperidone formulations Risperidone formulations in vials and in the PFS were tested for long-term stability. The risperidone formulations were tested as follows: a) Long-term at 5°C for 0, 3, 6, 9, 12, 18, 24, and 36 months; b) Accelerated at 25°C / 60%RH for 0, 3, and 6 months; c) Light Stability - The formulations were exposed to artificial daylight fluorescent lighting with a total illuminance of 1.2 million lux hours and an integrated near UV energy of ≥ 200 watt-hours per square meter at 25°C / 60% RH. Eleven primary batches were tested. The study was conducted to evaluate the light protection of both the formulation in the primary packaging (PFS) and the formulation in the secondary packaging (PFS in a sealed carton); d) Freeze-thaw cycling study - The formulations were stored at -20°C for 2 days, followed by 2 days at 25°C / 60%RH. 11 primary batches were tested. Three such cycles were repeated before testing. This study was performed to evaluate the susceptibility of the formulations to thermal cycling that may occur during storage and distribution; e) Freezing - The formulations were stored at -20°C for 2 weeks followed by 2 weeks at 5°C. Eleven primary batches were tested. This study was performed to assess the susceptibility of the formulations to freezing conditions that may occur during distribution. f) Thermal Excursion - The effect of long term (1 month) storage at 25°C / 60% RH on the stability of the formulation during the shelf life was studied. The study was performed at the beginning and repeated at the end of the shelf life (24 months and 36 months) for 11 batches to simulate temperature excursions that may occur during storage and distribution of the formulation. The effect of long term storage up to 3 months at 25°C / 60% RH was checked at the end of the shelf life (36 months) to evaluate longer temperature excursions that may occur during storage and distribution of the formulation. The formulations were stored horizontally during the study. g): Cumulative temperature effect to test the cumulative exposure of the formulation to 25°C / 60% RH at intervals of 7, 14, 21, and 28 days during the storage period. For the cumulative exposure of 28 days, the formulation was exposed to 25°C / 60% RH four times at 7-day intervals during the storage period of 0, 6, 12, and 24 months. This test was performed on 11 batches to simulate the product being repeatedly removed from the refrigerator and returned if not used during the storage period.

[0274] Batches of PFS containing 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 200 mg, and 250 mg risperidone formulations were tested.

[0275] Long-term and accelerated storage studies were performed on the PFS in horizontal, vertical, and inverted positions to evaluate the following characteristics: appearance, particulate matter, assay, related compounds, copolymer molecular weight, in vitro drug release and particle size distribution; viscosity and moisture content; and / or bacterial endotoxins and sterility under storage conditions and at room temperature.

[0276] Long-term and accelerated storage studies were performed with the PFS in trays in horizontal, vertical, and inverted positions to evaluate onset force; sustained force; container closure integrity, delivered dose, and delivered volume.

[0277] (result:) After storage for up to 24 months at 5°C and up to 6 months at 25°C / 60% RH, no significant changes in any of the above characteristics were observed for all batches for all parameters tested.

[0278] For all batches of drug product in primary packaging (PFS), changes in appearance parameters occurred during photostability testing. No such changes occurred when placed in secondary packaging. Secondary packaging provides adequate protection of drug product from light. Examples of secondary packaging include cartons, boxes, envelopes, pouches, aluminum foil covers, etc.

[0279] No significant changes in the quality of the formulation occurred during the freezing and cycling tests; the product tolerates freezing and short-term temperature cycling.

[0280] No significant changes in quality occurred during the thermal excursion test and at the beginning of the storage period; the product may be used within three months after thawing (from the freezer) when stored at room temperature.

[0281] The PFS can be stored at 2-8°C for at least 12 months, 24 months, or 30 months or 36 months. The risperidone formulation can be stored unopened at room temperature 68-77°F (20-25°C) for up to 90 days (e.g., up to 30 days, up to 60 days, or 90 days) and can be returned to refrigerated storage within 90 days as long as it is unopened. In some embodiments, the kit is stored in a refrigerator at 36-46°F (2-8°C) in the original carton to protect from light. Prior to use, the kit can be left in its packaging at room temperature for at least 30 minutes before administration. The kit can be stored unopened in its original packaging at room temperature for up to 90 days. If unopened, the kit can be returned to refrigerated storage within 90 days. The risperidone formulation can be frozen and "thawed", i.e., placed at room temperature, multiple times before use and continue to retain stability for use in human subjects. Once the carton is opened, the risperidone formulation can be administered subcutaneously.

[0282] All compositions and methods disclosed and claimed herein can be made and carried out without undue experimentation in light of the present disclosure. The compositions and methods of the present invention have been described with reference to preferred embodiments, but it will be apparent to one skilled in the art that modifications may be applied without departing from the spirit and scope of the present invention. All patents, patent applications, and publications disclosed herein 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 formulations, methods, and kits are specifically disclosed with reference to preferred embodiments and optional features, but it should be understood that modifications and variations of the concepts disclosed herein may 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.

[0283] The present invention is described in further detail with reference to the following clauses: 1. A method of treating a psychiatric disease or disorder in a subject, comprising administering to the subject: (a) risperidone or a pharma- ceutical acceptable salt thereof having a concentration of about 250 to 400 mg / mL in terms of risperidone; Formula (b): 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 50, and z is the number of 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, comprising subcutaneously administering 1 mL or less of a long-acting injectable risperidone formulation; wherein the formulation is administered subcutaneously no more frequently than once a month, and the formulation provides a therapeutically effective amount of risperidone for at least one month. 2. The method of clause 1, wherein the formulation is administered subcutaneously no more frequently than once every two months, and wherein the formulation provides a therapeutically effective amount of risperidone for at least two months. 3. The method of clause 1 or clause 2, wherein said subject is not administered a loading dose of oral risperidone. 4. The method of clause 1 or clause 3, wherein the formulation comprises from about 50 mg to about 125 mg of risperidone. 5. The method of clause 2 or clause 3, wherein the formulation comprises from about 100 mg to about 250 mg of risperidone. 6. The method according to any one of clauses 1 to 5, wherein said psychiatric disease or disorder is schizophrenia. 7. The method of clause 6, wherein said method results in a reduced risk of relapse in a subject with schizophrenia compared to placebo. 8. The method of clause 7, wherein said risk of recurrence is reduced by at least 50%. 9. The method according to clause 7, wherein the risk of recurrence is reduced by 60 to 80%. 10. The method of clause 6, wherein said method results in a reduced relapse rate in a subject with schizophrenia compared to placebo. 11. The method of clause 6, wherein said method extends the time to relapse in a subject with schizophrenia compared to placebo. 12. The method of clause 11, wherein the time to relapse is prolonged by at least 2-fold in a subject with schizophrenia compared to placebo. 13. The method of claim 11, wherein the time to relapse is extended by at least 2.5 to 5 fold in a subject with schizophrenia compared to placebo. 14. A method of switching a subject from daily oral risperidone therapy to long-acting injectable risperidone therapy, comprising: i. orally administering a final dose of said daily oral risperidone therapy (after which no further oral risperidone therapy is administered); and ii. The next day, the subject (a) risperidone or a pharma- ceutical acceptable salt thereof having a concentration of about 250 to 400 mg / mL in terms of risperidone; Formula (b): 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 50, and z is the number of units in the range of 7 to 327). A biodegradable diblock copolymer having the formula: and wherein the ratio of the (b) biodegradable triblock copolymer to the (c) biodegradable diblock copolymer 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; administering a long-acting injectable risperidone formulation subcutaneously; thereby switching the subject from daily oral risperidone therapy to long-acting injectable risperidone therapy. The method comprising: 15. The method of clause 14, wherein said long-acting injectable risperidone therapy comprises monthly administration of said long-acting injectable risperidone formulation. 16. The method of clause 14, wherein said long-acting injectable risperidone therapy comprises administration of said long-acting injectable risperidone formulation once every other month (i.e., once every two months). 17. The method of clause 15, wherein said long-acting injectable risperidone formulation comprises from about 50 mg to about 125 mg of risperidone. 18. The method of clause 16, wherein said long-acting injectable risperidone formulation comprises from about 100 mg to about 250 mg of risperidone. 19. A method of switching a subject from monthly long-acting injectable risperidone therapy to bimonthly (i.e., once every two months) long-acting injectable risperidone therapy without the need for adjunctive oral risperidone therapy, comprising: i. administering subcutaneously the final dose of said monthly long-acting injectable risperidone therapy; and ii. one month later, administering subcutaneously a long-acting injectable risperidone regimen once every other month (i.e., once every two months); Contains: wherein said monthly and bimonthly (i.e., once every two months) long-acting injectable risperidone therapy is (a) risperidone or a pharma- ceutical acceptable salt thereof having a concentration of about 250 to 400 mg / mL in terms of risperidone; (b) biodegradable triblock copolymers having the formula: poly(lactic acid)v-poly(ethylene glycol)w-poly(lactic acid)x, where 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) biodegradable diblock copolymers having the formula: methoxypoly(ethylene glycol)y-poly(lactic acid)z, where y and z are the numbers of repeating units, where y is the number of repeating units in the range of 3 to 50 and z is the number of units in the range of 7 to 327; and wherein the ratio of the (b) biodegradable triblock copolymer to the (c) biodegradable diblock copolymer 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; and wherein the method is performed without administering adjunctive oral risperidone therapy to the subject. The method. 20. A method of switching a subject from bimonthly (i.e., once every two months) long-acting injectable risperidone therapy to monthly long-acting injectable risperidone therapy without the need for adjunctive oral risperidone therapy, comprising: i. administering subcutaneously the final dose of said bimonthly (i.e., once every two months) long-acting injectable risperidone therapy; and ii. After 2 months, administer subcutaneously a long-acting injectable risperidone regimen once per month; Contains: wherein said monthly and bimonthly (i.e., once every two months) long-acting injectable risperidone therapy is (a) risperidone or a pharma- ceutical acceptable salt thereof having a concentration of about 250 to 400 mg / mL in terms of risperidone; (b) biodegradable triblock copolymers having the formula: poly(lactic acid)v-poly(ethylene glycol)w-poly(lactic acid)x, where 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) biodegradable diblock copolymers having the formula: methoxypoly(ethylene glycol)y-poly(lactic acid)z, where y and z are the numbers of repeating units, where y is the number of repeating units in the range of 3 to 50 and z is the number of units in the range of 7 to 327; and wherein the ratio of the (b) biodegradable triblock copolymer to the (c) biodegradable diblock copolymer 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; and wherein the method is performed without administering adjunctive oral risperidone therapy to the subject. The method. 21. A method of changing the risperidone dose administered to a subject receiving monthly or bimonthly (i.e., once every two months) long-acting injectable risperidone therapy from a first dose of a long-acting injectable risperidone formulation to a subsequent dose of a long-acting injectable risperidone formulation without the need for adjunctive oral risperidone therapy, comprising: i. administering a final dose of said initial dose of a long-acting injectable risperidone formulation subcutaneously; and ii. administering the subsequent dose of a long-acting injectable risperidone formulation subcutaneously at the next dose; Contains: wherein the initial dose and the subsequent doses of a long-acting injectable risperidone formulation are (a) risperidone or a pharma- ceutical acceptable salt thereof having a concentration of about 250 to 400 mg / mL in terms of risperidone; Formula (b): 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. 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 50, and z is the number of units in the range of 7 to 327). A biodegradable diblock copolymer having the formula: and wherein the ratio of the (b) biodegradable triblock copolymer to the (c) biodegradable diblock copolymer 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; and wherein the method is performed without administering to the patient any adjunctive oral risperidone therapy. The method. 22. The method of clause 21, wherein said first dose of a long-acting injectable risperidone formulation comprises a higher dose of risperidone than said subsequent dose of a long-acting injectable risperidone formulation. 23. The method of clause 21, wherein said first dose of a long-acting injectable risperidone formulation comprises a lower dose of risperidone than said subsequent doses of a long-acting injectable risperidone formulation. 24. The method of any one of clauses 21-23, wherein said subsequent dose of a long-acting injectable risperidone formulation is administered one month after administration of said initial dose of a long-acting injectable risperidone formulation. 25. The method of any one of clauses 21-23, wherein said subsequent dose of a long-acting injectable risperidone formulation is administered two months after administration of said initial dose of a long-acting injectable risperidone formulation. 26. The method of any one of clauses 1-25, wherein said subcutaneous administration is to the upper arm of said subject or to the abdomen of said subject. 27. The method of clause 26, wherein said subcutaneous administration is to the upper arm of said subject. 28. The method of clause 26, wherein said subcutaneous administration is to the abdomen of said subject. 29. The method of any one of clauses 1-28, wherein said long-acting injectable risperidone formulation is administered from a pre-filled syringe fitted with a needle having a gauge of 21 or greater and / or a length of 5 / 8 inch or less. 30. A method of administering risperidone to a subject receiving long-acting injectable risperidone therapy, wherein the subject has a history of missing a dose of the long-acting injectable risperidone formulation, comprising subcutaneously administering a dose of the long-acting injectable risperidone formulation once a month or once every other month (i.e., once every two months); wherein the long-acting injectable risperidone therapy is (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 where v and x are numbers of repeating units ranging from 24 to 682, and w is a number of repeating units ranging from 4 to 273, and v=x or v≠x; (c) Formula: Methoxy-poly(ethylene glycol) y -Poly(lactic acid) zwhere y and z are the number of repeating units, where y is the number of repeating units in the range of 3 to 50, and z is the number of units in the range of 7 to 327; and wherein the ratio of the (b) biodegradable triblock copolymer to the (c) biodegradable diblock copolymer 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; and wherein the method is performed without administering to the patient any adjunctive oral risperidone therapy. The method. 31. The method according to any one of clauses 1 to 30, wherein subcutaneous administration of said long-acting injectable risperidone formulation results in a decrease in the PANSS total score after stabilization. 32. The method according to any one of clauses 1 to 31, wherein subcutaneous administration of said long-acting injectable risperidone formulation results in a single absorption peak. 33. A prefilled syringe (PFS) for subcutaneous administration of a long-acting injectable risperidone formulation, i. A long-acting injectable risperidone formulation, wherein the formulation is (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 where v and x are numbers of repeating units ranging from 24 to 682, and w is a number of repeating units ranging from 4 to 273, and v=x or v≠x; (c) Formula: Methoxy-poly(ethylene glycol) y -Poly(lactic acid) z where y and z are the number of repeating units, where y is the number of repeating units in the range of 3 to 50, and z is the number of units in the range of 7 to 327; and wherein the ratio of (b) the biodegradable triblock copolymer to (c) the biodegradable diblock copolymer 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; ii. Needles having a gauge of 21 or greater and / or a length of 5 / 8 inch or less; The prefilled syringe comprising: 34. The prefilled syringe according to clause 33, wherein said long-acting injectable risperidone formulation is stable at room temperature for at least 30 days. 35. The prefilled syringe of clause 33 or clause 34, wherein said long-acting injectable risperidone formulation is stable at 2°-8° C. for at least 36 months. 36. i. A long-acting injectable risperidone formulation, wherein the formulation is 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 where v and x are numbers of repeating units ranging from 24 to 682, and w is a number of repeating units ranging from 4 to 273, and v=x or v≠x; c) Formula: Methoxy-poly(ethylene glycol) y -Poly(lactic acid) z wherein y and z are numbers of repeating units, where y is the number of repeating units in the range of 3 to 50, and z is the number of 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 formulation that is insoluble in an aqueous environment. Prefilled syringes containing ii. Needles having a gauge of 21 or greater and / or a length of 5 / 8 inch or less; and iii. Instructions for use Kit including: 37. The method of any one of clauses 1 to 32, the pre-filled syringe of any one of clauses 33 to 35, or the kit of clause 36, wherein said long-acting injectable risperidone formulation comprises 10% (w / w) of triblock copolymer and 15% (w / w) of diblock copolymer by total weight percentage of the formulation. 38. The method, pre-filled syringe, or kit of clause 37, wherein said long-acting injectable risperidone formulation comprises 45% DMSO by total weight percentage of the formulation. 39. The method, pre-filled syringe, or kit of clause 37 or clause 38, wherein said long-acting injectable risperidone formulation comprises 360 mg / mL of risperidone base by weight percentage of the formulation.

Claims

1. 1. A long-acting injectable risperidone formulation for switching a subject from daily oral risperidone therapy to a long-acting injectable risperidone formulation, the long-acting injectable risperidone formulation comprising: (a) risperidone or a pharma- ceutical acceptable salt thereof at a concentration of about 250 to 400 mg / mL in terms of risperidone; Formula (b): Poly(lactic acid) v -Poly(ethylene glycol) w -Poly(lactic acid) x (wherein v and x are the number of repeat units ranging from 24 to 682, and w is the number of repeat units ranging from 4 to 273, and v=x or v≠x). A biodegradable triblock copolymer having the formula: Formula (c): Methoxy-poly(ethylene glycol) y -Poly(lactic acid) z where y and z are the number of repeat units, where y is the number of repeat units ranging from 3 to 50, and z is the number of units ranging from 7 to 327. A biodegradable diblock copolymer having the formula: and wherein the ratio of (b) the biodegradable triblock copolymer to (c) the biodegradable diblock copolymer 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; i. the last dose of said daily oral risperidone therapy is orally administered, and thereafter no further oral risperidone therapy is administered; and ii. the next day, the long-acting injectable risperidone formulation is administered subcutaneously to the subject; whereby the subject is switched from daily oral risperidone therapy to said long-acting injectable risperidone formulation.

2. 1. A long-acting injectable risperidone formulation for switching a subject from a long-acting injectable antipsychotic to a long-acting injectable risperidone formulation without the need for adjunctive oral risperidone therapy, the long-acting injectable risperidone formulation comprising: a. Risperidone or a pharma- ceutical 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 where v and x are numbers of repeating units ranging from 24 to 682, and w is a number of repeating units ranging from 4 to 273, and v=x or v≠x; c.Formula: Methoxy-poly(ethylene glycol) y -Poly(lactic acid) z where y and z are the number of repeating units, where y is the number of repeating units ranging from 3 to 50, and z is the number of units ranging from 7 to 327; Contains : and wherein the ratio of (b) the biodegradable triblock copolymer to (c) the biodegradable diblock copolymer 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; i. a final dose of the long-acting injectable antipsychotic is administered; and ii. At the next dose, the long-acting injectable risperidone formulation is administered subcutaneously; and wherein said long-acting injectable risperidone formulation, wherein no adjunctive oral risperidone therapy is administered to said subject.

3. said long-acting injectable risperidone formulation is administered once a month; and / or the long-acting injectable risperidone formulation comprises about 50 mg to about 125 mg of risperidone in a volume of about 0.1 mL to about 0.5 mL; or the long-acting injectable risperidone formulation is administered once every two months; and / or 3. The long-acting injectable risperidone formulation of claim 1 or 2, wherein the long-acting injectable risperidone formulation comprises about 100 mg to about 250 mg of risperidone in a volume of about 0.2 mL to about 1.0 mL.

4. the long-acting injectable antipsychotic is a long-acting injectable intramuscular product or a long-acting injectable subcutaneous product; and / or 4. The long-acting injectable risperidone formulation of claim 2 or 3, wherein the long-acting injectable antipsychotic comprises risperidone, 9-OH-risperidone, or aripiprazole.

5. 1. A long-acting injectable risperidone formulation for switching a subject from a once-monthly long-acting injectable risperidone formulation to a once-every-other-month (i.e., once every two months) long-acting injectable risperidone formulation without the need for adjunctive oral risperidone therapy, wherein each of the monthly and bimonthly long-acting injectable risperidone formulations is (a) risperidone or a pharma- ceutical acceptable salt thereof at a concentration of about 250 to 400 mg / mL in terms of risperidone; Formula (b): Poly(lactic acid) v -Poly(ethylene glycol) w -Poly(lactic acid) x where v and x are numbers of repeating units ranging from 24 to 682, and w is a number of repeating units ranging from 4 to 273, and v=x or v≠x; Formula (c): Methoxy-poly(ethylene glycol) y -Poly(lactic acid) z where y and z are the number of repeating units, where y is the number of repeating units ranging from 3 to 50, and z is the number of units ranging from 7 to 327; and wherein the ratio of (b) the biodegradable triblock copolymer to (c) the biodegradable diblock copolymer 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 i. the final dose of said monthly long-acting injectable risperidone formulation is administered subcutaneously; and ii. one month later, said bimonthly (i.e., once every two months) administration of a long-acting injectable risperidone formulation is administered subcutaneously; and wherein said long-acting injectable risperidone formulation, wherein no adjunctive oral risperidone therapy is administered to said subject.

6. 1. A long-acting injectable risperidone formulation for switching a subject from a once every other month (i.e., once every two months) long-acting injectable risperidone formulation to a once monthly long-acting injectable risperidone formulation without the need for adjunctive oral risperidone therapy, wherein the monthly and bimonthly long-acting injectable risperidone formulations are (a) risperidone or a pharma- ceutical acceptable salt thereof at a concentration of about 250 to 400 mg / mL in terms of risperidone; Formula (b): Poly(lactic acid) v -Poly(ethylene glycol) w -Poly(lactic acid) x where v and x are numbers of repeating units ranging from 24 to 682, and w is a number of repeating units ranging from 4 to 273, and v=x or v≠x; Formula (c): Methoxypoly(ethylene glycol) y -Poly(lactic acid) z where y and z are the number of repeating units, where y is the number of repeating units ranging from 3 to 50, and z is the number of units ranging from 7 to 327; and wherein the ratio of (b) the biodegradable triblock copolymer to (c) the biodegradable diblock copolymer 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 i. the final dose of said bimonthly (i.e., once every two months) long-acting injectable risperidone formulation is administered subcutaneously; and ii. After 2 months, a long-acting injectable risperidone formulation is administered subcutaneously once per month; and The long-acting injectable risperidone formulation, wherein no adjunctive oral risperidone therapy is administered to the subject.

7. 1. A long-acting injectable risperidone formulation for switching risperidone dosage from a first dose of the long-acting injectable risperidone formulation to a subsequent dose of the long-acting injectable risperidone formulation, the long-acting injectable risperidone formulation being administered to a subject once a month or once every other month without the need for adjunctive oral risperidone therapy, wherein the initial dose and the subsequent doses of a long-acting injectable risperidone formulation are (a) risperidone or a pharma- ceutical acceptable salt thereof at a concentration of about 250 to 400 mg / mL in terms of risperidone; Formula (b): Poly(lactic acid) v -Poly(ethylene glycol) w -Poly(lactic acid) x (wherein v and x are the number of repeat units ranging from 24 to 682, and w is the number of repeat units ranging from 4 to 273, and v=x or v≠x). A biodegradable triblock copolymer having the formula: Formula (c): Methoxy-poly(ethylene glycol) y -Poly(lactic acid) z where y and z are the number of repeat units, where y is the number of repeat units ranging from 3 to 50, and z is the number of units ranging from 7 to 327. a biodegradable diblock copolymer having the formula: wherein the ratio of (b) the biodegradable triblock copolymer to (c) the biodegradable diblock copolymer 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 i. the final administration of said initial dose of a long-acting injectable risperidone formulation is administered subcutaneously; and ii. at the next dose, the subsequent dose of a long-acting injectable risperidone formulation is administered subcutaneously; and wherein said long-acting injectable risperidone formulation, wherein adjunctive oral risperidone therapy is not administered to said patient.

8. said first dose of a long-acting injectable risperidone formulation comprises a higher dose of risperidone than said subsequent doses of a long-acting injectable risperidone formulation; or 8. The long-acting injectable risperidone formulation of claim 7, wherein said first dose of the long-acting injectable risperidone formulation comprises a lower dose of risperidone than said subsequent doses of the long-acting injectable risperidone formulation.

9. said subsequent dose of a long-acting injectable risperidone formulation is administered one month after administration of said initial dose of a long-acting injectable risperidone formulation; or 9. The long-acting injectable risperidone formulation of claim 7 or 8, wherein the subsequent dose of the long-acting injectable risperidone formulation is administered two months after administration of the initial dose of the long-acting injectable risperidone formulation.

10. 10. The long-acting injectable risperidone formulation of any one of claims 1 to 9, wherein said subcutaneous administration is to the upper arm of the subject, optionally to the back of the upper arm of the subject or to the abdomen of the subject.

11. 1. A long-acting injectable risperidone formulation for treating a subject receiving long-acting injectable risperidone therapy, wherein the subject has missed a dose of the long-acting injectable risperidone formulation, comprising: wherein the long-acting injectable risperidone formulation is (a) risperidone or a pharma- ceutical acceptable salt thereof at a concentration of about 250 to 400 mg / mL in terms of risperidone; Formula (b): Poly(lactic acid) v -Poly(ethylene glycol) w -Poly(lactic acid) x where v and x are numbers of repeating units ranging from 24 to 682, and w is a number of repeating units ranging from 4 to 273, and v=x or v≠x; Formula (c): Methoxy-poly(ethylene glycol) y -Poly(lactic acid) z where y and z are the number of repeating units, where y is the number of repeating units ranging from 3 to 50, and z is the number of units ranging from 7 to 327; and wherein the ratio of the (b) biodegradable triblock copolymer to the (c) biodegradable diblock copolymer 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 wherein a monthly or bimonthly dose of a long-acting injectable risperidone formulation is subcutaneously administered to the subject; and wherein said long-acting injectable risperidone formulation, wherein no adjunctive oral risperidone therapy is administered to said subject.

12. 12. The long-acting injectable risperidone formulation of any one of claims 5-11, wherein said monthly long-acting injectable risperidone formulation comprises from about 50 mg to about 125 mg of risperidone and said bimonthly long-acting injectable risperidone formulation comprises from about 100 mg to about 250 mg of risperidone.

13. 13. The long-acting injectable risperidone formulation of any one of claims 1 to 12, wherein the long-acting injectable risperidone formulation is administered from a syringe fitted with a needle having a gauge of 21 or greater and / or a length of 5 / 8 inch or less, preferably the syringe is a pre-filled syringe.

14. the subject is suffering from a psychiatric disorder selected from schizophrenia, bipolar disorder, and autism associated irritability (IAA); or the subject suffers from schizophrenia; and / or 14. The long-acting injectable risperidone formulation of any one of claims 1 to 13, wherein subcutaneous administration of said long-acting injectable risperidone formulation results in a decrease in the PANSS total score after stabilization.

15. the subject is an adult between 18 and 65 years of age or an adolescent between 13 and 17 years of age; and / or The long-acting injectable risperidone formulation of any one of claims 1 to 14, wherein subcutaneous administration of said long-acting injectable risperidone formulation results in an average exposure of TAM (AUC0-tau) equivalent to that of oral risperidone (2 mg / day to 5 mg / day) administered over a comparable dosing period.

16. A pre-filled syringe (PFS) for subcutaneous administration of a long-acting injectable risperidone formulation, comprising: The long-acting injectable risperidone formulation, wherein the formulation comprises: (a) risperidone or a pharma- ceutical acceptable salt thereof at a concentration of about 250 to 400 mg / mL in terms of risperidone; Formula (b): Poly(lactic acid) v -Poly(ethylene glycol) w -Poly(lactic acid) x where v and x are numbers of repeating units ranging from 24 to 682, and w is a number of repeating units ranging from 4 to 273, and v=x or v≠x; Formula (c): Methoxy-poly(ethylene glycol) y -Poly(lactic acid) z where y and z are the number of repeating units, where y is the number of repeating units ranging from 3 to 50, and z is the number of units ranging from 7 to 327; and wherein the ratio of (b) the biodegradable triblock copolymer to (c) the biodegradable diblock copolymer 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 Needles with a gauge of 21 or greater and / or a length of 5 / 8 inch or less The prefilled syringe comprising:

17. the long-acting injectable risperidone formulation is stable at 2°-8° C. for at least 12 months, or at least 24 months, or at least 36 months; and / or the long-acting injectable risperidone formulation is stable at 20-25° C. for at least 30 days, at least 60 days, or at least 90 days; and / or the long-acting injectable risperidone formulation is stable at 25° C. and 60% relative humidity (RH) for at least 3 months or at least 6 months; and / or the long-acting injectable risperidone formulation is stable upon storage at -20°C for a first period of time and storage at 25°C and 60% relative humidity for a second period of time, thawing, and optionally repeating -20°C and thawing twice, wherein the first period of time is at least 2 days and the second period of time is at least 2 days; and / or 17. The pre-filled syringe of claim 16, wherein the long-acting injectable risperidone formulation is stable when stored at -20°C for a first period of time and thereafter at 5°C for a second period of time, wherein the first period of time is at least 2 weeks and the second period of time is up to 2 weeks.

18. A prefilled syringe according to claim 16 or 17; Needles having a gauge of 21 or greater and / or a length of 5 / 8 inch or less; and, optionally, User manual Kit including:

19. and / or further comprising a means for physically protecting said prefilled syringe; 20. The kit of claim 18, wherein the long-acting injectable risperidone formulation is photostable for up to 36 months.

20. the long-acting injectable risperidone formulation comprises 10% (w / w%) of a triblock copolymer and 15% (w / w%) of a diblock copolymer by total weight percentage of the formulation; and / or the long-acting injectable risperidone formulation further comprises DMSO; and / or 20. The long-acting injectable risperidone formulation of any one of claims 1 to 15, the pre-filled syringe of claim 16 or 17, or the kit of claim 18 or 19, wherein the long-acting injectable risperidone formulation comprises 360 mg / mL of risperidone base.

21. a subcutaneous administration of the long-acting injectable risperidone formulation into the upper arm followed by a subcutaneous administration of the long-acting injectable risperidone formulation into the abdomen at the next dose; or The long-acting injectable risperidone formulation is administered subcutaneously to the abdomen, followed by subcutaneous administration of the long-acting injectable risperidone formulation to the upper arm at the next dose.

21. The long-acting injectable risperidone formulation of any one of claims 1 to 15 or 20.

22. 1. A long-acting injectable risperidone formulation for treating a psychiatric disease or disorder in a subject, comprising: (a) risperidone or a pharma- ceutical acceptable salt thereof at a concentration of about 250 to 400 mg / mL in terms of risperidone; Formula (b): Poly(lactic acid) v -Poly(ethylene glycol) w -Poly(lactic acid) x (wherein v and x are the number of repeat units ranging from 24 to 682, and w is the number of repeat units ranging from 4 to 273, and v=x or v≠x). A biodegradable triblock copolymer having the formula: Formula (c): Methoxy-poly(ethylene glycol) y -Poly(lactic acid) z where y and z are the number of repeat units, where y is the number of repeat units ranging from 3 to 50, and z is the number of units ranging from 7 to 327. A biodegradable diblock copolymer having the formula: Contains : and wherein the ratio of (b) the biodegradable triblock copolymer to (c) the biodegradable diblock copolymer 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; wherein 1 mL or less of a long-acting injectable risperidone formulation is administered subcutaneously to the subject no more frequently than once every 28 days; and wherein the long-acting injectable risperidone formulation provides a therapeutically effective amount of risperidone for at least 28 days.

23. 23. The long-acting injectable risperidone formulation of claim 22, wherein the formulation is administered subcutaneously once a month, and wherein the formulation provides a therapeutically effective amount of risperidone for at least one month.

24. 23. The long-acting injectable risperidone formulation of claim 22, wherein the formulation is administered subcutaneously once every other month, and wherein the formulation provides a therapeutically effective amount of risperidone for at least two months.

25. 25. The long-acting injectable risperidone formulation of any one of claims 22 to 24, wherein the subject does not receive a loading dose of risperidone.

26. 26. The long-acting injectable risperidone formulation of any one of claims 22, 23, or 25, wherein the formulation comprises about 50 mg to about 125 mg of risperidone.

27. 26. The long-acting injectable risperidone formulation of any one of claims 22, 24, or 25, wherein the formulation comprises about 100 mg to about 250 mg of risperidone.

28. the psychiatric disease or disorder is schizophrenia; and / or said use results in a reduced risk of relapse in a subject with schizophrenia compared to placebo; and / or the risk of recurrence is reduced by at least 50% or at least 60-80%; and / or said use results in a reduced relapse rate in subjects with schizophrenia compared to placebo; and / or said use extends the time to relapse compared to placebo in a subject with schizophrenia; and / or the time to relapse is prolonged by at least 2-fold or 2.5-5-fold compared to placebo in subjects with schizophrenia; and / or the subject has an increased likelihood of remaining stable, wherein the increased likelihood is greater than 80% compared to a subject receiving a placebo; and / or the stability is maintained for at least six months; and / or the subject exhibits improvement after plateauing as assessed by the PANSS scale compared to subjects receiving a placebo; and / or 28. The long-acting injectable risperidone formulation of any one of claims 22 to 27, wherein said stable improvement is maintained for at least 12 months.

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