Reservoir system comprising cariprazine or salt thereof

Abstract

The present invention provides a long-acting parenteral pharmaceutical composition in a depot form comprising a therapeutically effective amount of cariprazine or a pharmaceutically acceptable salt thereof, suitable for administration at a medically acceptable location in a subject in need thereof. The depot composition is preferably in the form of an orthotopic implant suitable for subcutaneous or intramuscular administration and provides prolonged release of the cariprazine active ingredient and / or metabolites thereof demethylcariprazine (DDCAR) and didemethylcariprazine (DDCAR) after a single administration for a period of at least four weeks. The present invention also provides methods of treating schizophrenia, major depression, and bipolar disorder using the depot compositions.

Description

Technical Field

[0001] The present invention relates to a parenteral long-acting dosage form of cariprazine or a pharmacologically active salt thereof, such as a reservoir system providing a prolonged release of cariprazine and intended for use in the treatment of schizophrenia, major depression and bipolar disorder. Background Art

[0002] Cariprazine HCl It is an atypical antipsychotic. The chemical name of cariprazine HCl 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]

[0004] Cariprazine is indicated for: (1) treatment of schizophrenia in adults; (2) acute treatment of manic or mixed episodes associated with bipolar I disorder in adults; and (3) treatment of depressive episodes associated with bipolar I disorder (bipolar depression) in adults. The mechanism of action of cariprazine in the treatment of schizophrenia and bipolar I disorder is unclear. However, it is thought 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, desmethylcariprazine (DCAR) and didesmethylcariprazine (DDCAR), which have in vitro receptor binding properties similar to the parent drug.

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

[0006] Oral administration of cariprazine is known to be associated with serious and potentially fatal side effects, including an increased risk of death, particularly in the elderly with Alzheimer's-related psychosis, an increased risk of suicidal thoughts or behavior in children and adolescents, stroke, neuroleptic malignant syndrome (NMS), tardive dyskinesia, metabolic problems (such as high blood sugar and diabetes), low white blood cell counts, low blood pressure, falls, seizures, and difficulty controlling temperature.

[0007] Sustained-release compositions that reduce exposure to cariprazine and its metabolites and reduce the side effect profile are desirable. However, there are no long-acting formulations of cariprazine available on the market.

[0008] PCT International Patent Publication No. WO2018 / 015915 discloses a non-intestinal controlled-release composition comprising an atypical antipsychotic, particularly lurasidone, and one or more rate-controlling polymers in the form of an in situ gelling composition, which contacts body fluids to form a reservoir when administered in vivo, thereby providing extended release of the active agent.

[0009] Chinese patent application No. CN108261394 discloses a cariprazine hydrochloride injection preparation, which is in the form of an aqueous suspension and contains a stabilizer, a suspending agent, a buffer and a pH regulator. The particle size distribution and injection dose are controlled to achieve a long-lasting effect, and cariprazine hydrochloride is continuously released for at least one week after injection of the preparation.

[0010] PCT International Patent Publication No. WO2018 / 229641 discloses oral pharmaceutical compositions and methods for modified release delivery of cariprazine for less than daily dosing.

[0011] U.S. Patent Application Publication No. US2021 / 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 a salt form of a derivative thereof), a biodegradable and biocompatible polymer (containing a polymer 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 wherein the composition is in the form of microparticles, microspheres, nanoparticles or a combination thereof.

[0012] There is an unmet need for a long-acting formulation of cariprazine, particularly for patients who experience side effects from oral cariprazine. Summary of the invention

[0013] The present invention provides a long-acting non-intestinal pharmaceutical composition comprising a therapeutically effective amount of cariprazine or a pharmaceutically acceptable salt thereof, particularly cariprazine HCl. In some embodiments, the present invention provides a long-acting pharmaceutical composition in the form of a reservoir, comprising a therapeutically effective amount of cariprazine or a pharmaceutically acceptable salt thereof, which is suitable for parenteral administration at a medically acceptable location of a subject in need. The present invention also 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 parenteral administration of a composition comprising a therapeutically effective amount of cariprazine or a salt thereof to a subject in need.

[0014] The present invention is based in part on the unexpected discovery that long-acting cariprazine formulations (such as in situ implants) can provide metronomic therapy with a continuous flow of low-dose cariprazine over a longer period of time, thereby providing a significantly improved side effect profile. Surprisingly, it has now been found that long-acting pharmaceutical compositions according to the principles of the present invention provide superior therapeutic efficacy and reduced incidence and / or severity of systemic side effects compared to conventional oral immediate-release cariprazine formulations.

[0015] According to a first aspect, the present invention provides a long-acting non-intestinal pharmaceutical composition suitable for forming an in situ implant in a subject in need thereof after administration, the composition comprising a therapeutically effective amount of cariprazine or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable biodegradable carrier and a biocompatible solvent, the pharmaceutically acceptable biodegradable carrier comprising poly(lactic-co-glycolic acid) (PLGA), which contains a molar ratio of lactic acid monomers to glycolic acid monomers of 50:50 to 85:15 and an intrinsic viscosity in the range of about 0.1 to about 0.8 dl / g, wherein the composition releases cariprazine or a pharmaceutically acceptable salt thereof for at least 4 weeks after 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 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 HCl) per injection, including each value within the specified range. 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 HCl) per injection, including each value within the specified range. According to 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 HCl), including each value within the specified range.

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

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

[0020] According to some embodiments, the composition is administered at a frequency of about once a month to about once every 3 months, or any period therebetween.

[0021] According to other embodiments, the composition provides extended release of the cariprazine active ingredient over a period of at least about one month to about three 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 a poly(lactic-co-glycolic acid) (PLGA) comprising lactic and glycolic acid end groups. According to some embodiments, the carrier is a poly(lactic-co-glycolic acid) (PLGA) comprising lactate and glycolate end groups.

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

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

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

[0027] According to some embodiments, the ratio between cariprazine or a pharmaceutically acceptable salt thereof and the 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 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 composition of the present invention further comprises one or more pharmaceutically acceptable excipients selected from preservatives, sustained-release agents, buffers, pH regulators and any combination thereof. Each possibility represents a separate embodiment. According to one embodiment, the sustained-release agent is a bile salt selected from 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 triethyl citrate, triacetin and lecithin. Each possibility represents a separate embodiment. According to another embodiment, the pH regulator comprises a carboxylic acid selected from 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 pharmaceutically 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 pharmaceutically 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 its pharmaceutically acceptable salt in 1 week in an aqueous medium containing 0.1% sodium lauryl sulfate as measured using a Type II dissolution apparatus. According to some embodiments, the composition releases less than 30% of the cariprazine or its pharmaceutically acceptable salt in 1 week in an aqueous medium containing 0.1% sodium lauryl sulfate as measured using a Type II dissolution apparatus. According to some embodiments, the composition releases less than 20% of the cariprazine or its pharmaceutically acceptable salt in 1 week in an aqueous medium containing 0.1% sodium lauryl sulfate as measured using a Type II dissolution apparatus. According to some embodiments, the composition releases about 8% to about 40% of the cariprazine or its pharmaceutically acceptable salt in 1 week in an aqueous medium containing 0.1% sodium lauryl sulfate as measured using a Type II dissolution apparatus.

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

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

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

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

[0036] According to some embodiments, the composition provides a therapeutically effective plasma concentration of cariprazine for at least 4 weeks after a single administration. According to some embodiments, the composition provides a substantially constant plasma concentration of cariprazine between about 60 hours to about 600 hours after a single administration, including each value within the specified range.

[0037] The present invention encompasses the use of the long-acting cariprazine compositions disclosed herein in methods of 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] Therefore, according to some embodiments, the present invention provides a method of treating a disease or disorder selected from schizophrenia, major depression and bipolar disorder in a subject in need thereof, the method comprising administering to the subject a long-acting non-intestinal pharmaceutical composition disclosed herein. According to some embodiments, the present invention provides a long-acting non-intestinal pharmaceutical composition disclosed herein for treating a disease or disorder selected from schizophrenia, major depression and bipolar disorder. Each possibility represents a separate embodiment.

[0039] As contemplated herein, the reservoir compositions of the present invention provide equal or superior therapeutic efficacy compared to conventional immediate-release oral cariprazine formulations while reducing the incidence and / or severity of systemic side effects. According to some embodiments, the compositions of the present invention provide extended release or extended action of cariprazine and / or its metabolites demethylcariprazine (DCAR) and didesmethylcariprazine (DDCAR) in a subject compared to an immediate-release oral formulation.

[0040] Further embodiments and the full scope of applicability of the present invention will become apparent from the detailed description given below. However, it should be understood that the detailed description and specific examples, while indicating preferred embodiments of the present invention, are given only as illustrations, as those skilled in the art will clearly understand various changes and modifications within the spirit and scope of the present invention from the detailed description. BRIEF DESCRIPTION OF THE DRAWINGS

[0041] Figure 1 Cariprazine release from Formulation A in 0.1% SLS, 0.1 M HEPES, and 0.1 M acetate buffer media is shown.

[0042] Figure 2 The release of cariprazine from Formulation B in 0.1% SLS dissolution medium is shown.

[0043] Figure 3 Shown is the pharmacokinetic release profile obtained from a single administration of cariprazine Formulation B compared to the pharmacokinetic release profile obtained from daily oral administration of an immediate release formulation of cariprazine in a rat model.

[0044] Figure 4 The release of cariprazine from Formulation C in 0.1% SLS dissolution medium is shown.

[0045] Figure 5 The release of cariprazine from Formulation D in 0.1% SLS dissolution medium is shown.

[0046] Figure 6 The release of cariprazine from Formulation E in 0.1% SLS dissolution medium is shown.

[0047] Figure 7 The release of cariprazine from Formulation F in 0.1% SLS dissolution medium is shown. DETAILED DESCRIPTION

[0048] The present invention provides a long-acting in situ-formed reservoir composition of cariprazine or its salt, particularly cariprazine HCl, which provides a superior therapeutic efficacy than daily oral administration, thereby improving patient compliance. In addition to providing excellent therapeutic efficacy, the long-acting composition also reduces the side effects of cariprazine caused by the peak concentration of the drug in the blood.

[0049] The present invention therefore provides a long-acting non-intestinal pharmaceutical composition comprising a therapeutically effective amount of cariprazine or a pharmaceutically acceptable salt thereof, wherein the composition is in a reservoir form suitable for non-intestinal administration at a medically acceptable site of a subject in need thereof. The reservoir composition may be suitable for subcutaneous or intramuscular administration.

[0050] Reservoir system

[0051] Oral administration of small molecules is the most common and effective delivery method. However, the maximum duration of drug products in the gastrointestinal tract is limited to 18-36 hours. This requires frequent administration, which may reduce patient compliance. By using long-acting drug preparations, such as injectable reservoir preparations that can release drugs in a slow but predictable manner, it is possible to reduce the frequency of oral drug administration, thereby improving compliance. For most drugs, depending on the dose, the frequency of administration can be reduced from daily administration to once a week, once a month or twice, or even longer (once every 3 to 6 months). In addition to improving patient compliance, the less frequent administration of drugs in the form of reservoir preparations smoothes the plasma concentration-time curve by eliminating peaks and troughs. This smooth plasma curve is not only likely to promote therapeutic benefits, but also likely to reduce any adverse reactions, such as those associated with oral administration of cariprazine.

[0052] Microparticles, implants and gels are the most common forms of biodegradable polymer systems used in practice for extended in vivo drug release. Microparticles are usually suspended in an aqueous medium before injection to provide a suspension containing up to 40% solids. Implant / rod formulations can be injected subcutaneously (SC) and / or intramuscularly (IM) with the aid of a special needle in a dry state without the need for an aqueous medium.

[0053] Although microparticle reservoir formulations and implant / rod formulations allow for the delivery of higher doses of active ingredients, they generally present several disadvantages. The preparation process of microparticles generally involves a multi-step procedure, which limits their application in drug delivery systems. The complex manufacturing procedures also pose difficulties in scaling up production. In addition, parenteral sustained-release suspensions are dispersed heterogeneous systems containing insoluble drug particles that need to be resuspended before administration. However, stability issues caused by particle sedimentation often occur, limiting the use of parenteral suspensions as drug delivery systems. Although surgical implants show good controlled-release profiles and reproducible manufacturing procedures, they require surgery to insert the implant into the body, which is often painful, resulting in poor patient compliance.

[0054] Alternative drug delivery systems, i.e., in situ forming biodegradable implants for prolonged 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 consist of biodegradable polymers dissolved in a biocompatible solvent. Otherwise, these systems are in solution form and convert into gels upon contact with body fluids after administration. The drug present in these systems is embedded in the polymer matrix formed after gelation, thereby achieving its slow release by diffusion and degradation of the hardened gel matrix. These systems have several advantages over other controlled-release systems. In situ forming systems are prepared using a single-step process, which reduces process variability and achieves product uniformity and reproducibility. Other advantages include biocompatibility with biological systems, solubilization of low molecular weight hydrophobic drugs, and controlled release over weeks to months (Critical Reviews TM in Therapeutic Drug Carrier Systems, 36(2):93–136(2019)).

[0055] According to the principles of the present invention, the compositions disclosed herein are administered parenterally. As used herein, the term "parenteral" refers to a route of administration selected from subcutaneous (SC), intravenous (IV), intramuscular (IM), intradermal (ID), intraperitoneal (IP), etc. Each possibility represents a separate embodiment. According to a specific embodiment, the composition is administered via an intramuscular (IM) route.

[0056] According to 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 the subject after administration, thereby forming a long-acting in situ reservoir system. As used herein, the term "long-acting" refers to a composition that provides a lasting, continuous or extended release of the active ingredient of cariprazine to the subject's systemic circulation or the subject's local site of action. The term may also refer to a composition that provides a lasting, continuous or extended duration of action of cariprazine and / or its metabolites demethylcariprazine (DCAR) and didemethylcariprazine (DDCAR) in the subject.

[0057] Depending on the desired duration of action, each reservoir formulation generally contains about 1 to about 500 mg of active ingredient, including each value within the specified range. Suitable alternative dosages 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 based on various parameters, including the route of administration, age, weight, and severity of the patient's symptoms.

[0058] According to various embodiments of the present invention, for an adult with an average weight of about 70 kg, the therapeutically effective amount of cariprazine ranges from about 1 mg to about 10 mg / day, including each value within the specified range. Alternatively, such a therapeutically effective amount of cariprazine ranges from about 1.5 mg to about 6 mg / day, including each value within the specified range. Alternatively, such a therapeutically effective amount of cariprazine ranges from about 3 mg to about 6 mg / day, including each value within the specified range.

[0059] In some embodiments, the concentration range of cariprazine in the formulations of the present invention is from about 10 mg / mL to about 80 mg / mL, including each value within the specified range. In other embodiments, the concentration range of cariprazine in the formulations of the present invention is from about 20 mg / mL to about 60 mg / mL, including each value within the specified range. In other embodiments, the concentration range of cariprazine in the formulations of the present invention is from about 20 mg / mL to about 50 mg / mL, including each value within the specified range. In other embodiments, the concentration range of cariprazine in the formulations of the present invention is from about 10 mg / mL to about 100 mg / mL, including each value within the specified range.

[0060] In some embodiments, the concentration of cariprazine in the formulations of the present invention is from about 0.5% to about 20%, including each value within the specified range. In other embodiments, the concentration of cariprazine in the formulations of the present invention is from about 1% to about 10%, including each value within the specified range. In other embodiments, the concentration of cariprazine in the formulations of the present invention is from about 1% to about 5%, including each value within the specified range.

[0061] As expected herein, the reservoir composition of the present invention is designed to be used once in a time period of about 4 weeks to about 6 months, and the extended release of the cariprazine active ingredient is provided in this time period. The reservoir composition can be adjusted to release the cariprazine active ingredient in a desired time period, for example, in a time period of about 1 month, in a time period of about 3 months, or in any time period therebetween. Therefore, by way of example and not limitation, the composition of the present invention can be conveniently injected with a frequency of 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 time period therebetween. Each possibility represents a separate embodiment of the present invention.

[0062] As used herein, the term "cariprazine" 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. As used herein, the term "salt" covers base addition salts and acid addition salts, including but not limited to acid addition salts of amine nitrogen with organic or inorganic acids. 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, bile 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, etc. Each possibility represents a separate embodiment of the present invention. A currently preferred cariprazine salt is cariprazine hydrochloride (cariprazine HCl).

[0063] The present invention also includes solvates of cariprazine and its salts. As used herein, the term "solvate" refers to the physical association of cariprazine or its salt with one or more solvent molecules. This physical association involves varying degrees of ionic bonds and covalent bonds, including hydrogen bonds. In some cases, the solvate can be separated. "Solvate" encompasses solution phase and separable solvates. Non-limiting examples of suitable solvates include ethanolates, methanolates, etc. Each possibility represents a separate embodiment. When the solvent is water, cariprazine is a hydrate. The term "hydrate" encompasses but is not limited to monohydrates, dihydrates, trihydrates, tetrahydrates, pentahydrates, hemihydrates, sesquihydrates, disesquihydrates, etc. Each possibility represents a separate embodiment.

[0064] The present invention also includes polymorphs of cariprazine or cariprazine salts. As used herein, "polymorph" refers to a specific crystalline state of a substance, which is characterized by specific physical properties, such as X-ray diffraction, infrared spectrum, Raman spectrum, melting point, etc.

[0065] In some embodiments, the depot formulation of the present invention is in the form of a solution or suspension of cariprazine or a pharmaceutically acceptable salt thereof in water, oil or wax phase, a poorly soluble polyelectrolyte complex of cariprazine or a pharmaceutically acceptable salt thereof, and an "in situ" gel-forming matrix based on a combination of a water-miscible solvent and cariprazine or a pharmaceutically 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.

[0066] In certain embodiments, the dosage form includes, but is not limited to, a biodegradable injectable composition, also referred to as an injectable ISI (in situ implant), which is a solution or suspension capable of forming a reservoir system upon contact with body fluids after administration. The formation of the reservoir system is provided by the presence of a biodegradable polymer and a water-miscible solvent. Once the composition contacts the body fluid, the polymer gels or hardens to form a solid or semisolid implant, embedding the active ingredient in a polymer matrix. After the polymer matrix biodegrades, the active ingredient is released in a continuous and sustained manner.

[0067] As used herein, the term "biodegradable" refers to a component whose surface will erode or degrade over time, at least in part due to contact with substances in the surrounding tissue fluid or due to cellular action. In particular, the biodegradable component is a polymer, such as, but not limited to, a lactic acid-based polymer, such as polylactic acid, such as poly(D,L-lactic acid), i.e., PLA; a glycolic acid-based polymer, such as polyglycolic acid (PGA), such as Durect's Poly(D,L-lactic-co-glycolic acid), PLGA, (Boehringer RG-504, RG-502, RG-504H, RG-502H, RG-504S, RG-502S, and Durect ); polycaprolactone, such as poly(ε-caprolactone), i.e. PCL (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; poly(p-carboxyphenoxy)methane, CPM; poly(p-carboxyphenoxy)propane, CPP; poly(p-carboxyphenoxy)hexane CPH; polyamines, polyurethanes, polyesteramides, polyorthoesters {CHDM: cis / trans-cyclohexanedimethanol, HD: 1,6-hexanediol. DETOU: (3,9-diethylene-2,4,8,10-tetraoxaspiroundecane)}; polydioxanone; polyhydroxybutyrate; polyalkylene oxalate; polyamide; polyesteramide; polyurethane; polyacetal; polyketal; polycarbonate; polyorthocarbonate; polysiloxane; polyphosphazene; succinate; hyaluronic acid; polymalic acid; polyamino acid; polyhydroxyvalerate; polyalkylene succinate; polyvinylpyrrolidone; polystyrene; synthetic cellulose ester; polyacrylic acid; polybutyric acid; triblock copolymer (PLG A-PEG-PLGA), triblock copolymers (PEG-PLGA-PEG), poly(N-isopropylacrylamide) (PNIPAAm), poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) triblock copolymers (PEO-PPO-PEO), polyvaleric acid; polyethylene glycol; polyhydroxyalkyl cellulose; chitin; chitosan; polyorthoesters and copolymers, terpolymers; lipids such as cholesterol, lecithin; poly(glutamic acid-ethyl glutamate copolymer), etc., or mixtures thereof. Each possibility represents a separate embodiment.

[0068] According to the principles of the present invention, biodegradable polymers include, but are not limited to, polylactic acid, polyglycolic acid, polycaprolactone, polyanhydride, gelatin, collagen, cellulose, polyamide, polyurethane, polyesteramide, polyorthoester, polydioxanone, polyacetal, polyketal, polycarbonate, polyorthocarbonate, polyphosphazene, polyhydroxybutyrate, polyhydroxyvalerate, polyalkylene oxalate, polyalkylene succinate, polymalic acid, polyamino acid and copolymers thereof, terpolymers thereof and combinations thereof. Each possibility represents a separate embodiment of the present invention.

[0069] In some currently preferred embodiments, the biodegradable polymer is selected from poly(lactic-co-glycolic acid) (PLGA), polylactic acid (PLA), poly(glycolic acid) (PGA), and any combination thereof. Each possibility represents a separate embodiment of the present invention.

[0070] Biodegradable polyesters of poly(lactic acid) (PLA), polyglycolic acid (PGA), and copolymers of lactic and glycolic acid (PLGA), also known as poly(lactic-co-glycolic acid) (PLGA), are the most commonly used polymers in biodegradable dosage forms. PLA is a hydrophobic molecule, while PLGA degrades faster than PLA due to the presence of more hydrophilic glycolic acid groups. These biocompatible polymers cleave ester bonds via random, non-enzymatic, hydrolytic cleavage to form lactic and glycolic acids, which are normal metabolic compounds in the body. Absorbable sutures, clips, and implants were the earliest applications of these polymers.

[0071] In one embodiment, the biodegradable polymer is a lactic acid-based polymer, such as polylactic acid or poly (D, L-lactic acid-co-glycolic acid), i.e., PLGA. The amount of the biodegradable polymer may be about 20% to about 50% w / w of the composition, including each value within the specified range. The monomer ratio of lactic acid to glycolic acid of the lactic acid-based polymer is in the range of 100:0 to 0:100, for example, in the range of 100:0 to 10:90, and the average molecular weight is about 1,000 to about 200,000 Daltons, including each value within the specified range. However, it should be understood that the amount of the biodegradable polymer is determined by parameters such as the duration of use. PLGA polymers are available from multiple suppliers, such as Alkermes (Medisorb polymers), Absorbable Polymers International [formerly Birmingham Polymers (a division of Durect)], Ashland, Purac, and Boehringer Ingelheim.

[0072] The present invention encompasses a biodegradable carrier comprising poly(lactic-co-glycolic acid) (PLGA), the PLGA containing lactic acid monomers and glycolic acid monomers in a molar ratio of 50:50 to 85:15, and an intrinsic viscosity in the range of about 0.1 to about 0.8 dl / g, including each value in the specified range. 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 other embodiments, the molar ratio of lactic acid monomers to glycolic acid monomers in the PLGA is 85:15.

[0073] In some embodiments, the intrinsic viscosity of PLGA ranges from about 0.2 to about 0.7 dl / g, including each value within the specified range. In other embodiments, the intrinsic viscosity of PLGA ranges from about 0.3 to about 0.7 dl / g, including each value within the specified range. In other embodiments, the intrinsic viscosity of PLGA ranges from about 0.4 to about 0.6 dl / g, including each value within the specified range. Although a single PLGA polymer can be used in the composition of the present invention, it is contemplated that two or more PLGA polymers can be mixed and used in the ISI composition of the present invention to provide a combination of intrinsic viscosities within the desired range. Typically, PLGA with a higher intrinsic viscosity and PLGA with a lower intrinsic viscosity are present in the composition in a ratio of 2: 1 to 1: 1, including all ratios within this range.

[0074] According to some aspects and embodiments, PLGA is characterized by acid termination, i.e., the end groups of the polymer include lactic acid and / or glycolic acid. According to other aspects and embodiments, PLGA is characterized by ester termination, i.e., the end groups of the polymer include lactate and / or glycolate. Combinations of acid-terminated PLGA and ester-terminated PLGA are also encompassed by the present invention.

[0075] According to some embodiments, the ratio between cariprazine or its pharmaceutically acceptable salt and the PLGA carrier is about 1:1 to about 1:100, including each value in the specified range. Therefore, in some embodiments, the ratio between cariprazine or its pharmaceutically acceptable salt and the PLGA carrier is about 1:1 to about 1:75, including each value in the specified range. In other embodiments, the ratio between cariprazine or its pharmaceutically acceptable salt and the PLGA carrier is about 1:1 to about 1:50, including each value in the specified range. In other embodiments, the ratio between cariprazine or its pharmaceutically acceptable salt and the PLGA carrier is about 1:1 to about 1:40, including each value in the specified range. Preferably, the ratio between cariprazine or its pharmaceutically acceptable salt and the PLGA carrier is about 1:5 to about 1:25, including each value in the specified range.

[0076] 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 being able to dissolve the PLGA and cariprazine active ingredients. After the solution is administered, exposure to body fluids triggers an exchange between the solvent and water at the injection site, causing the solvent to diffuse out of the polymer and drug mixture, while water diffuses into the mixture, which hardens the polymer to form a matrix that entraps or encapsulates the drug. 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. It is currently preferred to use benzyl alcohol as a biocompatible solvent.

[0077] The composition of the present invention may further comprise one or more pharmaceutically acceptable excipients 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, defoamers, stabilizers (such as antioxidants), tonicity modifiers, buffers, pH regulators, sustained-release agents, oily components, emulsifiers, channel formers, osmotic regulators, or any other excipients known in the art. Each possibility represents a separate embodiment.

[0078] Suitable co-surfactants include, but are not limited to, polyethylene glycol, polyoxyethylene-polyoxypropylene block copolymers (known as "poloxamers"), polyglycerol fatty acid esters (such as decaglycerol monolaurate and decaglycerol 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 oil and hardened castor oil (such as polyoxyethylene hardened castor oil), etc. or mixtures thereof. Each possibility represents a separate embodiment of the present invention.

[0079] Suitable solvents / co-solvents include, but are not limited to, alcohols, triacetin, dimethyl isosorbide, furfuryl alcohol, propylene carbonate, water, dimethylacetamide, etc. or mixtures thereof. Each possibility represents a separate embodiment of the present invention.

[0080] Suitable antifoaming agents include, but are not limited to, silicone emulsions or sorbitan sesquioleate.

[0081] When present, examples of suitable stabilizers for preventing or reducing degradation of the components in the compositions of the present invention include, but are not limited to, antioxidants, such as glycine, α-tocopherol or ascorbic acid, BHA, BHT, etc., or mixtures thereof. Each possibility represents a separate embodiment of the present invention. In some embodiments, the composition does not contain a stabilizer. In other embodiments, the composition does not contain a component that reduces the surface tension of the composition. In other embodiments, the composition does not contain Tween, Span, poloxamer, tocopherol, cremophor, lecithin, polyethylene glycol, and / or polyethylene glycol esters.

[0082] Examples of suitable preservatives for use in the compositions of the present invention include, but are not limited to, quaternary ammonium halides, benzyl alcohol, thimerosal, disodium edetate, and phenylethyl alcohol. Each possibility represents a separate embodiment of the present invention.

[0083] Suitable tonicity modifiers for use in the compositions of the present invention include, but are not limited to, mannitol, sodium chloride, and dextrose.Each possibility represents a separate embodiment of the present invention.

[0084] When present, examples of suitable buffers for the compositions of the present invention include, but are not limited to, acetate buffers, borate buffers, tartrate buffers, lactate buffers, citrate buffers, phosphate buffers (e.g., potassium dihydrogen phosphate), citric acid / phosphate buffers, carbonate / carbonic acid buffers, succinate / succinic acid buffers, and tris(hydroxymethyl)aminomethane / hydrochloric acid buffers, etc. Each possibility represents a separate embodiment of the present invention. In some embodiments, the compositions of the present invention do not contain a buffer. In one embodiment, the composition does not contain a buffer selected from phosphate, acetic acid, citric acid, succinic acid, adipic acid, tartaric acid, ascorbic acid, and / or malic acid and salts thereof.

[0085] Suitable pH adjusting agents for the present composition can 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 a combination thereof. Each possibility represents a separate embodiment of the present invention. Exemplary pH adjusting agents 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. Currently preferred pH adjusting agent is benzoic acid.

[0086] 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. Currently preferred bile salts are sodium deoxycholate. Other 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. Currently preferred sustained-release agents are triethyl citrate, which can also be used as a pH regulator.

[0087] In some embodiments, the composition of the present invention does not contain sodium carboxymethylcellulose, gelatin, polyvinyl pyrrolidone, methylcellulose and / or gum arabic. In other embodiments, the composition of the present invention does not contain hydrochloric acid, acetic acid, phosphoric acid, sodium hydroxide, disodium hydrogen phosphate, calcium carbonate and / or magnesium hydroxide.

[0088] The composition of the present invention can be prepared by any means known in the art. For example, the composition can be prepared by dissolving a biodegradable polymer, cariprazine and optional excipients in a biocompatible organic solvent.

[0089] According to the principles of the present invention, the composition can also be provided as a kit, which includes a biodegradable polymer, cariprazine and a biocompatible organic solvent in one compartment or several compartments and instructions for use. The composition can also be provided as a pre-filled syringe, ready for use.

[0090] Release Distribution

[0091] According to the principles of the present invention, compared with the commercially available daily oral dosage form of cariprazine, the long-acting pharmaceutical composition of the present invention provides better therapeutic efficacy while reducing the incidence and / or severity of systemic side effects. ), the compositions of the present invention provide extended release or extended action of cariprazine and / or its metabolites desmethylcariprazine (DCAR) and didesmethylcariprazine (DDCAR) in a subject.

[0092] The scope of the present invention relates to an ISI composition, which provides a burst release of less than about 20% of cariprazine in an aqueous medium containing 0.1% sodium lauryl sulfate (SLS) measured using a Type II dissolution apparatus. According to the principles of the present invention, a reduced burst release (release of the active ingredient immediately after administration) is provided, thereby minimizing or eliminating adverse reactions caused by systemic exposure to high-dose cariprazine active ingredients within 24-48 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, measured using a Type II dissolution apparatus. Despite the low burst release, the composition releases cariprazine immediately after administration without a lag time. Therefore, the composition provides a gradual release of cariprazine in a continuous manner over an extended duration of at least 4 weeks after a single administration.

[0093] In some embodiments, less than 40% of the cariprazine is released in 1 week in an aqueous medium containing 0.1% SLS as measured using a Type II dissolution apparatus. In other embodiments, less than 30% of the cariprazine is released in 1 week in an aqueous medium containing 0.1% SLS as measured using a Type II dissolution apparatus. In other embodiments, less than 20% of the cariprazine is released in 1 week in an aqueous medium containing 0.1% SLS as measured using a Type II dissolution apparatus. Typically, the composition releases about 8% to about 40% of the cariprazine or a pharmaceutically acceptable salt thereof in 1 week in an aqueous medium containing 0.1% SLS as measured using a Type II dissolution apparatus.

[0094] In some embodiments, less than 55% of the cariprazine is released in 2 weeks in an aqueous medium containing 0.1% SLS as measured using a Type II dissolution apparatus. In other embodiments, less than 45% of the cariprazine is released in 2 weeks in an aqueous medium containing 0.1% SLS as measured using a Type II dissolution apparatus. In other embodiments, less than 35% of the cariprazine is released in 2 weeks in an aqueous medium containing 0.1% SLS as measured using a Type II dissolution apparatus. Typically, the composition releases about 15% to about 53% of the cariprazine or a pharmaceutically acceptable salt thereof in 2 weeks in an aqueous medium containing 0.1% SLS as measured using a Type II dissolution apparatus.

[0095] In some embodiments, less than 80% of the cariprazine is released in 3 weeks in an aqueous medium containing 0.1% SLS as measured using a Type II dissolution apparatus. In other embodiments, less than 70% of the cariprazine is released in 3 weeks in an aqueous medium containing 0.1% SLS as measured using a Type II dissolution apparatus. In other embodiments, less than 60% of the cariprazine is released in 3 weeks in an aqueous medium containing 0.1% SLS as measured using a Type II dissolution apparatus. Typically, the composition releases about 36% to about 71% of the cariprazine or a pharmaceutically acceptable salt thereof in 3 weeks in an aqueous medium containing 0.1% SLS as measured using a Type II dissolution apparatus.

[0096] In some embodiments, less than 90% of the cariprazine is released in 4 weeks in an aqueous medium containing 0.1% SLS as measured using a Type II dissolution apparatus. In other embodiments, less than 80% of the cariprazine is released in 4 weeks in an aqueous medium containing 0.1% SLS as measured using a Type II dissolution apparatus. In other embodiments, less than 70% of the cariprazine is released in 4 weeks in an aqueous medium containing 0.1% SLS as measured using a Type II dissolution apparatus. Typically, the composition releases about 45% to about 86% of the cariprazine or a pharmaceutically acceptable salt thereof in 4 weeks in an aqueous medium containing 0.1% SLS as measured using a Type II dissolution apparatus.

[0097] In some embodiments, more than 50% of the cariprazine is released in 5 weeks in an aqueous medium containing 0.1% SLS as measured using a Type II dissolution apparatus. In other embodiments, more than 60% of the cariprazine is released in 5 weeks in an aqueous medium containing 0.1% SLS as measured using a Type II dissolution apparatus. In other embodiments, more than 70% of the cariprazine is released in 5 weeks in an aqueous medium containing 0.1% SLS as measured using a Type II dissolution apparatus. Typically, the composition releases about 62% to about 92% of the cariprazine or a pharmaceutically acceptable salt thereof in an aqueous medium containing 0.1% SLS in 5 weeks as measured using a Type II dissolution apparatus.

[0098] According to some embodiments, the composition provides a therapeutically effective plasma concentration of cariprazine or its metabolites for at least 4 weeks (e.g., about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks or longer) after a single administration. Each possibility represents a separate embodiment. According to some embodiments, the composition provides a substantially constant plasma concentration of cariprazine between about 60 hours to about 600 hours after a single administration, including each value within the specified range. As used herein, the term "substantially constant" refers to a therapeutically effective plasma concentration, and there are no dramatic fluctuations, such as the peaks and troughs that often occur when administering an immediate release cariprazine formulation.

[0099] Therapeutic Uses

[0100] The depot formulations of the present invention are particularly useful in methods of treating diseases and conditions for which cariprazine has been shown to have therapeutic efficacy.

[0101] Thus, in some embodiments, the present invention is directed to a method of treating schizophrenia by administering a depot formulation comprising cariprazine or a salt thereof to a schizophrenia patient in need thereof.

[0102] In other embodiments, the present invention is directed to a method of treating MDD (major depressive disorder) by administering a depot formulation comprising cariprazine or a salt thereof to a patient in need thereof suffering from major depressive disorder.

[0103] In other embodiments, the present invention is directed to a method of treating bipolar disorder by administering a depot formulation comprising cariprazine or a salt thereof to a patient suffering from bipolar disorder in need thereof.

[0104] In other embodiments, the present invention is directed to a method of treating manic or mixed episodes associated with bipolar I disorder by administering a depot formulation comprising cariprazine or a salt thereof to a patient suffering from bipolar I disorder in need thereof.

[0105] In other embodiments, the present invention is directed 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 with bipolar I disorder in need thereof.

[0106] In other embodiments, the present invention is directed to a long-acting parenteral pharmaceutical composition in depot form comprising cariprazine or a salt thereof for use in the treatment of schizophrenia.

[0107] In other embodiments, 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 MDD (major depressive disorder).

[0108] In other embodiments, the present invention relates to a long-acting parenteral pharmaceutical composition in a depot form comprising cariprazine or a salt thereof for use in bipolar disorder.

[0109] In other embodiments, the present invention is directed to a long-acting parenteral pharmaceutical composition comprising cariprazine or a salt thereof in depot form for use in treating manic or mixed episodes associated with bipolar I disorder.

[0110] In other embodiments, the present invention is directed to a long-acting parenteral pharmaceutical composition in depot form comprising cariprazine or a salt thereof for use in treating depressive episodes associated with bipolar I disorder (bipolar depression).

[0111] As used herein, the term "schizophrenia" includes disorders that are generally described as schizophrenia or disorders with symptoms associated therewith. Schizophrenia can be viewed as a disease with a series of manifestations at various threshold levels of a chronic debilitating disorder, characterized by a range of psychopathology, including positive symptoms, such as abnormal or distorted mental representations (e.g., hallucinations, delusions), negative symptoms, characterized by a reduction in motivation and adaptive goal-oriented actions (e.g., lack of pleasure, flat affect, lack of will), and cognitive impairment. Schizophrenia can be diagnosed by a professional physician based on personal and medical history, interview consultation, and physical examination.

[0112] The term "major depressive disorder" or "MDD" refers to a severe depression characterized by a combination of symptoms that interfere with a person's ability to work, sleep, learn, eat, and enjoy activities that were once pleasurable. Major depressive disorder can be disabling and make it impossible for a person to function normally. Some people may experience only one episode in their lifetime, but more commonly, a person may have multiple episodes.

[0113] The term "bipolar disorder" or "BP" includes "bipolar I disorder" and "bipolar II disorder", and refers to a chronic mental / mood disorder characterized by significant mood changes, including depressive periods and euphoric manic periods. Bipolar I disorder is a form of BP characterized by severe mood episodes ranging from mania to depression. Bipolar II disorder is a milder form of mood elevation, involving alternating episodes of milder hypomania with severe depressive periods. The term "treatment of bipolar disorder" includes the treatment of manic or mixed episodes associated with bipolar I disorder and / or depressive episodes associated with bipolar I disorder (bipolar depression). Bipolar disorder can be diagnosed by a professional physician based on personal and medical history, interview consultation, and physical examination.

[0114] The term "mania" or "manic phase" or other variations refers to a period during which an individual exhibits some or all of the following characteristics: racing thoughts, rapid speech, heightened activity levels and agitation, as well as inflated self-esteem, euphoria, poor judgment, insomnia, difficulty concentrating, and aggression.

[0115] As used herein, the term "treat" refers to taking steps to obtain a beneficial or desired result, including a clinical result. Beneficial or desired clinical results include, but are not limited to, preventing or slowing the progression of a disease or disorder, or alleviating, ameliorating, or slowing 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).

[0116] As used herein, the term "therapeutically effective amount" is intended to quantify the amount of cariprazine that is used to achieve the purpose of treating schizophrenia, MDD, or bipolar disorder (e.g., manic or mixed episodes associated with bipolar I disorder and / or depressive episodes associated with bipolar I disorder (bipolar depression)).

[0117] The present invention includes a combination therapy of cariprazine or a pharmaceutically 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 amisulpride, nemonapride, remoxipride, sultopride, tiapride, cinuperone, melperone, setoperone, iloperidone, ocaperidone, paliperidone, risperidone, lurasidone, perospirone, revospirone, tiospirone, ziprasidone, amperozide, aripiprazole, The invention relates to a pharmaceutical composition comprising the following: aripiprazole, bifeprunox, brexpiprazole, amoxapine, asenapine, carpipramine, clocapramine, clorotepine, clotiapine, clozapine, flumezapine, fluperlapine, gevotroline, metitepine, mosapramine, olanzapine, quetiapine, tenilapine, zotepine, or one or more of a pharmaceutically acceptable salt thereof. Each possibility represents a separate embodiment of the invention.

[0118] According to some embodiments, the depot composition of the present invention can 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.

[0119] As used herein and in the appended claims, the term "about" refers to ± 10%.

[0120] 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 biocompatible solvent" includes a plurality of such solvents. It should be noted that the term "and" or the term "or" are generally used in their sense, including "and / or", unless the context clearly dictates otherwise.

[0121] The following examples are intended to more fully illustrate certain embodiments of the present invention. However, these examples should not be construed as limiting the broad scope of the present invention in any way. Those skilled in the art can easily design many variations and modifications of the principles disclosed herein without departing from the scope of the present invention.

[0122] Example

[0123] General preparation method for PLGA-based injectable in situ implant (ISI) formulations

[0124] According to certain embodiments of the present invention, the ISI depot formulation is prepared using the following general procedure. PLGA, a biodegradable polymer, is dissolved in benzyl alcohol with continuous stirring overnight at room temperature. Cariprazine hydrochloride and optional excipients are dissolved in benzyl alcohol, respectively, and added to the PLGA solution. The mixture is then stirred at room temperature until complete homogeneity is achieved.

[0125] Example 1.

[0126] preparation

[0127] The preparation process of the cariprazine reservoir formulation (named as formulation A) is as follows. Acid-terminated PLGA 50:50 with a viscosity of 0.15-0.25 dl / g was mixed with ester-terminated PLGA50:50 with a viscosity of 0.55-0.75 dl / g in a ratio of 1:1 and a concentration of 30% (w / w) (total solvent). The dry polymer mixture was suspended in benzyl alcohol and stirred continuously at room temperature until a clear solution was obtained. Then, triethyl citrate (2.4% (w / w) of the formulation) was 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 uniform mixture was obtained.

[0128] Effectiveness calculation

[0129] The potency of the formulations was analyzed using HPLC and calculated according to the following formula:

[0130]

[0131] in:

[0132] CRPR corresponds to cariprazine;

[0133] A sa The peak area corresponding to cariprazine in the sample solution;

[0134] A R The peak area corresponding to cariprazine in the standard solution;

[0135] C R corresponds to the concentration of cariprazine in the standard solution (mg / mL);

[0136] C S corresponds to the concentration of cariprazine in the sample solution (mg / mL);

[0137] P corresponds to the potency of the standard; and

[0138] For unit conversion (from mg to g), a multiplication by 1000 was performed.

[0139] In vitro release of cariprazine from the formulation

[0140] Choose from three types of dissolution media:

[0141] 1) 0.1% SLS aqueous solution containing 0.02% sodium azide

[0142] 2) 0.1 M HEPES buffer (pH = 5.2), and

[0143] 3) 0.1 M acetate buffer (pH = 5.0).

[0144] To evaluate the release of cariprazine incorporated into the biodegradable PLGA matrix, a standard dissolution method was employed using a Type II dissolution apparatus.

[0145] Description of the sampling process:

[0146] Take 1500 μl of sample from the dissolution container and centrifuge at 10,000 rpm for 5 minutes. Transfer 1000 μl of supernatant to a 5.0 ml volumetric flask and dilute with diluent (0.1% H 3 PO 4 HPLC was used to quantitatively analyze the samples.

[0147] The release of cariprazine from Formulation A was tested over a period of 1-2 months. The results of the API release studies are presented in Tables 1 and Figure 1 The percentage of API in the formulation is 2.2%.

[0148] Table 1.

[0149]

[0150] Example 2.

[0151] preparation

[0152] The cariprazine reservoir formulation (named as Formulation B) was prepared using ester-terminated PLGA75:25 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 with 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 uniform mixture was obtained.

[0153] In vitro release of cariprazine from the formulation

[0154] 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 Tables 2 and Figure 2 The percentage of API in the formulation is 2.2%.

[0155] Table 2.

[0156]

[0157] Pharmacokinetic studies

[0158] A comparative study of the pharmacokinetics of cariprazine following a single intramuscular administration of Formulation B (LAI) in male Sprague Dawley rats was conducted by comparison with repeated doses (oral administration) of an immediate release formulation of cariprazine hydrochloride.

[0159] Group assignments and treatments are described in Table 3 .

[0160] Table 3.

[0161]

[0162] Group 1: On Day 1, Formulation B was slowly administered intramuscularly over 20 seconds in the thigh area of ​​rats.

[0163] Group 2: An immediate release formulation (0.1% acetic acid in deionized water (dw)) was administered orally once daily by gavage until day 28.

[0164] Figure 3Results of a PK study are shown. Although cariprazine plasma concentrations were comparable, daily oral administration resulted in significant fluctuations, whereas there were no such fluctuations when the 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 after a single IM administration, with substantially constant plasma concentrations.

[0165] Example 3.

[0166] preparation

[0167] The cariprazine reservoir formulation (named as Formulation C) was prepared using ester-terminated PLGA75:25 with a viscosity of 0.4-0.6 dl / g. The formulation was prepared by dissolving the polymer in benzyl alcohol with continuous stirring at room temperature. Cariprazine hydrochloride was dissolved in benzyl alcohol at a concentration of 18% ((w / w) of the solvent). After complete dissolution, the cariprazine solution was added to the polymer solution and stirred until a uniform mixture was obtained.

[0168] In vitro release of cariprazine from the formulation

[0169] In vitro release studies were conducted in aqueous media containing 0.1% SLS as described in Example 1. The results are shown in Tables 4 and Figure 4 The percentage of API in the preparation was 2.57%, and the amount of API injected was 45.03 mg.

[0170] Table 4.

[0171]

[0172] Thus, Formulation C provided release extended over two months.

[0173] Example 4.

[0174] preparation

[0175] A cariprazine reservoir formulation (designated as 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 with continuous stirring at room temperature. Cariprazine hydrochloride was dissolved in benzyl alcohol at a concentration of 18% ((w / w) of the solvent). After complete dissolution, the cariprazine solution was added to the polymer solution and stirred until a uniform mixture was obtained.

[0176] In vitro release of cariprazine from the formulation

[0177] In vitro release studies were conducted in aqueous media containing 0.1% SLS as described in Example 1. The results are shown in Tables 5 and Figure 5The percentage of API in the preparation was 4.52% and the amount of API injected was 44.32 mg.

[0178] Table 5.

[0179]

[0180] Thus, Formulation D provided release extended over two months.

[0181] Example 5.

[0182] preparation

[0183] The preparation process of the cariprazine reservoir formulation (named as formulation E) is as follows. Acid-terminated PLGA85:15 with a viscosity of 0.4-0.6 dl / g and acid-terminated PLGA85:15 with a viscosity of 0.2-0.4 dl / g are mixed in a ratio of 2:1 and a concentration of 40% (w / w). The polymer mixture is dissolved in benzyl alcohol with continuous stirring at room temperature. Cariprazine hydrochloride (15% (w / w) polymer) is added to the polymer solution and stirred until completely dissolved to obtain a uniform mixture.

[0184] In vitro release of cariprazine from the formulation

[0185] In vitro release studies were conducted in aqueous media containing 0.1% SLS as described in Example 1. The results are shown in Tables 6 and Figure 6 The percentage of API in the preparation was 4.07% and the amount of API injected was 44.4 mg.

[0186] Table 6.

[0187]

[0188] Thus, Formulation E provided release extended over two months.

[0189] Example 6.

[0190] preparation

[0191] The preparation process of cariprazine depot formulation (designated as Formulation F) is as follows: Ester-terminated PLGA 85:15 with a viscosity of 0.6-0.8 dl / g and acid-terminated PLGA 85:15 with a viscosity of 0.2-0.4 dl / g were mixed at a ratio of 1:1 and a concentration of 30% (w / w).

[0192] The polymer mixture was dissolved in benzyl alcohol at room temperature with continuous stirring. 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.

[0193] In vitro release of cariprazine from the formulation

[0194] In vitro release studies were conducted in aqueous media containing 0.1% SLS as described in Example 1. The results are shown in Tables 7 and Figure 7 The percentage of API in the preparation was 2.2% and the amount of API injected was 47.09 mg.

[0195] Table 7.

[0196]

[0197] Thus, Formulation F provided release extended over two months.

[0198] Although the present invention has been described in detail, it will be appreciated by those skilled in the art that many variations and modifications may be made. Therefore, the present invention should not be interpreted as being limited to the specifically described embodiments, and by referring to the following claims, it will be easier to understand the scope and concept of the present invention.

Claims

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

2. The composition according to claim 1, which is in the form of a solution.

3. The composition according to claim 1, which is in the form of a suspension.

4. The composition according to any one of claims 1 to 3, wherein the cariprazine salt is cariprazine HCl.

5. The composition according to any one of claims 1 to 4, which is administered at a frequency of about once a month to about once every 3 months.

6. The composition according to any one of claims 1 to 5, comprising a dosage of about 1 mg to about 100 mg of cariprazine or a pharmaceutically acceptable salt thereof.

7. The composition of any one of claims 1 to 5, comprising from about 1% to about 10% of cariprazine or a pharmaceutically acceptable salt thereof.

8. The composition of any one of claims 1 to 5, comprising about 20 mg / mL to about 60 mg / mL of cariprazine or a pharmaceutically acceptable salt thereof.

9. The composition of any one of claims 1 to 8, wherein the carrier is poly(lactic-co-glycolic acid) (PLGA) comprising lactic and glycolic acid end groups.

10. The composition of any one of claims 1 to 8, wherein the carrier is poly(lactic-co-glycolic acid) (PLGA) comprising lactate and glycolate end groups.

11. The composition of any one of claims 1 to 10, wherein the molar ratio of lactic acid monomers to glycolic acid monomers in the poly(lactic-co-glycolic acid) (PLGA) is 50:

50.

12. The composition of any one of claims 1 to 10, wherein the molar ratio of lactic acid monomers to glycolic acid monomers in the poly(lactic-co-glycolic acid) (PLGA) is 75:

25.

13. The composition of any one of claims 1 to 10, wherein the molar ratio of lactic acid monomers to glycolic acid monomers in the poly(lactic-co-glycolic acid) (PLGA) is 85:

15.

14. The composition of any one of claims 1 to 13, wherein the poly(lactic-co-glycolic acid) (PLGA) has an intrinsic viscosity in the range of about 0.2 dl / g to about 0.7 dl / g.

15. The composition of claim 14, wherein the poly(lactic-co-glycolic acid) (PLGA) has an intrinsic viscosity in the range of about 0.3 dl / g to about 0.7 dl / g.

16. The composition of claim 15, wherein the poly(lactic-co-glycolic acid) (PLGA) has an intrinsic viscosity in the range of about 0.4 dl / g to about 0.6 dl / g.

17. The composition of any one of claims 1 to 13 comprising a single PLGA polymer.

18. The composition of any one of claims 1 to 13, comprising a combination of two or more PLGA polymers having different intrinsic viscosities.

19. The composition according to any one of claims 1 to 18, wherein the biocompatible solvent is selected from benzyl alcohol, methyl benzoate, ethyl benzoate, n-propyl benzoate, isopropyl benzoate, butyl benzoate, isobutyl benzoate, tert-butyl benzoate and benzyl benzoate.

20. The composition of claim 19, wherein the biocompatible solvent is benzyl alcohol.

21. The composition according to any one of claims 1 to 20, further comprising one or more pharmaceutically acceptable excipients selected from preservatives, sustained-release agents, buffers, pH adjusters, and any combination thereof.

22. The composition according to claim 21, wherein the sustained release agent is a bile salt selected from sodium deoxycholate, sodium glycocholate, sodium taurocholate, sodium fusidate, sodium glycodeoxycholate and sodium taurodihydrofusidate.

23. The composition of claim 21, wherein the sustained release agent is selected from the group consisting of triethyl citrate, triacetin and lecithin.

24. The composition of claim 21, wherein the pH adjuster is a carboxylic acid selected from 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.

25. A composition according to any one of claims 1 to 24, in, The composition provides a burst release of less than about 20% 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.

26. The composition according to claim 25, in, The composition provides a burst release of 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.

27. A composition according to any one of claims 1 to 26, in, The composition releases less than 40% of cariprazine or a pharmaceutically acceptable salt thereof in an aqueous medium containing 0.1% sodium lauryl sulfate within 1 week as measured using a Type II dissolution apparatus.

28. The composition according to claim 27, in, The composition releases about 8% to about 40% of cariprazine or a pharmaceutically acceptable salt thereof in an aqueous medium containing 0.1% sodium lauryl sulfate within 1 week as measured using a Type II dissolution apparatus.

29. A composition according to any one of claims 1 to 28, in, The composition releases less than about 55% of cariprazine or a pharmaceutically acceptable salt thereof in an aqueous medium containing 0.1% sodium lauryl sulfate within 2 weeks as measured using a Type II dissolution apparatus.

30. The composition according to claim 29, in, The composition releases about 15% to about 53% of cariprazine or a pharmaceutically acceptable salt thereof in an aqueous medium containing 0.1% sodium lauryl sulfate within 2 weeks as measured using a Type II dissolution apparatus.

31. A composition according to any one of claims 1 to 30, in, The composition releases less than about 80% of cariprazine or a pharmaceutically acceptable salt thereof in an aqueous medium containing 0.1% sodium lauryl sulfate within 3 weeks as measured using a Type II dissolution apparatus.

32. The composition according to claim 31, in, The composition releases about 36% to about 71% of cariprazine or a pharmaceutically acceptable salt thereof in an aqueous medium containing 0.1% sodium lauryl sulfate over 3 weeks as measured using a Type II dissolution apparatus.

33. A composition according to any one of claims 1 to 32, in, The composition releases less than about 90% of cariprazine or a pharmaceutically acceptable salt thereof in an aqueous medium containing 0.1% sodium lauryl sulfate within 4 weeks as measured using a Type II dissolution apparatus.

34. The composition according to claim 33, in, The composition releases about 45% to about 86% of cariprazine or a pharmaceutically acceptable salt thereof in an aqueous medium containing 0.1% sodium lauryl sulfate over a period of 4 weeks as measured using a Type II dissolution apparatus.

35. A composition according to any one of claims 1 to 34, in, The composition releases less than about 50% of cariprazine or a pharmaceutically acceptable salt thereof in an aqueous medium containing 0.1% sodium lauryl sulfate over a period of 5 weeks as measured using a Type II dissolution apparatus.

36. The composition according to claim 35, in, The composition releases about 62% to about 92% of cariprazine or a pharmaceutically acceptable salt thereof in an aqueous medium containing 0.1% sodium lauryl sulfate over 5 weeks as measured using a Type II dissolution apparatus.

37. The composition of any one of claims 1 to 36, which provides therapeutically effective plasma concentrations of cariprazine for at least 4 weeks after a single administration.

38. The composition of any one of claims 1 to 37, which provides a substantially constant plasma concentration of cariprazine from about 60 hours to about 600 hours after a single administration.

39. The composition according to any one of claims 1 to 38, which provides equal or superior therapeutic efficacy compared to conventional immediate release oral cariprazine formulations while reducing the incidence and / or severity of side effects at the systemic level.

40. The composition of any one of claims 1 to 39, which provides extended release or prolonged action of cariprazine and / or its metabolites desmethylcariprazine (DCAR) and didesmethylcariprazine (DDCAR) in a subject compared to an immediate release oral formulation.

41. A composition according to any one of claims 1 to 40 for use in treating a disease or disorder selected from schizophrenia, major depressive disorder and bipolar disorder.

42. The composition for use according to claim 41, wherein treating bipolar disorder comprises treating a manic or mixed episode associated with bipolar I disorder and / or a depressive episode associated with bipolar I disorder.

43. 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 the long-acting parenteral pharmaceutical composition of any one of claims 1 to 40.

44. The method of claim 43, wherein treating bipolar disorder comprises treating a manic or mixed episode associated with bipolar I disorder and / or a depressive episode associated with bipolar I disorder.

Images