Depot system containing cariprazine or its salt

Abstract

The present invention provides a long-acting parenteral pharmaceutical composition comprising a therapeutically effective amount of cariprazine or a salt thereof in a depot form suitable for administration to a medically acceptable location in a subject in need thereof. The depot composition is preferably in the form of an in situ implant suitable for subcutaneous or intramuscular administration and provides sustained release of the cariprazine active ingredient and / or its metabolites desmethyl cariprazine (DCAR) and didesmethyl cariprazine (DDCAR) for at least four weeks after a single administration. The present invention further provides methods of using the depot composition for the treatment of schizophrenia, major depressive disorder, and bipolar disorder.

Description

[Technical field]

[0001] The present invention relates to parenteral long-acting dosage forms of cariprazine or a pharmacologically active salt thereof, such as depot systems, that provide sustained release of cariprazine for the treatment of schizophrenia, major depressive disorder, and bipolar disorder. [Background technology]

[0002] Cariprazine hydrochloride (VRAYLAR®) is an atypical antipsychotic drug. Its chemical name is trans-N-{4-[2-[4-(2,3-dichlorophenyl)piperazin-1-yl]ethyl]cyclohexyl}-N',N'-dimethylurea hydrochloride and its chemical structure is represented by the following formula:

[0003] [ka]

[0004] Cariprazine is indicated for the treatment of (1) schizophrenia in adults, (2) acute treatment of manic or mixed episodes associated with bipolar I disorder in adults, and (3) treatment of depressive episodes (bipolar depression) associated with bipolar I disorder in adults. The mechanism of action of cariprazine in the treatment of schizophrenia and bipolar I disorder is unclear. However, it is believed that the efficacy of cariprazine may be mediated by a combination of partial agonist activity at central dopamine D2 and serotonin 5-HT1A receptors and antagonist activity at serotonin 5-HT2A receptors. Cariprazine forms two major metabolites, desmethyl cariprazine (DCAR) and didesmethyl cariprazine (DDCAR), which have similar in vitro receptor binding properties as the parent drug.

[0005] Cariprazine is administered orally in capsules once daily with or without food. Like most lipophilic antipsychotics, it undergoes extensive hepatic metabolism by cytochrome P450 (CYP), primarily 3A4, with the formation of active metabolites. However, the compound - particularly its active didesmethyl metabolite - is eliminated very slowly, with elimination half-lives in schizophrenia patients ranging from 2-5 days for cariprazine to 2-3 weeks for didesmethylcariprazine.

[0006] Oral administration of cariprazine is well known to be associated with serious and potentially fatal side effects including an increased risk of death in elderly people, especially those with dementia-related psychosis, an increased risk of suicidal thoughts or behavior in children and young adults, stroke, Neuroleptic Malignant Syndrome (NMS), episodic dyskinesia, metabolic problems such as hyperglycemia and diabetes, low white blood cells, low blood pressure, falls, seizures and difficulties regulating body temperature.

[0007] Slow-release compositions that lower the exposure and reduce the side effect profile of cariprazine and its metabolites are desirable, however, no long-acting dosage forms of cariprazine are commercially available.

[0008] PCT International Publication No. WO2018 / 015915 discloses a parenteral sustained release composition comprising an atypical antipsychotic, in particular lurasidone, and one or more rate-controlling polymers in the form of an in situ gelling composition which upon in vivo administration contacts body fluids to form a depot, thereby providing a sustained release of the active agent.

[0009] Chinese patent application CN108261394 discloses a cariprazine hydrochloride injection formulation in the form of an aqueous suspension, which includes a stabilizer, a suspending agent, a buffer, and a pH adjusting agent. The particle size distribution and injection dose are controlled to achieve a long-acting effect, and cariprazine hydrochloride is continuously released for at least one week after the formulation is injected.

[0010] PCT International Publication No. WO2018 / 229641 discloses oral pharmaceutical compositions and methods for controlled release delivery of cariprazine for sub-daily dosing.

[0011] U.S. Patent Application Publication No. 2021 / 0177768 discloses a pharmaceutical composition comprising a therapeutically effective amount of an active agent selected from cariprazine, a salt thereof, or a derivative thereof, including its derivative salt form, a biodegradable and biocompatible polymer comprising a polymeric matrix material, and a non-ionic water soluble colloid, wherein the active agent is ionically complexed with the biodegradable and biocompatible polymer or the active agent is dispersed in the matrix material, and the composition is in the form of microparticles, microspheres, nanoparticles, or combinations thereof.

[0012] There is an unmet need for long-acting cariprazine dosage forms, especially for patients who suffer from the side effects of oral cariprazine. Summary of the Invention

[0013] The present invention provides a long-acting parenteral pharmaceutical composition comprising a therapeutically effective amount of cariprazine or a pharma- ceutically acceptable salt thereof, particularly cariprazine hydrochloride. In some embodiments, the present invention provides a long-acting pharmaceutical composition comprising a therapeutically effective amount of cariprazine or a pharma- ceutically acceptable salt thereof in a depot form suitable for parenteral administration at a medically acceptable location in a subject in need thereof. The present invention further provides a method for treating schizophrenia, major depressive disorder, and bipolar disorder, particularly manic or mixed episodes associated with bipolar I disorder, or depressive episodes associated with bipolar I disorder (bipolar depression), by parenterally administering a composition comprising a therapeutically effective amount of cariprazine or a salt thereof to a subject in need thereof.

[0014] The present invention is based in part on the unexpected discovery that long-acting cariprazine formulations, such as in situ implants, provide metronomic treatment with a continuous flow of low doses of cariprazine over an extended period of time, and therefore provide a dramatically improved side effect profile. Surprisingly, it has now been discovered that long-acting pharmaceutical compositions according to the principles of the present invention provide superior therapeutic efficacy with a reduced incidence and / or reduced severity of side effects at a systemic level, as compared to conventional oral immediate release cariprazine formulations.

[0015] According to a first aspect, the present invention provides a long-acting parenteral pharmaceutical composition suitable for forming an in situ implant in a subject in need thereof following administration, the composition comprising a therapeutically effective amount of cariprazine or a pharma- ceutically acceptable salt thereof, a pharma- ceutically acceptable biodegradable carrier comprising poly(lactic-co-glycolic acid) (PLGA) having a molar ratio of lactic acid monomers to glycolic acid monomers of from 50:50 to 85:15 and an intrinsic viscosity in the range of about 0.1 to about 0.8 dl / g, and a biocompatible solvent, wherein the composition releases cariprazine or a pharma- ceutically acceptable salt thereof for at least four weeks following a single administration.

[0016] According to one embodiment, the pharmaceutical composition is in the form of a solution. According to another embodiment, the pharmaceutical composition is in the form of a suspension.

[0017] According to some embodiments, the pharmaceutical composition comprises cariprazine hydrochloride (cariprazine hydrochloride, Cariprazine HCl) as an active ingredient. According to other embodiments, the long-acting composition comprises a dose of about 1 to about 500 mg of cariprazine or a salt thereof (e.g., cariprazine hydrochloride) per injection, inclusive of each value within the range specified. According to other embodiments, the long-acting composition comprises a dose of about 1 to about 100 mg of cariprazine or a salt thereof (e.g., cariprazine hydrochloride) per injection, inclusive of each value within the range specified. According to still other embodiments, the long-acting composition releases a daily dose of about 1 to about 10 mg of cariprazine or a salt thereof (e.g., cariprazine hydrochloride), inclusive of each value within the range specified.

[0018] According to some embodiments, the long-acting composition comprises from about 0.5% to about 20% cariprazine or a salt thereof (e.g., cariprazine hydrochloride) per injection, inclusive of each value within the range specified. According to other embodiments, the long-acting composition comprises from about 1% to about 10% cariprazine or a salt thereof (e.g., cariprazine hydrochloride) per injection, inclusive of each value within the range specified. According to still other embodiments, the long-acting composition comprises from about 1% to about 5% cariprazine or a salt thereof (e.g., cariprazine hydrochloride) per injection, inclusive of each value within the range specified.

[0019] According to some embodiments, the long-acting composition comprises about 10 to about 80 mg / mL of cariprazine or a salt thereof (e.g., cariprazine hydrochloride) per injection, inclusive of each value within the range specified. According to other embodiments, the long-acting composition comprises about 20 to about 60 mg / mL of cariprazine or a salt thereof (e.g., cariprazine hydrochloride) per injection, inclusive of each value within the range specified. According to still other embodiments, the long-acting composition comprises about 20 to about 50 mg / mL of cariprazine or a salt thereof (e.g., cariprazine hydrochloride) per injection, inclusive of each value within the range specified.

[0020] According to some embodiments, the composition is administered about once a month to about once every three months, or any frequency therebetween.

[0021] According to other embodiments, the composition provides an extended sustained release of the cariprazine active ingredient for a period of at least about 1 month to about 3 months, or any period therebetween.

[0022] According to certain embodiments, the composition is administered by intramuscular injection.

[0023] According to some embodiments, the carrier is poly(lactic-co-glycolic acid) (PLGA) comprising lactic acid and glycolic acid end groups. According to some embodiments, the carrier is poly(lactic-co-glycolic acid) (PLGA) comprising lactic acid ester end groups and glycolic acid ester end groups.

[0024] According to some embodiments, the poly(lactic-co-glycolic acid) (PLGA) contains a molar ratio of lactic acid monomers to glycolic acid monomers of 50:50. According to some embodiments, the poly(lactic-co-glycolic acid) (PLGA) contains a molar ratio of lactic acid monomers to glycolic acid monomers of 75:25. According to some embodiments, the poly(lactic-co-glycolic acid) (PLGA) contains a molar ratio of lactic acid monomers to glycolic acid monomers of 85:15.

[0025] According to some embodiments, the poly(lactic-co-glycolic acid) (PLGA) has an intrinsic viscosity in the range of about 0.2 to about 0.7 dl / g, inclusive of each value within the specified range. According to some embodiments, the poly(lactic-co-glycolic acid) (PLGA) has an intrinsic viscosity in the range of about 0.3 to about 0.7 dl / g, inclusive of each value within the specified range. According to some embodiments, the poly(lactic-co-glycolic acid) (PLGA) has an intrinsic viscosity in the range of about 0.4 to about 0.6 dl / g, inclusive of each value within the specified range.

[0026] According to some embodiments, the composition comprises a single PLGA polymer. According to other embodiments, the composition comprises a combination of two or more PLGA polymers having different intrinsic viscosities. According to still other embodiments, the composition comprises a combination of two PLGA polymers having different intrinsic viscosities. According to further embodiments, the ratio between the PLGA polymer having the higher intrinsic viscosity and the PLGA polymer having the lower intrinsic viscosity ranges from 2:1 to 1:1. According to further embodiments, the combination of PLGA polymers has an intrinsic viscosity ranging from about 0.4 to about 0.6 dl / g, including each value within the specified range.

[0027] According to some embodiments, the ratio of cariprazine or a pharma- ceutically acceptable salt thereof to PLGA polymer is from about 1:1 to about 1:100, preferably from about 1:5 to about 1:25, including each value within the specified range.

[0028] According to some embodiments, the biocompatible solvent is selected from the group consisting of benzyl alcohol, methyl benzoate, ethyl benzoate, n-propyl benzoate, isopropyl benzoate, butyl benzoate, isobutyl benzoate, tert-butyl benzoate, and benzyl benzoate. Each possibility represents a separate embodiment. According to one embodiment, the biocompatible solvent is benzyl alcohol.

[0029] According to further embodiments, the compositions of the present invention further comprise one or more pharma- ceutically acceptable excipients selected from the group consisting of preservatives, sustained release agents, buffers, pH adjusters, and any combination thereof. Each possibility represents a separate embodiment. According to one embodiment, the sustained release agent is a bile salt selected from the group consisting of sodium glycocholate, sodium deoxycholate, sodium taurocholate, sodium fusidate, sodium glycodeoxycholate, and sodium taurodihydrofusidate. Each possibility represents a separate embodiment. According to another embodiment, the sustained release agent is selected from the group consisting of triethyl citrate, triacetin, and lecithin. Each possibility represents a separate embodiment. According to yet another embodiment, the pH adjuster comprises a carboxylic acid selected from the group consisting of benzoic acid, sorbic acid, fumaric acid, adipic acid, citric acid, succinic acid, glutaric acid, malic acid, malonic acid, tartaric acid, acetic acid, glycolic acid, propionic acid, lauric acid, caprylic acid, capric acid, and myristic acid. Each possibility represents a separate embodiment.

[0030] According to some embodiments, the composition provides a burst release of less than about 20% of cariprazine or a pharma- ceutically acceptable salt thereof in an aqueous medium containing 0.1% sodium lauryl sulfate as measured using a Type II dissolution apparatus. According to some embodiments, the composition provides a burst release of about 2% to about 19% of cariprazine or a pharma- ceutically acceptable salt thereof in an aqueous medium containing 0.1% sodium lauryl sulfate as measured using a Type II dissolution apparatus.

[0031] According to some embodiments, the composition releases less than 40% of the cariprazine or pharma- ceutically acceptable salt thereof within one week in an aqueous medium containing 0.1% sodium lauryl sulfate as measured using a dissolution apparatus type II. According to some embodiments, the composition releases less than 30% of the cariprazine or pharma- ceutically acceptable salt thereof within one week in an aqueous medium containing 0.1% sodium lauryl sulfate as measured using a dissolution apparatus type II. According to some embodiments, the composition releases less than 20% of the cariprazine or pharma- ceutically acceptable salt thereof within one week in an aqueous medium containing 0.1% sodium lauryl sulfate as measured using a dissolution apparatus type II. According to some embodiments, the composition releases about 8% to about 40% of the cariprazine or pharma- ceutically acceptable salt thereof within one week in an aqueous medium containing 0.1% sodium lauryl sulfate as measured using a dissolution apparatus type II.

[0032] According to some embodiments, the composition releases less than 55% of the cariprazine or pharma- ceutically acceptable salt thereof within 2 weeks in an aqueous medium containing 0.1% sodium lauryl sulfate as measured using a dissolution apparatus type II. According to some embodiments, the composition releases less than 45% of the cariprazine or pharma- ceutically acceptable salt thereof within 2 weeks in an aqueous medium containing 0.1% sodium lauryl sulfate as measured using a dissolution apparatus type II. According to some embodiments, the composition releases less than 35% of the cariprazine or pharma- ceutically acceptable salt thereof within 2 weeks in an aqueous medium containing 0.1% sodium lauryl sulfate as measured using a dissolution apparatus type II. According to some embodiments, the composition releases about 15% to about 53% of the cariprazine or pharma- ceutically acceptable salt thereof within 2 weeks in an aqueous medium containing 0.1% sodium lauryl sulfate as measured using a dissolution apparatus type II.

[0033] According to some embodiments, the composition releases less than 80% of the cariprazine or pharma- ceutically acceptable salt thereof within 3 weeks in an aqueous medium containing 0.1% sodium lauryl sulfate as measured using a dissolution apparatus type II. According to some embodiments, the composition releases less than 70% of the cariprazine or pharma- ceutically acceptable salt thereof within 3 weeks in an aqueous medium containing 0.1% sodium lauryl sulfate as measured using a dissolution apparatus type II. According to some embodiments, the composition releases less than 60% of the cariprazine or pharma- ceutically acceptable salt thereof within 3 weeks in an aqueous medium containing 0.1% sodium lauryl sulfate as measured using a dissolution apparatus type II. According to some embodiments, the composition releases about 36% to about 71% of the cariprazine or pharma- ceutically acceptable salt thereof within 3 weeks in an aqueous medium containing 0.1% sodium lauryl sulfate as measured using a dissolution apparatus type II.

[0034] According to some embodiments, the composition releases less than 90% of the cariprazine or pharma- ceutically acceptable salt thereof within 4 weeks in an aqueous medium containing 0.1% sodium lauryl sulfate as measured using a dissolution apparatus type II. According to some embodiments, the composition releases less than 80% of the cariprazine or pharma- ceutically acceptable salt thereof within 4 weeks in an aqueous medium containing 0.1% sodium lauryl sulfate as measured using a dissolution apparatus type II. According to some embodiments, the composition releases less than 70% of the cariprazine or pharma- ceutically acceptable salt thereof within 4 weeks in an aqueous medium containing 0.1% sodium lauryl sulfate as measured using a dissolution apparatus type II. According to some embodiments, the composition releases about 45% to about 86% of the cariprazine or pharma- ceutically acceptable salt thereof within 4 weeks in an aqueous medium containing 0.1% sodium lauryl sulfate as measured using a dissolution apparatus type II.

[0035] According to some embodiments, the composition releases more than 50% of the cariprazine or a pharma- ceutically acceptable salt thereof within 5 weeks in an aqueous medium containing 0.1% sodium lauryl sulfate as measured using a dissolution apparatus type II. According to some embodiments, the composition releases more than 60% of the cariprazine or a pharma- ceutically acceptable salt thereof within 5 weeks in an aqueous medium containing 0.1% sodium lauryl sulfate as measured using a dissolution apparatus type II. According to some embodiments, the composition releases more than 70% of the cariprazine or a pharma- ceutically acceptable salt thereof within 5 weeks in an aqueous medium containing 0.1% sodium lauryl sulfate as measured using a dissolution apparatus type II. According to some embodiments, the composition releases about 62% to about 92% of the cariprazine or a pharma- ceutically acceptable salt thereof within 5 weeks in an aqueous medium containing 0.1% sodium lauryl sulfate as measured using a dissolution apparatus type II.

[0036] According to some embodiments, the compositions provide therapeutically effective plasma concentrations of cariprazine for at least four weeks following a single dose. According to some embodiments, the compositions provide substantially constant plasma concentrations of cariprazine for about 60 hours to about 600 hours, including each value within the specified range, following a single dose.

[0037] The present invention encompasses the use of long-acting cariprazine compositions disclosed herein in methods for treating schizophrenia, major depressive disorder, and / or bipolar disorder, particularly manic or mixed episodes associated with bipolar I disorder and / or depressive episodes associated with bipolar I disorder (bipolar depression).

[0038] Thus, according to some embodiments, the present invention provides a method of treating a disease or disorder selected from schizophrenia, major depressive disorder, and bipolar disorder in a subject in need thereof, the method comprising administering to the subject a long-acting parenteral pharmaceutical composition as disclosed herein. According to some embodiments, the present invention provides a long-acting parenteral pharmaceutical composition as disclosed herein for use in treating a disease or disorder selected from schizophrenia, major depressive disorder, and bipolar disorder. Each possibility represents a separate embodiment.

[0039] As contemplated herein, the depot compositions of the present invention provide comparable or superior therapeutic efficacy compared to conventional immediate release oral cariprazine formulations, with a reduced incidence and / or severity of side effects at a systemic level. According to some embodiments, the compositions of the present invention provide a sustained release or sustained action of cariprazine and / or its metabolites desmethylcariprazine (DCAR) and didesmethylcariprazine (DDCAR) in a subject compared to immediate release oral formulations.

[0040] Further embodiments and their full scope of applicability will become apparent from the detailed description given hereinafter. It should be understood, however, that the detailed description and specific examples, while indicating preferred embodiments of the invention, are given by way of illustration only, since various changes and modifications within the spirit and scope of the invention will become apparent to those skilled in the art from this detailed description. [Brief description of the drawings]

[0041] [Figure 1] 1 shows cariprazine release from formulation A in 0.1% SLS, 0.1 M HEPES, and 0.1 M acetate buffer media. [Diagram 2] 1 shows cariprazine release from formulation B in 0.1% SLS dissolution medium. [Diagram 3]1 shows the pharmacokinetic release profile obtained following daily oral administration of an immediate release formulation of cariprazine versus a single dose of cariprazine Formulation B in a rat model. [Figure 4] 1 shows cariprazine release from Formulation C in 0.1% SLS dissolution medium. [Diagram 5] 1 shows cariprazine release from Formulation D in 0.1% SLS dissolution medium. [Figure 6] 1 shows cariprazine release from Formulation E in 0.1% SLS dissolution medium. [Figure 7] 1 shows cariprazine release from Formulation F in 0.1% SLS dissolution medium. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0042] The present invention provides long-acting in situ forming depot compositions of cariprazine or its salts, particularly cariprazine hydrochloride, which provide superior therapeutic efficacy over daily oral administration and therefore improve patient compliance. In addition to providing superior therapeutic efficacy, the long-acting compositions reduce cariprazine side effects resulting from peak concentrations of the drug in the blood.

[0043] Thus, the present invention provides a long-acting parenteral pharmaceutical composition comprising a therapeutically effective amount of cariprazine or a pharma- ceutically acceptable salt thereof, which is in a depot form suitable for administration at a medically acceptable location in a subject in need thereof. The depot composition may be adapted for subcutaneous or intramuscular administration.

[0044] Depot System Oral administration of small molecules is the most common and effective form of delivery. However, the maximum duration of drug products in the gastrointestinal tract is limited to 18-36 hours. This may require frequent drug administration and reduce patient compliance. Reducing the frequency of oral drug administration can be achieved by the use of long-acting pharmaceutical formulations, such as injectable depot formulations, which can release the drug in a slow but predictable manner, thereby improving compliance. For most drugs, depending on the dose, it may be possible to reduce the frequency of administration from daily administration to once a week, once or twice a month, or even longer (once every 3-6 months). In addition to improving patient compliance, less frequent administration of the drug in the form of a depot formulation smooths the plasma concentration-time profile by eliminating its ups and downs. Such smoothing of the plasma profile has the potential to not only enhance the therapeutic benefit, but also reduce any undesirable effects, such as those associated with oral cariprazine administration.

[0045] Microparticles, implants, and gels are the most common forms of biodegradable polymer systems used in practice to extend the release of drugs in the body. Microparticles are typically suspended in an aqueous medium before injection to provide a suspension containing up to 40% solids. Implant / rod formulations may be delivered subcutaneously (SC) and / or intramuscularly (IM) using special needles in a dry state without the need for an aqueous medium.

[0046] Although microparticle-based depot formulations as well as implant / rod formulations allow for the delivery of higher doses of active ingredients, they often suffer from some drawbacks. The process for the preparation of microparticles typically involves multi-step procedures that limit their application in drug delivery systems. The complex manufacturing procedures also lead to difficulties in scale-up. Furthermore, parenteral sustained release suspensions are dispersed heterogeneous systems that contain insoluble drug particles that need to be resuspended before administration. However, stability problems due to the sedimentation of microparticles are often encountered, thereby limiting the use of parenteral suspensions as drug delivery systems. Surgical implants show sufficient sustained release properties and reproducible manufacturing procedures, but require surgical insertion of the implant into the body, which is often painful, thereby resulting in poor patient compliance.

[0047] Alternative drug delivery systems, i.e. in situ formed biodegradable implants for extended sustained release of active ingredients, constitute a promising approach to overcome the problems of parenteral sustained release drug delivery systems in the form of microparticles or solid implants / rods. These systems are composed of biodegradable polymers dissolved in biocompatible solvents. Otherwise in solution form, these systems transform into gels when in contact with body fluids after administration. The drugs present in these systems become trapped within the polymer matrix formed after gelation, thereby resulting in a sustained release of the drug by diffusion and upon degradation of the hardened gel matrix. These systems present several advantages with respect to other sustained release systems. In situ formed systems are prepared in a single-step process, which reduces process variability and results in uniformity and reproducibility of the product. Further advantages include biocompatibility with biological systems, solubilization of low molecular weight hydrophobic drugs, and controlled release over weeks to months (Critical Reviews™ in Therapeutic Drug Carrier Systems, 36(2):93-136 (2019)).

[0048] In accordance with the principles of the present invention, the compositions disclosed herein are administered parenterally. The term "parenteral" as used herein refers to a route of administration selected from subcutaneous (SC), intravenous (IV), intramuscular (IM), intradermal (ID), intraperitoneal (IP), and the like. Each possibility represents a separate embodiment. According to certain embodiments, the compositions are administered via the intramuscular (IM) route.

[0049] In accordance with the principles of the present invention, the composition in the form of a solution or suspension is configured to form an in situ implant in a subject after administration, thereby forming a long-acting in situ depot system. As used herein, the term "long-acting" refers to a composition that provides a sustained, sustained, or extended release of cariprazine active ingredient to the subject's systemic circulation or to a local site of action in the subject. The term may further refer to a composition that provides an extended, sustained, or extended duration of action of cariprazine and / or its metabolites desmethylcariprazine (DCAR) and didesmethylcariprazine (DDCAR) in a subject.

[0050] Depending on the desired duration of action required, each depot formulation typically contains about 1 to about 500 mg of active ingredient, including each value within the specified range. Alternative suitable doses include, but are not limited to, about 1 mg to about 100 mg, about 5 mg to about 100 mg, about 1 mg to about 50 mg, about 10 mg to about 50 mg, about 20 mg to about 500 mg, etc., including each value within the specified range. However, it should be understood that the amount of cariprazine administered will be determined by the physician according to various parameters, including the route of administration, age, weight, and severity of the patient's symptoms.

[0051] According to various embodiments of the present invention, a therapeutically effective amount of cariprazine ranges from about 1 mg to about 10 mg / day, inclusive, for an average adult weighing about 70 kg. Alternatively, such therapeutically effective amount of cariprazine ranges from about 1.5 mg to about 6 mg / day, inclusive, for an average adult weighing about 70 kg. Alternatively, such therapeutically effective amount of cariprazine ranges from about 3 mg to about 6 mg / day, inclusive, for an average adult weighing about 70 kg.

[0052] In some embodiments, the concentration of cariprazine in the formulations of the invention ranges from about 10 mg / mL to about 80 mg / mL, inclusive of each value within the range specified. In other embodiments, the concentration of cariprazine in the formulations of the invention ranges from about 20 mg / mL to about 60 mg / mL, inclusive of each value within the range specified. In other embodiments, the concentration of cariprazine in the formulations of the invention ranges from about 20 mg / mL to about 50 mg / mL, inclusive of each value within the range specified. In other embodiments, the concentration of cariprazine in the formulations of the invention ranges from about 10 mg / mL to about 100 mg / mL, inclusive of each value within the range specified.

[0053] In some embodiments, the concentration of cariprazine in the formulations of the invention is from about 0.5% to about 20%, inclusive of each value within the ranges specified. In other embodiments, the concentration of cariprazine in the formulations of the invention is from about 1% to about 10%, inclusive of each value within the ranges specified. In yet other embodiments, the concentration of cariprazine in the formulations of the invention is from about 1% to about 5%, inclusive of each value within the ranges specified.

[0054] As contemplated herein, the depot composition of the present invention is designed to be administered once every about 4 weeks to about 6 months and provide sustained release of the cariprazine active ingredient over this time frame. The depot composition can be adapted to release the cariprazine active ingredient over a desired period of time, for example, over a period of about 1 month, or over a period of about 3 months, or any period in between. Thus, by way of example and not limitation, the composition of the present invention can be conveniently injected once every 4 weeks, once a month, once every 2 months, once every 3 months, once every 4 months, once every 5 months, once every 6 months, or any period in between. Each possibility represents a separate embodiment of the present invention.

[0055] The term "cariprazine" as used herein refers to the compound trans-N-{4-[2-[4-(2,3-dichlorophenyl)piperazin-1-yl]ethyl]cyclohexyl}-N',N'-dimethylurea. The present invention also includes salts of cariprazine. The term "salt" as used herein encompasses both base and acid addition salts, including, but not limited to, acid addition salts of an amine nitrogen with an organic or inorganic acid. Such acids include, but are not limited to, hydrochloric acid, hydrobromic acid, hydrofluoric acid, trifluoroacetic acid, sulfuric acid, phosphoric acid, acetic acid, succinic acid, citric acid, lactic acid, maleic acid, fumaric acid, palmitic acid, cholic acid, pamoic acid, mucic acid, D-glutamic acid, D-camphoric acid, glutaric acid, phthalic acid, tartaric acid, lauric acid, stearic acid, salicylic acid, methanesulfonic acid, benzenesulfonic acid, sorbic acid, picric acid, benzoic acid, cinnamic acid, and the like. Each possibility represents a separate embodiment of the invention. A currently preferred cariprazine salt is cariprazine hydrochloride (cariprazine hydrochloride).

[0056] The present invention also includes solvates of cariprazine and its salts. As used herein, the term "solvate" refers to a physical association of cariprazine or its salt with one or more solvent molecules. This physical association includes varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain cases, the solvate may be isolated. "Solvate" includes both solution-phase and isolatable solvates. Non-limiting examples of suitable solvates include ethanolate, methanolate, and the like. Each possibility represents a separate embodiment. When the solvent is water, cariprazine is a hydrate. The term "hydrate" includes, but is not limited to, monohydrate, dihydrate, trihydrate, tetrahydrate, pentahydrate, hemihydrate, sesquihydrate, hemipentahydrate, and the like. Each possibility represents a separate embodiment.

[0057] The present invention also includes polymorphs of cariprazine or cariprazine salts. As used herein, "polymorph" refers to a particular crystalline state of a substance, which may be characterized by particular physical properties, such as X-ray diffraction, Infrared Radiation (IR) spectrum, Raman spectrum, melting point, etc.

[0058] In some embodiments, the depot formulation of the present invention is in the form of a solution or suspension of cariprazine or a pharma- ceutically acceptable salt thereof in an aqueous, oily, or wax phase, a poorly soluble polyelectrolyte complex of cariprazine or a pharma- ceutically acceptable salt thereof, and an "in-situ" gel-forming matrix based on a combination of a water-miscible solvent and cariprazine or a pharma- ceutically acceptable salt thereof. Each possibility represents a separate embodiment of the present invention. According to certain embodiments, the depot formulation of the present invention does not contain microparticles, microspheres, nanoparticles, or nanospheres.

[0059] In certain embodiments, the dosage form includes, but is not limited to, a biodegradable injectable composition, also known as an injectable ISI (In Situ Implant), which is a solution or suspension that can form a depot system when administered in contact with body fluids. The formation of the depot system is brought about by the presence of a biodegradable polymer and a water-miscible solvent. When the composition contacts body fluids, the polymer gels or hardens to form a solid or semi-solid implant that entraps the active ingredient within the polymer matrix. When the polymer matrix biodegrades, the active ingredient is released in a continuous and sustained manner.

[0060] The term "biodegradable" as used herein refers to a component that erodes or degrades over time at its surface due, at least in part, to contact with materials found in the surrounding tissue fluids or by cellular action.In particular, the biodegradable components include, but are not limited to, polylactides, e.g., poly(D,L-lactide), i.e., lactic acid-based polymers such as PLA, polyglycolides (PGA), e.g., glycolic acid-based polymers such as Lactel® from Durect, and poly(D,L-lactide-co-glycolide), i.e., PLGA, (Resomer® RG-504 from Boehringer, Resomer® RG-505 from Boehringer, Resomer® RG-506 from Boehringer, Resomer® RG-507 from Boehringer, Resomer® RG-508 from Boehringer, Resomer® RG-509 ... RG-502, Resomer® RG-504H, Resomer® RG-502H, Resomer® RG-504S, Resomer® RG-502S, Lactel® from Durect, poly(ε-caprolactone), i.e. polycaprolactone such as PCL (Lactel® from Durect), polyanhydrides, poly(sebacic acid), SA, poly(ricinoleic acid), RA, poly(fumaric acid), FA, poly(fatty acid dimer), FAD, poly(terephthalic acid), TA, poly(isophthalic acid), IPA, acid), poly(p-{carboxyphenoxy}methane), CPM), poly(p-{carboxyphenoxy}propane), CPP), poly(p-{carboxyphenoxy}hexane), CPH), polyamines, polyurethanes, polyesteramides, polyorthoesters {CHDM: cis / trans cyclohexyldimethanol, HD: 1,6-hexanediol.DETOU:(3,9-diethylidene-2,4,8,10-tetraoxaspirondecane), polydioxanones, polyhydroxybutyrates, polyalkylene oxalates, polyamides, polyesteramides, polyurethanes, polyacetals, polyketals, polycarbonates, polyorthocarbonates, polysiloxanes, polyphosphazenes, succinates, hyaluronic acid, poly(malic acid), poly(amino acids), polyhydroxyvaleric acid, polyalkylene succinates, polyvinylpyrrolidone, polystyrene, synthetic cellulose esters, polyacrylic acid, polybutyric acid, triblock copolymers (PLGA Examples of suitable polymers include poly(N-isopropylacrylamide) (PNIPAAm), poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) triblock copolymers (PEO-PPO-PEO), polyvaleric acid, polyethylene glycol, polyhydroxyalkylcellulose, chitin, chitosan, polyorthoesters and copolymers, terpolymers, lipids such as cholesterol, lecithin, poly(glutamic acid-co-ethyl glutamate), and the like, or mixtures thereof. Each possibility represents a separate embodiment.

[0061] In accordance with the principles of the present invention, biodegradable polymers include, but are not limited to, polylactides, polyglycolides, polycaprolactones, polyanhydrides, gelatin, collagen, cellulose, polyamides, polyurethanes, polyesteramides, polyorthoesters, polydioxanones, polyacetals, polyketals, polycarbonates, polyorthocarbonates, polyphosphazenes, polyhydroxybutyrates, polyhydroxyvalerates, polyalkylene oxalates, polyalkylene succinates, poly(malic acid), poly(amino acids), and copolymers, terpolymers, and combinations thereof, with each possibility representing a separate embodiment of the present invention.

[0062] In some currently preferred embodiments, the biodegradable polymer is selected from the group consisting of poly(lactic-co-glycolic acid) (PLGA), poly(lactic acid) (PLA), poly(glycolic acid) (PGA), and any combination thereof, with each possibility representing a separate embodiment of the present invention.

[0063] Biodegradable polyesters of lactide and glycolide copolymers called poly(lactic acid) (PLA), polyglycolide (PGA), and poly(lactide-co-glycolide) (PLGA) are the most common polymers used in biodegradable dosage forms. PLA is a hydrophobic molecule, and PLGA degrades faster than PLA due to the presence of the more hydrophilic glycolide group. These biocompatible polymers undergo random nonenzymatic hydrolytic cleavage of ester bonds to form lactic and glycolic acids, which are normal metabolic compounds in the body. Resorbable sutures, clips, and implants were the earliest applications of these polymers.

[0064] In one embodiment, the biodegradable polymer is a lactic acid-based polymer, such as polylactide, or poly(D,L-lactide-co-glycolide), i.e., PLGA. The biodegradable polymer may be present in an amount between about 20% and about 50% w / w of the composition, inclusive of each value within the range specified. The lactic acid-based polymer has a monomer ratio of lactic acid to glycolic acid ranging from 100:0 to 0:100, e.g., ranging from 100:0 to 10:90, inclusive of each value within the specified range, and has an average molecular weight of about 1,000 to about 200,000 Daltons. However, it is understood that the amount of biodegradable polymer is determined by parameters such as duration of use and the like. PLGA polymers are commercially available from several sources, including Alkermes (Medisorb polymers), Absorbable Polymers International (formerly Birmingham Polymers, a division of Durect), Ashland, Purac, and Boehringer Ingelheim.

[0065] Included in the present invention are biodegradable carriers comprising poly(lactic-co-glycolic acid) (PLGA) containing lactic acid monomers and glycolic acid monomers in a molar ratio of 50:50 to 85:15, including values ​​within the specified ranges, and having an intrinsic viscosity in the range of about 0.1 to about 0.8 dl / g. In some embodiments, the molar ratio of lactic acid monomers to glycolic acid monomers in the PLGA is 50:50. In other embodiments, the molar ratio of lactic acid monomers to glycolic acid monomers in the PLGA is 75:25. In yet other embodiments, the molar ratio of lactic acid monomers to glycolic acid monomers in the PLGA is 85:15.

[0066] In some embodiments, the intrinsic viscosity of the PLGA is in the range of about 0.2 to about 0.7 dl / g, inclusive of each value within the specified range. In other embodiments, the intrinsic viscosity of the PLGA is in the range of about 0.3 to about 0.7 dl / g, inclusive of each value within the specified range. In other embodiments, the intrinsic viscosity of the PLGA is in the range of about 0.4 to about 0.6 dl / g, inclusive of each value within the specified range. Although a single PLGA polymer may be used in the compositions of the invention, it is contemplated that two or more PLGA polymers may be mixed and used in the ISI compositions of the invention to obtain a desired range of combined intrinsic viscosities. Typically, the PLGA having a higher intrinsic viscosity and the PLGA having a lower intrinsic viscosity are present in the composition in a ratio of 2:1 to 1:1, including all ratios within this range.

[0067] According to some aspects and embodiments, the PLGA is characterized by acid termination, i.e., the end groups of the polymer comprise lactic acid and / or glycolic acid. According to other aspects and embodiments, the PLGA is characterized by ester termination, i.e., the end groups of the polymer comprise lactic acid esters and / or glycolic acid esters. Combinations of acid-terminated PLGA and ester-terminated PLGA are also encompassed by the present invention.

[0068] According to some embodiments, the ratio of cariprazine or a pharma- ceutically acceptable salt thereof to the PLGA carrier is about 1:1 to about 1:100, inclusive of each value within the specified range. Thus, in some embodiments, the ratio between cariprazine or a pharma- ceutically acceptable salt thereof to the PLGA carrier is about 1:1 to about 1:75, inclusive of each value within the specified range. In other embodiments, the ratio between cariprazine or a pharma- ceutically acceptable salt thereof to the PLGA carrier is about 1:1 to about 1:50, inclusive of each value within the specified range. In still other embodiments, the ratio between cariprazine or a pharma- ceutically acceptable salt thereof to the PLGA carrier is about 1:1 to about 1:40, inclusive of each value within the specified range. Preferably, the ratio between cariprazine or a pharma- ceutically acceptable salt thereof to the PLGA carrier is about 1:5 to about 1:25, inclusive of each value within the specified range.

[0069] According to some aspects and embodiments, the ISI composition of the present invention comprises a solvent that is biocompatible (i.e., non-toxic) and water-miscible while also providing dissolution of the PLGA and cariprazine active ingredient. Upon administration of the solution, exposure to bodily fluids causes an exchange between the solvent and water present at the injection site, such that the solvent diffuses out of the polymer-drug mixture while the water diffuses into the mixture, where it hardens the polymer, thereby forming a matrix that traps or encapsulates the drug therein. Suitable biocompatible solvents within the scope of the present invention include, but are not limited to, benzyl alcohol, methyl benzoate, ethyl benzoate, n-propyl benzoate, isopropyl benzoate, butyl benzoate, isobutyl benzoate, tert-butyl benzoate, and benzyl benzoate. Each possibility represents a separate embodiment. Currently preferred is the use of benzyl alcohol as a biocompatible solvent.

[0070] The compositions of the present invention may further comprise one or more pharma- ceutically acceptable excipient(s) selected from, but not limited to, co-surfactants, solvents / co-solvents including organic solvents, water-immiscible solvents, water and water-miscible solvents, and hydrophilic solvents, preservatives, antifoaming agents, stabilizers such as antioxidants, tonicity adjusting agents, buffering agents, pH adjusting agents, sustained release agents, oily components, emulsifiers, channel formers, osmolality adjusting agents, or any other excipients known in the art. Each possibility represents a separate embodiment.

[0071] Suitable co-surfactants include, but are not limited to, polyethylene glycols, polyoxyethylene-polyoxypropylene block copolymers, known as "poloxamers", polyglycerin fatty acid esters such as decaglyceryl monolaurate and decaglyceryl monomyristate, sorbitan fatty acid esters such as sorbitan monostearate, polyoxyethylene sorbitan fatty acid esters such as polyoxyethylene sorbitan monooleate (Tween), polyethylene glycol fatty acid esters such as polyoxyethylene monostearate, polyoxyethylene alkyl ethers such as polyoxyethylene lauryl ether, polyoxyethylene castor oils and hydrogenated castor oils such as polyoxyethylene hydrogenated castor oil, and the like, or mixtures thereof. Each possibility represents a separate embodiment of the present invention.

[0072] Suitable solvents / co-solvents include, but are not limited to, alcohol, triacetin, dimethyl isosorbide, glycofurol, propylene carbonate, water, dimethylacetamide, and the like, or mixtures thereof. Each possibility represents a separate embodiment of the present invention.

[0073] Suitable anti-foaming agents include, but are not limited to, silicone emulsion or sorbitan sesquioleate.

[0074] Suitable stabilizers, when present, to prevent or reduce degradation of components in the compositions of the invention include, but are not limited to, antioxidants such as glycine, alpha-tocopherol or ascorbate, BHA (butylated hydroxyanisole), BHT (butylated hydroxytoluene), and the like, or mixtures thereof. Each possibility represents a separate embodiment of the invention. In some embodiments, the composition does not include a stabilizer. In other embodiments, the composition does not include a component that reduces the surface tension of the composition. In other embodiments, the composition does not include Tween, Span, poloxamer, tocopherol, cremophor, lecithin, polyethylene glycol, and / or polyethylene glycol ester.

[0075] Examples of preservatives suitable for compositions according to the present invention may be selected from, but are not limited to, quaternary ammonium halides, phenylcarbinol, thimerosal, edetate disodium, and phenylethyl alcohol, each possibility representing a separate embodiment of the present invention.

[0076] Examples of suitable tonicity adjusting agents for compositions according to the present invention include, but are not limited to, mannitol, sodium chloride, and glucose, with each possibility representing a separate embodiment of the present invention.

[0077] Examples of buffers suitable for compositions according to the invention, if present, include, but are not limited to, acetate buffer, borate buffer, tartrate buffer, lactate buffer, citrate buffer, phosphate buffer (e.g., potassium dihydrogen phosphate), citrate / phosphate buffer, carbonate / carbonate buffer, succinate / succinate buffer, and tris(hydroxymethyl)aminomethane / hydrochloric acid buffer. Each possibility represents a separate embodiment of the invention. In some embodiments, the composition of the invention does not include a buffer. In one embodiment, the composition does not include a buffer selected from the group consisting of phosphate, acetate, citric acid, succinic acid, adipic acid, tartaric acid, ascorbic acid, and / or malic acid, and salts thereof.

[0078] Suitable pH adjusters for the compositions according to the present invention may be selected from, but are not limited to, sodium hydroxide, hydrochloric acid, citric acid, acetic acid, fumaric acid, hydrochloric acid, malic acid, nitric acid, phosphoric acid, propionic acid, sulfuric acid, tartaric acid, or combinations thereof. Each possibility represents a separate embodiment of the present invention. Exemplary pH adjusters include, but are not limited to, benzoic acid, sorbic acid, fumaric acid, adipic acid, citric acid, succinic acid, glutaric acid, malic acid, malonic acid, tartaric acid, acetic acid, glycolic acid, propionic acid, lauric acid, caprylic acid, capric acid, and myristic acid. Each possibility represents a separate embodiment. The currently preferred pH adjuster is benzoic acid.

[0079] Suitable sustained release agents include, but are not limited to, bile salts such as sodium glycocholate, sodium deoxycholate, sodium taurocholate, sodium fusidate, sodium glycodeoxycholate, and sodium taurodihydrofusidate. Each possibility represents a separate embodiment. A currently preferred bile salt is sodium deoxycholate. Additional sustained release agents within the scope of the present invention include, but are not limited to, triethyl citrate, triacetin, and lecithin. Each possibility represents a separate embodiment. A currently preferred sustained release agent is triethyl citrate, which can also be used as a pH adjusting agent.

[0080] In some embodiments, the compositions of the present invention do not include sodium carboxymethylcellulose, gelatin, polyvinylpyrrolidone, methylcellulose, and / or acacia, hi other embodiments, the compositions of the present invention do not include hydrochloric acid, acetic acid, phosphoric acid, sodium hydroxide, sodium hydrogen phosphate, calcium carbonate, and / or magnesium hydroxide.

[0081] The composition of the present invention can be prepared in any manner known in the art. For example, the composition can be prepared by dissolving the biodegradable polymer, cariprazine, and optional excipients in a biocompatible organic solvent.

[0082] In accordance with the principles of the present invention, the composition may also be provided as a kit comprising the biodegradable polymer, cariprazine, and a biocompatible organic solvent in one or several compartments, and including instructions for use. The composition may also be provided as a pre-filled syringe, ready to use.

[0083] Emission Characteristics In accordance with the principles of the present invention, the long-acting pharmaceutical compositions of the present invention provide superior therapeutic efficacy with a reduced incidence of side effects and / or reduced severity of side effects at the systemic level compared to commercially available daily oral dosage forms of cariprazine. In some embodiments, the compositions of the present invention provide a sustained release or sustained action of cariprazine and / or its metabolites desmethylcariprazine (DCAR) and didesmethylcariprazine (DDCAR) in a subject compared to immediate release oral formulations such as VRAYLAR®.

[0084] Within the scope of the present invention are ISI compositions that provide a burst release of less than about 20% of cariprazine when measured using a dissolution apparatus type II in an aqueous medium containing 0.1% sodium lauryl sulfate (SLS). The principles of the present invention provide a reduction in burst release (release of active ingredient immediately after administration), thereby minimizing or eliminating adverse effects resulting from systemic exposure to high doses of cariprazine active ingredient for 24 to 48 hours after administration. In some embodiments, the composition provides a burst release of about 2% to about 19% of cariprazine in an aqueous medium containing 0.1% SLS when measured using a dissolution apparatus type II. Despite the low burst release, the composition provides a release of cariprazine immediately after administration without a time lag. Thus, the gradual release of cariprazine from the composition is provided continuously over an extended period of at least 4 weeks after a single dose.

[0085] In some embodiments, less than 40% of the cariprazine is released within one week when measured in an aqueous medium containing 0.1% SLS using a dissolution apparatus Type II. In other embodiments, less than 30% of the cariprazine is released within one week when measured in an aqueous medium containing 0.1% SLS using a dissolution apparatus Type II. In yet other embodiments, less than 20% of the cariprazine is released within one week when measured in an aqueous medium containing 0.1% SLS using a dissolution apparatus Type II. Typically, the composition releases about 8% to about 40% of the cariprazine or a pharma- ceutically acceptable salt thereof within one week when measured in an aqueous medium containing 0.1% SLS using a dissolution apparatus Type II.

[0086] In some embodiments, less than 55% of the cariprazine is released within 2 weeks when measured in an aqueous medium containing 0.1% SLS using a dissolution apparatus Type II. In other embodiments, less than 45% of the cariprazine is released within 2 weeks when measured in an aqueous medium containing 0.1% SLS using a dissolution apparatus Type II. In yet other embodiments, less than 35% of the cariprazine is released within 2 weeks when measured in an aqueous medium containing 0.1% SLS using a dissolution apparatus Type II. Typically, the composition releases about 15% to about 53% of the cariprazine or a pharma- ceutically acceptable salt thereof within 2 weeks when measured in an aqueous medium containing 0.1% SLS using a dissolution apparatus Type II.

[0087] In some embodiments, less than 80% of the cariprazine is released within 3 weeks when measured in an aqueous medium containing 0.1% SLS using a dissolution apparatus Type II. In other embodiments, less than 70% of the cariprazine is released within 3 weeks when measured in an aqueous medium containing 0.1% SLS using a dissolution apparatus Type II. In still other embodiments, less than 60% of the cariprazine is released within 3 weeks when measured in an aqueous medium containing 0.1% SLS using a dissolution apparatus Type II. Typically, the composition releases about 36% to about 71% of the cariprazine or a pharma- ceutically acceptable salt thereof within 3 weeks when measured in an aqueous medium containing 0.1% SLS using a dissolution apparatus Type II.

[0088] In some embodiments, less than 90% of the cariprazine is released within 4 weeks when measured in an aqueous medium containing 0.1% SLS using a dissolution apparatus Type II. In other embodiments, less than 80% of the cariprazine is released within 4 weeks when measured in an aqueous medium containing 0.1% SLS using a dissolution apparatus Type II. In still other embodiments, less than 70% of the cariprazine is released within 4 weeks when measured in an aqueous medium containing 0.1% SLS using a dissolution apparatus Type II. Typically, the composition releases about 45% to about 86% of the cariprazine or a pharma- ceutically acceptable salt thereof within 4 weeks when measured in an aqueous medium containing 0.1% SLS using a dissolution apparatus Type II.

[0089] In some embodiments, greater than 50% of the cariprazine is released within 5 weeks when measured in an aqueous medium containing 0.1% SLS using a dissolution apparatus Type II. In other embodiments, greater than 60% of the cariprazine is released within 5 weeks when measured in an aqueous medium containing 0.1% SLS using a dissolution apparatus Type II. In yet other embodiments, greater than 70% of the cariprazine is released within 5 weeks when measured in an aqueous medium containing 0.1% SLS using a dissolution apparatus Type II. Typically, the composition releases about 62% to about 92% of the cariprazine or a pharma- ceutically acceptable salt thereof within 5 weeks when measured in an aqueous medium containing 0.1% SLS using a dissolution apparatus Type II.

[0090] According to some embodiments, the composition provides a therapeutically effective plasma concentration of cariprazine or a metabolite thereof for at least 4 weeks, e.g., about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks or more, after a single dose. Each possibility represents a separate embodiment. According to some embodiments, the composition provides a substantially constant plasma concentration of cariprazine for about 60 hours to about 600 hours, including each value within the specified range, after a single dose. As used herein, the term "substantially constant" refers to a plasma concentration that is therapeutically effective and does not experience rapid fluctuations, such as highs and lows, that often occur when immediate release cariprazine formulations are administered.

[0091] Therapeutic Use The depot formulations of the present invention are particularly useful in methods of treating diseases and conditions for which cariprazine has been shown to be therapeutically effective.

[0092] Thus, in some embodiments, the present invention relates to methods of treating schizophrenia by administering to a schizophrenic patient in need thereof a depot formulation comprising cariprazine or a salt thereof.

[0093] In another embodiment, the present invention relates to a method of treating Major Depressive Disorder (MDD) by administering a depot formulation comprising cariprazine or a salt thereof to a patient having Major Depressive Disorder in need thereof.

[0094] In another embodiment, the present invention relates to a method of treating bipolar disorder by administering a depot formulation comprising cariprazine or a salt thereof to a patient having bipolar disorder in need thereof.

[0095] In another embodiment, the present invention relates to a method of treating a manic or mixed episode associated with bipolar I disorder by administering a depot formulation comprising cariprazine or a salt thereof to a patient with bipolar I disorder in need thereof.

[0096] In another embodiment, the present invention relates to a method of treating a depressive episode associated with bipolar I disorder (bipolar depression) by administering a depot formulation comprising cariprazine or a salt thereof to a patient having bipolar I disorder in need thereof.

[0097] In another embodiment, the present invention relates to a long acting parenteral pharmaceutical composition in depot form comprising cariprazine or a salt thereof for use in the treatment of schizophrenia.

[0098] In another embodiment, the present invention relates to a long acting parenteral pharmaceutical composition in depot form comprising cariprazine or a salt thereof for use in the treatment of MDD (Major Depressive Disorder).

[0099] In another embodiment, the present invention relates to a long-acting parenteral pharmaceutical composition in depot form comprising cariprazine or a salt thereof for use in the treatment of bipolar disorder.

[0100] In another embodiment, the present invention relates to a long-acting parenteral pharmaceutical composition in a depot form comprising cariprazine or a salt thereof for use in the treatment of manic or mixed episodes associated with bipolar I disorder.

[0101] In another embodiment, the present invention relates to a long-acting parenteral pharmaceutical composition in depot form comprising cariprazine or a salt thereof for use in the treatment of depressive episodes associated with bipolar I disorder (bipolar depression).

[0102] As used herein, the term "schizophrenia" includes conditions generally described as schizophrenia or conditions with symptoms related thereto. Schizophrenia can be considered as a disease with a spectrum of manifestations with various threshold levels of chronic debilitating disorders characterized by a psychopathological spectrum including positive symptoms such as abnormal or distorted mental conceptions (e.g., hallucinations, delusions), negative symptoms characterized by reduced motivation and adaptive goal-directed behavior (e.g., anhedonia, blunted affect, loss of motivation), and cognitive impairment. Schizophrenia can be diagnosed by a skilled physician based on personal and medical history, interview and physical examination.

[0103] The term "Major Depressive Disorder" or "MDD" refers to major depression characterized by a combination of symptoms that interfere with a person's ability to work, sleep, study, eat, and enjoy activities that were once enjoyable. Major depression is a mental disorder that prevents a person from functioning normally. Some people may only experience a single episode in their lifetime, but more often a person may have multiple episodes.

[0104] The term "bipolar disorder" or "BP" includes bipolar type I disorder and bipolar type II disorder and refers to a chronic psychological / mood disorder that can be characterized by significant mood changes, including periods of depression and periods of mania. Bipolar type I disorder is a form of BP that is characterized by periods of severe mood episodes ranging from mania to depression. Bipolar type II disorder is a milder form of mood elevation, with milder episodes of hypomania alternating with periods of severe depression. The term "treatment of bipolar disorder" includes treatment of manic or mixed episodes associated with bipolar type I disorder and / or depressive episodes (bipolar depression) associated with bipolar type I disorder. Bipolar disorder can be diagnosed by a skilled physician based on personal and medical history, medical examination, and physical examination.

[0105] The terms "mania" or "manic periods" or other variations refer to periods during which an individual exhibits some or all of the following characteristics: racing thoughts, rapid speech, increased levels of activity and agitation, as well as feelings of elevated self-esteem, euphoria, poor judgment, insomnia, poor concentration and aggression.

[0106] The term "treating" as used herein refers to taking measures to obtain beneficial or desired results, including clinical results, including, but not limited to, prevention or slowing of the progression of a disease or disorder, or reduction, amelioration, or slowing of the progression of one or more symptoms associated with the disease being treated, such as schizophrenia, MDD, or bipolar disorder (particularly mania and / or depression).

[0107] The term "therapeutically effective amount" as used herein is intended to qualify the amount of cariprazine that achieves the goal of treating schizophrenia, MDD, or bipolar disorder, e.g., manic episodes or mixed episodes associated with bipolar I disorder, and / or depressive episodes associated with bipolar I disorder (bipolar depression).

[0108] Included in the present invention is combination therapy of cariprazine or a pharma- ceutically acceptable salt of cariprazine with at least one other active agent. Active agents within the scope of the present invention include, but are not limited to, antipsychotics, which may be selected from one or more of amisulpiride, nemonapride, remoxipride, sultopride, tiapride, sinuperone, melperone, setoperone, iloperidone, ocaperidone, paliperidone, risperidone, lurasidone, perospirone, levospirone, thiospirone, ziprasidone, amperozide, aripiprazole, bifeprunox, brexpiprazole, amoxapine, asenapine, carpipramine, clocapramine, chlorothepine, clothiapine, clozapine, flumezapine, fluperlapine, gevotroline, metythepine, mosapramine, olanzapine, quetiapine, tenilapine, zotepine, or a pharma- ceutically acceptable salt thereof. Each possibility represents a separate embodiment of the present invention.

[0109] According to some embodiments, the depot composition of the present invention may be administered in vivo to a subject in need thereof. In some embodiments, the "subject" to which the depot composition is administered is a mammal, preferably, but not limited to, a human.

[0110] As used in this specification and the appended claims, the term "about" refers to ±10%.

[0111] As used herein and in the appended claims, the singular forms "a," "an," and "the" include plural references unless the context clearly dictates otherwise. Thus, for example, a reference to "a biocompatible solvent" includes a plurality of such solvents. It should be noted that the terms "and" and "or" are generally employed in the sense of including "and / or" unless the context clearly dictates otherwise.

[0112] The following examples are presented in order to more fully illustrate certain embodiments of the present invention. However, they should in no way be construed as limiting the broad scope of the present invention. Those skilled in the art can readily devise numerous variations and modifications of the principles disclosed herein without departing from the scope of the present invention. EXAMPLES

[0113] General Method for Preparation of PLGA-Based Injectable In-Situ Implant (ISI) Formulations ISI depot formulations according to certain embodiments of the present invention were prepared using the following general procedure: PLGA as a biodegradable polymer was dissolved in benzyl alcohol by continuous stirring at room temperature overnight. Cariprazine hydrochloride and any excipients were dissolved separately in benzyl alcohol and added to the PLGA solution. The mixture was then stirred at room temperature until complete homogenization was achieved.

[0114] Example 1. preparation A cariprazine depot formulation, designated Formulation A, was prepared as follows: Acid-terminated PLGA 50:50 with a viscosity of 0.15-0.25 dl / g was mixed with ester-terminated PLGA 50:50 with a viscosity of 0.55-0.75 dl / g in a 1:1 ratio and at a concentration of 30% (w / w) (total solvent). The mixture of dry polymers was suspended in benzyl alcohol and stirred continuously at room temperature until a clear solution was obtained. Triethyl citrate (2.4% (w / w) of the formulation) was then added to the polymer solution. Cariprazine hydrochloride (10% (w / w) of the polymer) was dissolved in benzyl alcohol. After complete dissolution, the cariprazine solution was added to the polymer solution and stirred until a homogenous mixture was obtained.

[0115] Potency Calculation The potency of the formulation was analyzed using HPLC (High Performance Liquid Chromatography) and calculated according to the following formula:

[0116]

number

[0117] In vitro release of cariprazine from formulations Three dissolution media were selected: 1) A 0.1% solution of SLS in water containing 0.02% sodium azide; 2) 0.1 M HEPES buffer (pH = 5.2), and 3) 0.1M acetate buffer (pH=5.0).

[0118] To assess the release of incorporated cariprazine from the biodegradable PLGA matrices, a standard dissolution method was employed using a dissolution apparatus type II.

[0119] Description of the sampling process: A 1500 μl sample was taken from the dissolution vessel and centrifuged at 10,000 rpm for 5 minutes. 1000 μl of the supernatant was transferred to a 5.0 ml volumetric flask and diluted with diluent (0.1% H 3 PO 4 The volume was adjusted to constant using MeOH (MeOH). Quantitative analysis of the sample was carried out using an HPLC system.

[0120] The release of cariprazine from Formulation A was studied over a period of 1 to 2 months. The results of the API release study are shown in Table 1 and Figure 1. The percentage of API in the formulation was 2.2%.

[0121] [Table 1]

[0122] Example 2. preparation A cariprazine depot formulation, designated Formulation B, was prepared using ester-terminated PLGA 75:25 with a viscosity of 0.4-0.6 dl / g at a concentration of 30% (w / w) (total solvent). The formulation was prepared by dissolving the polymer in benzyl alcohol by continuous stirring at room temperature. Cariprazine hydrochloride and benzoic acid (3.7 molar equivalents of cariprazine) were dissolved in benzyl alcohol. After complete dissolution, the cariprazine solution was added to the polymer solution and stirred until a homogenous mixture was obtained.

[0123] In vitro release of cariprazine from formulations In vitro release studies were conducted in aqueous media containing 0.1% sodium lauryl sulfate (SLS) as described in Example 1. The results are shown in Table 2 and Figure 2. The percentage of API in the formulation was 2.2%.

[0124] [Table 2]

[0125] Pharmacokinetic studies A comparative pharmacokinetic study of cariprazine following a single intramuscular administration of Formulation B (LAI) compared with multiple doses (oral) of an immediate release formulation of cariprazine hydrochloride was conducted in male Sprague Dawley rats (SD rats).

[0126] Group assignments and treatments are shown in Table 3.

[0127] [Table 3]

[0128] Group 1: Formulation B was administered intramuscularly slowly over 20 seconds into the thigh of rats on day 1.

[0129] Group 2: Immediate release formulation (0.1% acetic acid in deionized water (dw)) was administered orally by gavage once daily until the 28th day.

[0130] Figure 3 shows the results of the PK study. Although the cariprazine plasma concentrations were comparable, daily oral administration resulted in significant fluctuations that were not present when a depot formulation according to certain embodiments of the present invention was administered. Thus, the formulation of the present invention provides continuous in vivo release of cariprazine for at least one month at a substantially constant plasma concentration after a single IM administration.

[0131] Example 3. preparation A cariprazine depot formulation, designated Formulation C, was prepared using ester-terminated PLGA 75:25 with a viscosity of 0.4-0.6 dl / g. The formulation was prepared by dissolving the polymer in benzyl alcohol by continuous stirring at room temperature. Cariprazine hydrochloride was dissolved in benzyl alcohol at a concentration of 18% (w / w of solvent). After complete dissolution, the cariprazine solution was added to the polymer solution and stirred until a homogenous mixture was obtained.

[0132] In vitro release of cariprazine from formulations In vitro release studies were performed in aqueous media containing 0.1% SLS as described in Example 1. The results are shown in Table 4 and Figure 4. The percentage of API in the formulation was 2.57% and the amount of API injected was 45.03 mg.

[0133] [Table 4]

[0134] Thus, Formulation C provides a sustained release for 2 months.

[0135] Example 4. preparation A cariprazine depot formulation, designated Formulation D, was prepared using acid-terminated PLGA 85:15 with a viscosity of 0.4-0.6 dl / g at a concentration of 30% (w / w) (total solvent). The formulation was prepared by dissolving the polymer in benzyl alcohol by continuous stirring at room temperature. Cariprazine hydrochloride was dissolved in benzyl alcohol at a concentration of 18% (w / w) of solvent. After complete dissolution, the cariprazine solution was added to the polymer solution and stirred until a homogenous mixture was obtained.

[0136] In vitro release of cariprazine from formulations In vitro release studies were performed in aqueous media containing 0.1% SLS as described in Example 1. The results are shown in Table 5 and Figure 5. The percentage of API in the formulation was 4.52% and the amount of API injected was 44.32 mg.

[0137] [Table 5]

[0138] Thus, formulation D provides a sustained release for 2 months.

[0139] Example 5. preparation A cariprazine depot formulation, designated Formulation E, was prepared as follows: Acid-terminated PLGA 85:15 with a viscosity of 0.4-0.6 dl / g was mixed with Acid-terminated PLGA 85:15 with a viscosity of 0.2-0.4 dl / g in a 2:1 ratio and at a concentration of 40% (w / w). The mixture of polymers was dissolved in benzyl alcohol by continuous stirring at room temperature. Cariprazine hydrochloride (15% (w / w) polymer) was added to the polymer solution and stirred until complete dissolution was achieved, resulting in a homogenous mixture.

[0140] In vitro release of cariprazine from formulations In vitro release studies were performed in aqueous media containing 0.1% SLS as described in Example 1. The results are shown in Table 6 and Figure 6. The percentage of API in the formulation was 4.07% and the amount of API injected was 44.4 mg.

[0141] [Table 6]

[0142] Thus, formulation E provides a sustained release for 2 months.

[0143] Example 6. preparation A cariprazine depot formulation, designated Formulation F, was prepared as follows: Ester-terminated PLGA 85:15 having a viscosity of 0.6-0.8 dl / g was mixed with acid-terminated PLGA 85:15 having a viscosity of 0.2-0.4 dl / g in a 1:1 ratio and at a concentration of 30% (w / w).

[0144] The mixture of polymers was dissolved in benzyl alcohol by continuous stirring at room temperature. Triethyl citrate (2.4% (w / w) of the formulation) was added to the polymer solution. Cariprazine hydrochloride and sodium deoxycholate (0.6 molar equivalent of cariprazine) were dissolved in benzyl alcohol. After complete dissolution, the cariprazine solution was added to the polymer solution and stirred until a homogeneous mixture was obtained.

[0145] In vitro release of cariprazine from formulations In vitro release studies were performed in aqueous media containing 0.1% SLS as described in Example 1. The results are shown in Table 7 and Figure 7. The percentage of API in the formulation was 2.2% and the amount of API injected was 47.09 mg.

[0146] [Table 7]

[0147] Thus, formulation F provides a sustained release for 2 months.

[0148] Although the present invention has been specifically described, it should be understood that many variations and modifications may occur to those skilled in the art. Accordingly, the present invention is not to be construed as being limited to the specifically described embodiments, and the scope and spirit of the present invention will be more readily understood by reference to the following claims.

Claims

Claim 1: A long-acting parenteral pharmaceutical composition suitable for forming an in situ implant after administration in a subject in need thereof, comprising: The composition comprises: cariprazine or a pharmaceutically acceptable salt thereof; a pharmaceutically acceptable biodegradable carrier comprising poly(lactic-co-glycolic acid) (PLGA) having a molar ratio of lactic acid monomers to glycolic acid monomers of 50:50 to 85:15 and an intrinsic viscosity ranging from about 0.1 to about 0.8 dl / g; a biocompatible solvent; Including, the composition releases a therapeutically effective amount of cariprazine or a pharmaceutically acceptable salt thereof for at least 4 weeks after a single administration. composition.

2. The composition of claim 1 in the form of a solution.

3. 10. The composition of claim 1 in the form of a suspension.

4. 10. The composition of claim 1, which is administered at a frequency of about once a month to about once every three months.

5. a dose of about 1 to about 100 mg of cariprazine or a pharmaceutically acceptable salt thereof; or about 1% to about 10% cariprazine or a pharmaceutically acceptable salt thereof; or about 20 to about 60 mg / mL of cariprazine or a pharmaceutically acceptable salt thereof; or Cariprazine salts include cariprazine hydrochloride; The composition of claim 1.

6. the carrier is poly(lactic-co-glycolic acid) (PLGA) containing lactic acid end groups and glycolic acid end groups; or The carrier is poly(lactic-co-glycolic acid) (PLGA) containing lactate and glycolate end groups; The composition of claim 1.

7. 10. The composition of claim 1, wherein the poly(lactic-co-glycolic acid) (PLGA) contains a molar ratio of lactic acid monomers to glycolic acid monomers of 50:50, 75:25, or 85:

15.

8. 10. The composition of claim 1, wherein the poly(lactic-co-glycolic acid) (PLGA) has an intrinsic viscosity in the range of about 0.2 to about 0.7 dl / g, preferably in the range of about 0.3 to about 0.7 dl / g, and more preferably in the range of about 0.4 to about 0.6 dl / g.

9. a single PLGA polymer; or A combination of two or more PLGA polymers having different intrinsic viscosities; The composition of claim 1 comprising:

10. 2. The composition of claim 1, wherein the biocompatible solvent is selected from the group consisting of benzyl alcohol, methyl benzoate, ethyl benzoate, n-propyl benzoate, isopropyl benzoate, butyl benzoate, isobutyl benzoate, tert-butyl benzoate, and benzyl benzoate, preferably the biocompatible solvent is benzyl alcohol.

11. 10. The composition of claim 1, further comprising one or more pharmaceutically acceptable excipients selected from the group consisting of preservatives, sustained-release agents, buffering agents, pH adjusting agents, and any combination thereof.

12. the sustained-release agent is a bile salt selected from the group consisting of sodium deoxycholate, sodium glycocholate, sodium taurocholate, sodium fusidate, sodium glycodeoxycholate, and sodium taurodihydrofusidate; or the sustained release agent is selected from the group consisting of triethyl citrate, triacetin, and lecithin; or the pH adjuster is a carboxylic acid selected from the group consisting of benzoic acid, sorbic acid, fumaric acid, adipic acid, citric acid, succinic acid, glutaric acid, malic acid, malonic acid, tartaric acid, acetic acid, glycolic acid, propionic acid, lauric acid, caprylic acid, capric acid, and myristic acid; The composition of claim 11.

13. providing a burst release of less than 20%, preferably from about 2% to about 19%, of cariprazine or a pharmaceutically acceptable salt thereof in an aqueous medium containing 0.1% sodium lauryl sulfate, as measured using a Type II dissolution apparatus; and / or In an aqueous medium containing 0.1% sodium lauryl sulfate, as measured using a Type II dissolution apparatus, (i) releases less than 40%, preferably about 8% to about 40%, of the cariprazine or pharmaceutically acceptable salt thereof within one week; (ii) releases less than 55%, preferably about 15% to about 53%, of the cariprazine or pharmaceutically acceptable salt thereof within 2 weeks; (iii) releases less than 80%, preferably about 36% to about 71%, of the cariprazine or pharmaceutically acceptable salt thereof within 3 weeks; (iv) releases less than 90%, preferably about 45% to about 86%, of the cariprazine or pharmaceutically acceptable salt thereof within 4 weeks; and / or (v) releases greater than 50%, preferably about 62% to about 92%, of the cariprazine or pharmaceutically acceptable salt thereof within 5 weeks; The composition of claim 1.

14. providing therapeutically effective plasma concentrations of cariprazine for at least 4 weeks after a single dose; and / or providing a substantially constant cariprazine plasma concentration for about 60 hours to about 600 hours after a single dose; and / or provide equivalent or superior therapeutic efficacy compared to conventional immediate-release oral cariprazine formulations, with a reduced incidence and / or severity of side effects at the systemic level; and / or providing a sustained release or sustained action of cariprazine and / or its metabolites desmethylcariprazine (DCAR) and didesmethylcariprazine (DDCAR) in a subject compared to immediate release oral formulations; The composition of claim 1.

15. 15. The composition of any one of claims 1 to 14 for use in the treatment of a disease or disorder selected from schizophrenia, major depressive disorder, and bipolar disorder, preferably wherein treating bipolar disorder comprises treating a manic episode or mixed episode associated with bipolar I disorder, and / or a depressive episode associated with bipolar I disorder.

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