Pharmaceutical composition containing a cannabinoid agonist

Abstract

The present disclosure relates to a pharmaceutical composition comprising Compound I or a pharmaceutically acceptable salt thereof as an active ingredient. The pharmaceutical composition is suitable for use in an immediate-release pharmaceutical formulation. The pharmaceutical formulation is suitable for use in treating medical conditions that benefit from treatment with a CB1 / CB2 receptor agonist.

Description

Technical Field

[0001] The present disclosure relates to a pharmaceutical composition comprising N-(2-(tert-butyl)-1-((4,4-difluorocyclohexyl)methyl)-1H-benzimidazol-5-yl)ethanesulfonamide, or a pharmaceutically acceptable salt thereof, as an active substance. The pharmaceutical composition is suitable for use in an immediate-release pharmaceutical preparation. The pharmaceutical preparation is suitable for use in the treatment of medical conditions for which treatment with a CB1 / CB2 receptor agonist is beneficial. Background Art

[0002] N-(2-(tert-butyl)-1-((4,4-difluorocyclohexyl)methyl)-1H-benzimidazol-5-yl)ethanesulfonamide is a highly potent, peripherally restricted synthetic dual cannabinoid agonist that targets peripheral CB1 / CB2 receptors (Groblewski T, Yu XH, Lessard E. Pre-clinical pharmacological properties of novel peripherally acting CB1-CB2 agonists. 20th Annual Symposium of the International Cannabinoid Research Society; 2010; Abstract #37). The structure of N-(2-(tert-butyl)-1-((4,4-difluorocyclohexyl)methyl)-1H-benzimidazol-5-yl)ethanesulfonamide (Compound I) is shown below. Chemical Diagram

[0003] Compound I and the synthetic route for preparing the same were first disclosed in International Publication No. WO 2006 / 033631 A1. Compound I has been evaluated in several Phase I clinical trials as a potential therapeutic agent for pain.

[0004] Cannabinoid agonists have potential applications in several clinical situations, including pain relief and cancer treatment (Cancer Prev Res(Phila).2011 January;4(1):65-75).

[0005] Furthermore, numerous cannabinoid agonists have been approved in the U.S. and other major markets for the treatment of cancer-related nausea and vomiting, and clinical trials are underway to evaluate the potential of cannabinoids for cancer-related anorexia and cachexia.

[0006] Compound I has been shown to stimulate appetite in a dose-dependent manner. Compound I acts peripherally on the portion of the endocannabinoid system that stimulates hunger and does not produce CNS psychostimulant effects.

[0007] Due to the high potency of compound I, very low therapeutic doses (in the microgram range) of the active substance are required. Pharmaceutical formulations requiring very small amounts of the active substance are difficult to manufacture because achieving an acceptable level of uniformity of the contents can be challenging. To ensure that patients receiving the pharmaceutical formulation receive the intended dose, it is essential that the pharmaceutical formulation has an acceptable level of uniformity of its contents. This is important from the standpoint of safety and efficacy. In the example of the present invention, the minimum dose is expected to be as low as 50 μg.

[0008] Because only very small amounts of the active substance are required, problems can arise during the mixing and formulation of the active substance, for example, due to segregation, homogeneity of contents, and physical stability. The required small amount of active substance must be uniformly distributed throughout the powder blend. This is particularly difficult if the active substance has poor fluidity and / or is prone to aggregation.

[0009] Furthermore, compound I is readily degraded when present in solution and exposed to light. See Example 1 of this specification. This poses a problem when considering a viable formulation of this active substance. The active substance must be stable during the manufacturing process of the pharmaceutical formulation, and the resulting formulation must also be stable over a long period of time.

[0010] The combination of requiring low doses of compound I and its instability in solution presents challenges in developing appropriate pharmaceutical formulations.

[0011] In the present invention, the immediate-release pharmaceutical formulation containing compound I also needs to provide optimal absorption. Therefore, an immediate-release oral dosage form of compound I is required that has good uniformity of contents and good physical and chemical stability over a long period of time.

[0012] This disclosure was conceived with the above in mind. [Overview of the project] [Means for solving the problem]

[0013] This specification discloses a pharmaceutical composition for oral use comprising compound I or a pharmaceutically acceptable salt thereof as an active substance, and an immediate-release pharmaceutical formulation comprising the pharmaceutical composition.

[0014] According to a first aspect of the present disclosure, a pharmaceutical composition for oral use is provided, comprising compound I or a pharmaceutically acceptable salt thereof as an active substance, and a non-aqueous solvent for the active substance.

[0015] According to a second aspect of the present disclosure, a pharmaceutical composition for oral use is provided, comprising compound I or a pharmaceutically acceptable salt thereof as an active substance, wherein the pharmaceutical composition is semi-solid at room temperature.

[0016] A further aspect of the present disclosure provides a pharmaceutical composition for oral use comprising compound I or a pharmaceutically acceptable salt thereof as an active substance, wherein the active substance is stable in the pharmaceutical composition for at least about two weeks, about one month, about two months, about three months, about six months, about twelve months, or about twenty-four months.

[0017] A further aspect of this disclosure provides a pharmaceutical composition for oral use comprising compound I or a pharmaceutically acceptable salt thereof as an active substance: a. At least about 75% of the total amount of active substance contained in the pharmaceutical composition is released within approximately the first 45 minutes when the pharmaceutical composition is subjected to an in vitro dissolution test using 0.1 M HCl or pH 6.8 phosphate buffer as the dissolution medium, and the dissolution profile is determined at 37°C using a rotation speed of 50 rpm, as described in the United States Pharmacopeia; b. The pharmaceutical composition is semi-solid at room temperature.

[0018] A further aspect of the present disclosure provides a pharmaceutical composition for oral use comprising compound I or a pharmaceutically acceptable salt thereof as an active substance and a non-aqueous solvent for the active substance, wherein the active substance is homogeneously distributed throughout the non-aqueous solvent.

[0019] In a further embodiment, there exists a method for producing the pharmaceutical composition described herein, which includes the step of mixing compound I or a pharmaceutically acceptable salt thereof as an active substance in a non-aqueous solvent.

[0020] In a further embodiment, an immediate-release pharmaceutical formulation for oral use is provided, comprising a pharmaceutical composition as defined herein.

[0021] In a further embodiment, a pharmaceutical composition as defined herein, or an immediate-release pharmaceutical formulation as defined herein, for use as a pharmaceutical is provided.

[0022] Any preferred, appropriate, and incidental features of any particular aspect of this disclosure are also preferred, appropriate, and incidental features of any other aspect.

[0023] For a better understanding of the present disclosure, and to show how embodiments of the present disclosure may be implemented, reference is made herein to the following drawings by way of example. BRIEF DESCRIPTION OF THE DRAWINGS

[0024] [Figure 1] Dissolution profile in 0.1 M HCl for 50 µg active substance capsules (50 mg fill) prepared using D-α-tocopherol polyethylene glycol 1000 succinate (vitamin E TPGS). [Figure 2] Dissolution profile in 0.1 M HCl for 50 µg active substance capsules (50 mg fill) prepared using polyethylene glycol (PEG) 1500. [Figure 3] Dissolution profile in 0.1 M HCl for 200 µg active substance capsules (50 mg fill) prepared using vitamin E TPGS. [Figure 4] Dissolution profile in 0.1 M HCl for 200 µg active substance capsules (50 mg fill) prepared using PEG 1500. [Figure 5] Dissolution profile in 0.1 M HCl for 200 µg active substance capsules (200 mg fill) prepared using vitamin E TPGS. [Figure 6] Dissolution profile in 0.1 M HCl for 200 µg active substance capsules (200 mg fill) prepared using PEG 1500. [Figure 7] Dissolution profile in pH 6.8 phosphate buffer for 50 µg active substance capsules (50 mg fill) prepared using vitamin E TPGS. [Figure 8] Dissolution profile in pH 6.8 phosphate buffer for 50 µg active substance capsules (50 mg fill) prepared using PEG 1500. [Figure 9]Dissolution profile of 200 μg active substance immediate-release (IR) capsules (50 mg filled) prepared using vitamin E TPGS in pH 6.8 phosphate buffer. [Figure 10] Dissolution profile of 200 μg active substance capsules (50 mg filled) manufactured using PEG1500 in pH 6.8 phosphate buffer. [Figure 11] Dissolution profile of 200 μg active substance capsules (200 mg filled) manufactured using Vitamin E TPGS in pH 6.8 phosphate buffer. [Figure 12] Dissolution profile of 200 μg active substance capsules (200 mg filled) manufactured using PEG1500 in pH 6.8 phosphate buffer. [Figure 13] Percentage area of ​​the RRT 1.35 peak in vial aliquots of 50 μg packed fluid as a function of incubation time at 60°C. [Figure 14] Average release of active substance from a 50 μg capsule in 0.1 M HCl and pH 6.8 medium (% of label claim) versus time. [Figure 15] Average release of active substance (in percentage) from a 200 μg capsule in 0.1 M HCl and pH 6.8 media versus time. [Figure 16] Average release of active substance (percentage of nominal dose) for 0.4% w / w API and solvent capsules (solvent = vitamin E TPGS, PEG1500, PEG6000, PEG1500:TPGS(1:1), PEG1500:TPGS(9:1), and PEG1500:TPGS(1:9)) [Figure 17] Average release of active substances (normalized data) from 0.4% w / w API and solvent capsules (solvent = vitamin E TPGS, PEG1500, PEG6000, PEG1500:TPGS(1:1), PEG1500:TPGS(9:1), and PEG1500:TPGS(1:9)). [Figure 18] Average release of active substance (percentage of nominal dose) for single solvents and API capsules [Figure 19]Average release of active substances (normalized data) for single solvents and API capsules. [Figure 20] Average release of active substance (percentage of nominal dose) from two-component solvents and API capsules [Figure 21] Average release of active substances from two-component solvents and API capsules (normalized data) [Figure 22] Average release (% dissolution) of active substance from a 50 μg capsule stored in 0.1 M HCl at 25°C / 60% RH. [Figure 23] Average release (% dissolution) of active substance from a 50 μg capsule stored in 0.1 M HCl at 40°C / 75% RH. [Figure 24] Average release (% dissolution) of active substance from a 50 μg capsule stored in pH 6.8 phosphate buffer at 25°C / 60% RH. [Figure 25] Average release (% dissolution) of active substance from a 50 μg capsule stored in pH 6.8 phosphate buffer at 40°C / 75% RH. [Figure 26] Average release of active substance (% dissolved) from a 200 μg capsule stored in 0.1 M HCl at 25°C / 60% RH. [Figure 27] Average release of active substance (% dissolution) from a 200 μg capsule stored in 0.1 M HCl at 40°C / 75% RH. [Figure 28] Average release (% dissolution) of active substance from a 200 μg capsule stored in pH 6.8 phosphate buffer at 25°C / 60% RH. [Figure 29] Average release (% dissolution) of active substance from a 200 μg capsule stored in pH 6.8 phosphate buffer at 40°C / 75% RH. [Modes for carrying out the invention]

[0025] Unless otherwise specified, the following terms used in the specification and claims have the meanings set forth below.

[0026] The disclosed compositions, formulations, manufacturing processes and methods can be more readily understood by referring to the following detailed description in conjunction with the accompanying drawings that form part of this disclosure. It should be understood that the disclosed compositions, formulations, manufacturing processes and methods are not limited to the specific compositions, formulations, manufacturing processes and methods described and / or shown herein, and that the terms used herein are intended to illustrate specific embodiments only and are not intended to limit the claimed compositions, formulations, manufacturing processes and methods.

[0027] A reference to a specific number includes at least that specific value unless the context clearly indicates otherwise. Where a range of values ​​is expressed, another embodiment includes from one specific value to / or other specific values. Furthermore, a reference to a value specified by a range includes all values ​​within that range. All ranges are inclusive and combinable.

[0028] When a value is expressed as an approximation using the antecedent "approximately," it will be understood that a particular value forms another embodiment.

[0029] When the term “about” is used in reference to a numerical range, cutoff, or specific value, it is used to indicate that the listed value may vary by up to 10% from the listed value. Since many of the numerical values ​​used herein are determined experimentally, those skilled in the art should understand that such determined values ​​may often vary between different experiments. The values ​​used herein should not be considered unduly limited by this inherent variation. Accordingly, the term “about” is used to encompass variations of ±10%, ±5%, ±1%, ±0.5%, or ±0.1% from a given value.

[0030] For clarity, certain features of the disclosed compositions, formulations, manufacturing processes, and methods described herein in the context of separate embodiments may be provided in combination in a single embodiment. Conversely, various features of the disclosed compositions, formulations, manufacturing processes, and methods described in the context of a single embodiment may be provided separately or in any subcombination.

[0031] As used herein, the singular forms, "a," "an," and "the" include the plural.

[0032] When a composition is said to contain a specified component, this means a composition containing one type of specified component or a mixture of several types of specified components. For example, the composition may contain at least one type, e.g., at least two types, at least three types, or at least four types of specified components. Preferably, the composition contains one type of specified component, two types of specified components, three types of specified components, or four types of specified components.

[0033] When a composition is said to contain a specified component (in the specified amount or concentration, as may be), the composition may contain further components other than those specified. However, in certain embodiments, a composition said to contain a specified component is, in fact, essentially composed of, or may consist of, all of the specified components.

[0034] In this specification, when a composition is said to "essentially consist of" a particular component, the composition appropriately comprises at least 70% by weight of the component, appropriately at least 80% by weight of the component, appropriately at least 90% by weight of the component, appropriately at least 95% by weight of the component, and most appropriately at least 99% by weight of the component. Preferably, a composition said to "essentially consist of" a particular component comprises the component with one or more trace impurities.

[0035] In this specification, the term semi-solid is used to describe a material that is solid at room temperature and liquid at temperatures above room temperature, for example, a material having a melting point of at least about 30°C, e.g., at least about 35°C, or at least about 40°C. Preferably, a material having a melting point of about 35°C to about 80°C, e.g., about 35°C to about 70°C, about 35°C to about 60°C, about 35°C to about 50°C, or about 40°C to about 50°C. Preferably, a material having a melting point of at least 30°C, e.g., at least 35°C, or at least 40°C. Preferably, a material having a melting point of 35°C to 80°C, e.g., 35°C to 70°C, 35°C to 60°C, 35°C to 50°C, or 40°C to 50°C.

[0036] Room temperature is defined herein as a temperature of about 15°C to about 25°C, for example, about 20°C to about 25°C. Preferably, room temperature is about 20°C. Preferably, room temperature is 15°C to 25°C, for example, 20°C to 25°C. Preferably, room temperature is 20°C.

[0037] The reference to “treating” or “treatment” should be understood to include prevention and the reduction of established symptoms of a condition. Accordingly, “treating” or “treatment” of a condition, disorder or condition includes: (1) preventing or delaying the onset of the clinical symptoms of a condition, disorder or condition in a person who is susceptible to or prone to a condition, disorder or condition but has not yet experienced or shown any clinical or subclinical symptoms of the condition, disorder or condition; (2) inhibiting the condition, disorder or condition or at least one of its clinical or subclinical symptoms, i.e., preventing, reducing or delaying the onset or recurrence of the disease (in the case of maintenance therapy); or (3) reducing or attenuating the disease, i.e., regressing the condition, disorder or condition or at least one of its clinical or subclinical symptoms.

[0038] As used herein, the expression “therapeutic dose” means the amount of a pharmaceutical composition or immediate-release pharmaceutical formulation containing an active substance as described herein that is effective in achieving, for example, a specific biological or therapeutic outcome, but not limited to, those disclosed, described or illustrated herein. The therapeutic dose may vary depending on factors such as the individual’s disease state, age, sex, and weight, and the composition’s ability to produce a desired response in the subject. Such outcomes, as determined by any means appropriate in the art, include, but are not limited to, reduction, remission, and / or regression of a benign or malignant disease, or prevention of the onset of a benign or malignant disease.

[0039] As used herein, “subjects” includes vertebrates; mammals, such as primates, humans, dogs, cattle, and horses; or livestock.

[0040] Pharmaceutical composition According to a first aspect of the present disclosure, a pharmaceutical composition for oral use is provided, comprising compound I or a pharmaceutically acceptable salt thereof as an active substance, and a non-aqueous solvent for the active substance.

[0041] Appropriately: a. Compound I or a pharmaceutically acceptable salt thereof as the active substance; and b. Non-aqueous solvents for active substances A pharmaceutical composition for oral use is provided, comprising the above.

[0042] Preferably, a pharmaceutical composition for oral use is provided, comprising compound I or a pharmaceutically acceptable salt thereof as an active substance, and a non-aqueous solvent for the active substance, wherein the pharmaceutical composition is semi-solid at room temperature.

[0043] Preferably, a pharmaceutical composition for oral use is provided, comprising compound I or a pharmaceutically acceptable salt thereof as an active substance, and a non-aqueous solvent for the active substance, wherein the non-aqueous solvent is semi-solid at room temperature.

[0044] Preferably, a pharmaceutical composition for oral use is provided, comprising compound I or a pharmaceutically acceptable salt thereof as an active substance and a non-aqueous solvent for the active substance, wherein the active substance has a solubility in the non-aqueous solvent of at least about 0.1% w / w at room temperature.

[0045] Suitable non-aqueous solvents include polyethylene glycol, ethanol, stearoyl polyoxyglyceride, polyoxyethylene stearate, medium-chain fatty acids, long-chain monoglycerides, long-chain diglycerides, medium-chain monoglycerides, medium-chain diglycerides, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, polyoxyethylated 12-hydroxystearic acid, caprylocaproyl polyoxyglyceride, oleoyl polyoxyglyceride, propylene glycol monofatty acid esters, propylene glycol difatty acid esters, diethylene glycol monoethyl ether, poloxamer, or vitamin E TPGS or a combination thereof.

[0046] Suitable non-aqueous solvents include polyethylene glycol, stearoyl polyoxyglycerides, polyoxyethylene stearate, long-chain fatty acids, medium-chain fatty acids, long-chain monoglycerides, long-chain diglycerides, medium-chain monoglycerides, medium-chain diglycerides, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, polyoxyethylated 12-hydroxystearic acid, caprylocaproyl polyoxyglycerides, propylene glycol monofatty acid esters, propylene glycol difatty acid esters, diethylene glycol monoethyl ethers, or poloxamers or combinations thereof.

[0047] Preferably, a pharmaceutical composition for oral use is provided, comprising compound I or a pharmaceutically acceptable salt thereof as an active substance, and a non-aqueous solvent for the active substance, wherein the active substance has a solubility in the non-aqueous solvent of at least about 0.1% w / w at room temperature, and the pharmaceutical composition is semi-solid at room temperature.

[0048] A pharmaceutical composition for oral use is provided, preferably comprising compound I or a pharmaceutically acceptable salt thereof as an active substance, and a non-aqueous solvent for the active substance, wherein the active substance is dissolved in the non-aqueous solvent.

[0049] Preferably, a pharmaceutical composition for oral use is provided, comprising compound I or a pharmaceutically acceptable salt thereof as an active substance, and a non-aqueous solvent for the active substance, wherein the non-aqueous solvent is water-soluble.

[0050] Preferably, a pharmaceutical composition for oral use is provided, comprising compound I or a pharmaceutically acceptable salt thereof as an active substance and a non-aqueous solvent for the active substance, wherein the pharmaceutical composition comprises at least about 20% w / w of the non-aqueous solvent, for example, at least about 30% w / w, at least about 40% w / w, at least about 50% w / w, at least about 60% w / w, at least about 70% w / w, at least about 80% w / w, at least about 90% w / w, at least about 95% w / w, at least about 96% w / w, at least about 97% w / w, at least about 98% w / w, at least about 99% w / w, at least about 99.2% w / w, or at least about 99.5% w / w, based on the weight of the total pharmaceutical composition.

[0051] Preferably, a pharmaceutical composition for oral use is provided, comprising compound I or a pharmaceutically acceptable salt thereof as an active substance, and a non-aqueous solvent for the active substance, wherein the pharmaceutical composition is present in a concentration of approximately 20 to approximately 99.99% w / w, for example, approximately 30 to approximately 99.99% w / w, approximately 40 to approximately 99.99% w / w, approximately 50 to approximately 99.99% w / w, approximately 60 to approximately 99.99% w / w, approximately 70 to approximately 99.99% w / w, approximately 80 to approximately 99.99% w / w, approximately 90 to approximately 99.99% w / w, approximately 95 to approximately 99.99% w / w, approximately 96 to approximately 99.99% w / w, approximately 97 to approximately 99.99% w / w, approximately 98 to approximately 99.99% w / w, and approximately 99 to approximately 99.99% w / w based on the weight of the total pharmaceutical composition. It contains a non-aqueous solvent in w / w, approximately 99.2 to 99.99% w / w, or approximately 99.5 to 99.99% w / w.

[0052] Preferably, a pharmaceutical composition for oral use is provided, comprising compound I or a pharmaceutically acceptable salt thereof as an active substance and a non-aqueous solvent for the active substance, wherein the pharmaceutical composition comprises at least about 20% w / w of the non-aqueous solvent and about 0.001 to about 0.8% w / w of the active substance based on the weight of the total pharmaceutical composition.

[0053] Preferably, a pharmaceutical composition for oral use is provided, comprising compound I or a pharmaceutically acceptable salt thereof as an active substance and a non-aqueous solvent for the active substance, wherein the pharmaceutical composition comprises about 20 to about 99.99% w / w of the non-aqueous solvent and about 0.001 to about 0.8% w / w of the active substance based on the weight of the total pharmaceutical composition.

[0054] Preferably, a pharmaceutical composition for oral use is provided, comprising compound I or a pharmaceutically acceptable salt thereof as an active substance, and a non-aqueous solvent for the active substance, wherein the non-aqueous solvent comprises polyethylene glycol.

[0055] Preferably, a pharmaceutical composition for oral use is provided, comprising compound I or a pharmaceutically acceptable salt thereof as an active substance, and a non-aqueous solvent for the active substance, wherein the non-aqueous solvent comprises polyethylene glycol, the polyethylene glycol having an average molecular weight of about 200 to about 25000 g / mol, for example, about 400 to about 6000 g / mol, for example, about 1000 to about 6000 g / mol, for example, about 1200 to about 1800 g / mol, for example, about 1400 to about 1600 g / mol. Preferably, the polyethylene glycol has an average molecular weight of about 400 g / mol, about 1500 g / mol, about 4000 g / mol, or about 6000 g / mol.

[0056] A pharmaceutical composition for oral use is provided, preferably comprising compound I or a pharmaceutically acceptable salt thereof as an active substance, and a non-aqueous solvent for the active substance: a. The non-aqueous solvent is polyethylene glycol; b. The pharmaceutical composition contains approximately 20 to approximately 99.99% w / w of a non-aqueous solvent based on the weight of the total pharmaceutical composition; c. The pharmaceutical composition contains approximately 0.001 to approximately 0.8% w / w of the active substance relative to the total weight of the pharmaceutical composition.

[0057] A pharmaceutical composition for oral use is provided, preferably comprising compound I or a pharmaceutically acceptable salt thereof as an active substance, and a non-aqueous solvent for the active substance: a. The non-aqueous solvent is polyethylene glycol, which has an average molecular weight of approximately 200 to 25,000 g / mol; b. The pharmaceutical composition contains approximately 50 to approximately 99.99% w / w of a non-aqueous solvent based on the weight of the total pharmaceutical composition; c. The pharmaceutical composition contains approximately 0.01 to approximately 0.8% w / w of the active substance relative to the total weight of the pharmaceutical composition.

[0058] A pharmaceutical composition for oral use is provided, preferably comprising compound I or a pharmaceutically acceptable salt thereof as an active substance, and a non-aqueous solvent for the active substance: a. The non-aqueous solvent is polyethylene glycol, which has an average molecular weight of approximately 1000 to 6000 g / mol; b. The pharmaceutical composition contains approximately 50 to approximately 99.99% w / w of a non-aqueous solvent based on the weight of the total pharmaceutical composition; c. The pharmaceutical composition contains approximately 0.01 to approximately 0.8% w / w of the active substance relative to the total weight of the pharmaceutical composition.

[0059] A pharmaceutical composition for oral use is provided, preferably comprising compound I or a pharmaceutically acceptable salt thereof as an active substance, a non-aqueous solvent for the active substance, and vitamin E TPGS; the non-aqueous solvent comprises polyethylene glycol.

[0060] Preferably, a pharmaceutical composition for oral use is provided, comprising compound I or a pharmaceutically acceptable salt thereof as an active substance and a non-aqueous solvent for the active substance, wherein the active substance is stable in the pharmaceutical composition for at least about 2 weeks, about 1 month, about 2 months, about 3 months, about 6 months, about 12 months, or about 24 months.

[0061] A pharmaceutical composition for oral use is provided, preferably comprising compound I or a pharmaceutically acceptable salt thereof as an active substance, and a non-aqueous solvent for the active substance: a. The total amount of degradation products of the active substance is less than or equal to about 4 area % as determined by chromatography when the pharmaceutical composition is stored at 25°C / 60%RH and / or 40°C / 75%RH for at least about 2 weeks, about 1 month, about 2 months, about 3 months, about 6 months, about 12 months, or about 24 months; and / or b. The assay of the active substance is determined by chromatography to be approximately 90-110% of the nominal value when the pharmaceutical composition is stored at 25°C / 60%RH and / or 40°C / 75%RH for at least about 2 weeks, about 1 month, about 2 months, about 3 months, about 6 months, about 12 months, or about 24 months.

[0062] Suitablely, a pharmaceutical composition for oral use is provided, comprising compound I or a pharmaceutically acceptable salt thereof as the active substance and a non-aqueous solvent for the active substance, wherein at least about 75% of the total amount of the active substance contained in the pharmaceutical composition is released within approximately the first 45 minutes when the pharmaceutical composition is subjected to an in vitro dissolution test using 0.1 M HCl or pH 6.8 phosphate buffer as the dissolution medium, and the dissolution profile is determined at 37°C using a rotation speed of 50 rpm as described in the United States Pharmacopeia.

[0063] Preferably, a pharmaceutical composition for oral use is provided, comprising compound I or a pharmaceutically acceptable salt thereof as an active substance, and a non-aqueous solvent for the active substance, wherein the active substance is homogeneously distributed throughout the non-aqueous solvent.

[0064] According to a second aspect of the present disclosure, a pharmaceutical composition for oral use is provided, comprising compound I or a pharmaceutically acceptable salt thereof as an active substance, wherein the pharmaceutical composition is semi-solid at room temperature.

[0065] A semi-solid is any material that is solid at room temperature and liquid at temperatures above room temperature. Suitablely, room temperature is approximately 15°C to 25°C, for example, approximately 20°C to 25°C. Suitablely, room temperature is approximately 20°C. Suitablely, room temperature is 15°C to 25°C, for example, 20°C to 25°C. Suitablely, room temperature is 20°C.

[0066] Advantageously, the semi-solid nature of the pharmaceutical composition promotes a continuous and uniform distribution of the active substance in a non-aqueous solvent during storage, and / or an acceptable stability profile of the pharmaceutical composition when the active substance is dispersed / dissolved in a semi-solid state under typical storage conditions, i.e., at room temperature. Furthermore, during manufacturing, the pharmaceutical composition is liquid, which also promotes a uniform distribution of the active substance throughout the pharmaceutical composition.

[0067] Preferably, a pharmaceutical composition for oral use is provided, comprising compound I or a pharmaceutically acceptable salt thereof as an active substance, the pharmaceutical composition being semi-solid at room temperature and having a melting point of at least about 30°C, for example, at least about 35°C, or at least about 40°C.

[0068] Preferably, a pharmaceutical composition for oral use is provided, comprising compound I or a pharmaceutically acceptable salt thereof as an active substance, the pharmaceutical composition being semi-solid at room temperature and having a melting point of about 35°C to about 80°C, for example, about 35°C to about 70°C, about 35°C to about 60°C, about 35°C to about 50°C, or about 40°C to about 50°C.

[0069] Preferably, a pharmaceutical composition for oral use is provided, comprising compound I or a pharmaceutically acceptable salt thereof as an active substance, wherein the pharmaceutical composition is semi-solid at room temperature and comprises a non-aqueous solvent for the active substance.

[0070] Preferably, a pharmaceutical composition for oral use is provided, comprising compound I or a pharmaceutically acceptable salt thereof as an active substance, wherein the pharmaceutical composition is semi-solid at room temperature, and the active substance is stable in the pharmaceutical for at least about 2 weeks, about 1 month, about 2 months, about 3 months, about 6 months, about 12 months, or about 24 months.

[0071] A pharmaceutical composition for oral use is provided, preferably comprising compound I or a pharmaceutically acceptable salt thereof as an active substance, wherein the pharmaceutical composition is semi-solid at room temperature: a. The total amount of degradation products of the active substance is less than or equal to about 4 area % as determined by chromatography when the pharmaceutical composition is stored at 25°C / 60%RH and / or 40°C / 75%RH for at least about 2 weeks, about 1 month, about 2 months, about 3 months, about 6 months, about 12 months, or about 24 months; and / or b. The assay of the active substance is determined by chromatography to be approximately 90-110% of the nominal value when the pharmaceutical composition is stored at 25°C / 60%RH and / or 40°C / 75%RH for at least about 2 weeks, about 1 month, about 2 months, about 3 months, about 6 months, about 12 months, or about 24 months.

[0072] Suitablely, a pharmaceutical composition for oral use is provided, comprising compound I or a pharmaceutically acceptable salt thereof as the active substance, wherein the pharmaceutical composition is semi-solid at room temperature, and at least about 75% of the total amount of the active substance contained in the pharmaceutical composition is released within approximately the first 45 minutes when the pharmaceutical composition is subjected to an in vitro dissolution test using 0.1 M HCl or pH 6.8 phosphate buffer as the dissolution medium, and the dissolution profile is determined at 37°C using a rotation speed of 50 rpm as described in the United States Pharmacopeia.

[0073] Preferably, a pharmaceutical composition for oral use is provided, comprising compound I or a pharmaceutically acceptable salt thereof as an active substance, and a non-aqueous solvent for the active substance, wherein the pharmaceutical composition is semi-solid at room temperature, and the active substance is homogeneously distributed throughout the non-aqueous solvent.

[0074] A further aspect of the present disclosure provides a pharmaceutical composition for oral use comprising compound I or a pharmaceutically acceptable salt thereof as an active substance, wherein the active substance is stable in the pharmaceutical composition for at least about two weeks, about one month, about two months, about three months, about six months, about twelve months, or about twenty-four months.

[0075] Advantageously, the active substance is stable in the pharmaceutical composition. The stability of the pharmaceutical composition ensures that the end user, i.e., the patient, receives the intended dose of the active substance and is not exposed to its degradation products. This is important from the standpoint of patient safety and efficacy. Furthermore, stable pharmaceutical compositions that do not require special storage conditions, such as refrigeration, are advantageous because they result in a simpler and / or less expensive supply chain.

[0076] Suitablely, a pharmaceutical composition for oral use is provided, comprising compound I or a pharmaceutically acceptable salt thereof as an active substance, wherein the active substance is stable in the pharmaceutical composition for at least 2 weeks, 1, 2, 3, 6, 12, or 24 months.

[0077] Preferably, a pharmaceutical composition for oral use is provided comprising compound I or a pharmaceutically acceptable salt thereof as an active substance, wherein the active substance is stable in the pharmaceutical composition when the pharmaceutical composition is stored at 25°C / 60%RH and / or 40°C / 75%RH for at least about two weeks, about one month, about two months, about three months, about six months, about twelve months, or about twenty-four months.

[0078] Suitablely, a pharmaceutical composition for oral use is provided, comprising compound I or a pharmaceutically acceptable salt thereof as an active substance, wherein the active substance is stable in the pharmaceutical composition when the pharmaceutical composition is stored at 25°C / 60%RH and / or 40°C / 75%RH for 2 weeks, 1, 2, 3, 6, 12, or 24 months.

[0079] A pharmaceutical composition for oral use is provided, preferably comprising compound I or a pharmaceutically acceptable salt thereof as the active substance: a. The total amount of degradation products of the active substance is less than or equal to about 4 area % as determined by chromatography when the pharmaceutical composition is stored at 25°C / 60%RH and / or 40°C / 75%RH for at least about 2 weeks, about 1 month, about 2 months, about 3 months, about 6 months, about 12 months, or about 24 months; and / or b. The assay of the active substance is determined by chromatography to be approximately 90-110% of the nominal value when the pharmaceutical composition is stored at 25°C / 60%RH and / or 40°C / 75%RH for at least about 2 weeks, about 1 month, about 2 months, about 3 months, about 6 months, about 12 months, or about 24 months.

[0080] A pharmaceutical composition for oral use is provided, preferably comprising compound I or a pharmaceutically acceptable salt thereof as the active substance: a. The total amount of degradation products of the active substance is less than or equal to about 3 area % as determined by chromatography when the pharmaceutical composition is stored at 25°C / 60%RH and / or 40°C / 75%RH for at least about 2 weeks, about 1 month, about 2 months, about 3 months, about 6 months, about 12 months, or about 24 months; and / or b. The assay of the active substance is determined by chromatography to be approximately 95-105% of the nominal value when the pharmaceutical composition is stored at 25°C / 60%RH and / or 40°C / 75%RH for at least about 2 weeks, about 1 month, about 2 months, about 3 months, about 6 months, about 12 months, or about 24 months.

[0081] A pharmaceutical composition for oral use is provided, preferably comprising compound I or a pharmaceutically acceptable salt thereof as the active substance: a. The total amount of degradation products of the active substance is less than or equal to about 2 area % as determined by chromatography when the pharmaceutical composition is stored at 25°C / 60%RH and / or 40°C / 75%RH for at least about 2 weeks, about 1 month, about 2 months, about 3 months, about 6 months, about 12 months, or about 24 months; and / or b. The assay of the active substance is determined by chromatography to be approximately 95-105% of the nominal value when the pharmaceutical composition is stored at 25°C / 60%RH and / or 40°C / 75%RH for at least about 2 weeks, about 1 month, about 2 months, about 3 months, about 6 months, about 12 months, or about 24 months.

[0082] A pharmaceutical composition for oral use is provided, comprising compound I or a pharmaceutically acceptable salt thereof as an active substance, wherein the active substance is stable in the pharmaceutical composition for at least about 2 weeks, about 1 month, about 2 months, about 3 months, about 6 months, about 12 months, or about 24 months, and the pharmaceutical composition is semi-solid at room temperature.

[0083] Suitablely, the non-aqueous solvent includes polyethylene glycol, stearoyl polyoxyglycerides, medium-chain fatty acids, medium-chain monoglycerides, medium-chain diglycerides, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, polyoxyethylated 12-hydroxystearic acid, propylene glycol difatty acid esters, diethylene glycol monoethyl ether, or poloxamer or a combination thereof. Suitablely, the polyoxyethylene castor oil derivative includes polyoxyl 40 hydrogenated castor oil. Suitablely, the polyoxyethylene castor oil derivative is polyoxyl 40 hydrogenated castor oil.

[0084] Suitable non-aqueous solvents include polyethylene glycol, stearoyl polyoxyglycerides, polyoxyethylene stearates, medium-chain monoglycerides, medium-chain diglycerides, polyoxyethylene sorbitan fatty acid esters, propylene glycol difatty acid esters, or combinations thereof.

[0085] Suitablely, a pharmaceutical composition for oral use is provided, comprising compound I or a pharmaceutically acceptable salt thereof as the active substance, wherein the active substance is stable in the pharmaceutical composition for at least about 2 weeks, about 1 month, about 2 months, about 3 months, about 6 months, about 12 months, or about 24 months, and at least about 75% of the total amount of the active substance contained in the pharmaceutical composition is released within approximately the first 45 minutes when the pharmaceutical composition is subjected to an in vitro dissolution test using 0.1 M HCl or pH 6.8 phosphate buffer as the dissolution medium, and the dissolution profile is determined at 37°C using a rotation speed of 50 rpm as described in the United States Pharmacopeia.

[0086] A pharmaceutical composition for oral use is provided, comprising compound I or a pharmaceutically acceptable salt thereof as an active substance and a non-aqueous solvent for the active substance, wherein the active substance is stable in the pharmaceutical composition for at least about 2 weeks, about 1 month, about 2 months, about 3 months, about 6 months, about 12 months, or about 24 months.

[0087] A pharmaceutical composition for oral use is provided, comprising compound I or a pharmaceutically acceptable salt thereof as an active substance, and a non-aqueous solvent for the active substance, wherein the active substance is stable in the pharmaceutical composition for at least about 2 weeks, about 1 month, about 2 months, about 3 months, about 6 months, about 12 months, or about 24 months, and the active substance is homogeneously dispersed throughout the non-aqueous solvent.

[0088] A further aspect of this disclosure provides a pharmaceutical composition for oral use comprising compound I or a pharmaceutically acceptable salt thereof as an active substance: a. At least about 75% of the total amount of active substance contained in the pharmaceutical composition is released within approximately the first 45 minutes when the pharmaceutical composition is subjected to an in vitro dissolution test using 0.1 M HCl or pH 6.8 phosphate buffer as the dissolution medium, and the dissolution profile is determined at 37°C using a rotation speed of 50 rpm, as described in the United States Pharmacopeia; b. The pharmaceutical composition is semi-solid at room temperature.

[0089] Advantageously, the rate of release of the active substance from the pharmaceutical composition provides optimal absorption of the pharmaceutical composition after oral administration to the patient.

[0090] A pharmaceutical composition for oral use is provided, preferably comprising compound I or a pharmaceutically acceptable salt thereof as the active substance: a. At least about 75% of the total amount of active substance contained in the pharmaceutical composition is released within approximately the first 45 minutes when the pharmaceutical composition is subjected to an in vitro dissolution test using 0.1 M HCl or pH 6.8 phosphate buffer as the dissolution medium, and the dissolution profile is determined at 37°C using a rotation speed of 50 rpm, as described in the United States Pharmacopeia; b. The pharmaceutical composition is semi-solid at room temperature; c. The pharmaceutical composition contains a non-aqueous solvent.

[0091] Suitable non-aqueous solvents include polyethylene glycol, stearoyl polyoxyglycerides, polyoxyethylene stearate, medium-chain fatty acids, long-chain monoglycerides, long-chain diglycerides, medium-chain monoglycerides, medium-chain diglycerides, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, polyoxyethylated 12-hydroxystearic acid, caprylocaproyl polyoxyglycerides, propylene glycol monofatty acid esters, propylene glycol difatty acid esters, diethylene glycol monoethyl ether, poloxamer, vitamin E TPGS, or combinations thereof.

[0092] Suitable non-aqueous solvents include polyethylene glycol, polyoxyethylene stearate, polyoxyethylene castor oil derivatives, polyoxyethylated 12-hydroxystearic acid, diethylene glycol monoethyl ether, or poloxamer, vitamin E TPGS, or combinations thereof.

[0093] A pharmaceutical composition for oral use is provided, preferably comprising compound I or a pharmaceutically acceptable salt thereof as the active substance: a. At least about 75% of the total amount of active substance contained in the pharmaceutical composition is released within approximately the first 30 minutes when the pharmaceutical composition is subjected to an in vitro dissolution test using 0.1 M HCl or pH 6.8 phosphate buffer as the dissolution medium, and the dissolution profile is determined at 37°C using a rotation speed of 50 rpm, as described in the United States Pharmacopeia; b. The pharmaceutical composition is semi-solid at room temperature.

[0094] A pharmaceutical composition for oral use is provided, preferably comprising compound I or a pharmaceutically acceptable salt thereof as the active substance: a. At least 85% of the total amount of active substance contained in the pharmaceutical composition is released within approximately the first 15 minutes when the pharmaceutical composition is subjected to an in vitro dissolution test using 0.1 M HCl or pH 6.8 phosphate buffer as the dissolution medium, and the dissolution profile is determined at 37°C using a rotation speed of 50 rpm, as described in the United States Pharmacopeia; b. The pharmaceutical composition is semi-solid at room temperature.

[0095] A pharmaceutical composition for oral use is provided, preferably comprising compound I or a pharmaceutically acceptable salt thereof as the active substance: a. At least 85% of the total amount of active substance contained in the pharmaceutical composition is released within approximately the first 15 minutes when the pharmaceutical composition is subjected to an in vitro dissolution test using 0.1 M HCl or pH 6.8 phosphate buffer as the dissolution medium, and the dissolution profile is determined at 37°C using a rotation speed of 50 rpm, as described in the United States Pharmacopeia; b. The pharmaceutical composition is semi-solid at room temperature; c. Pharmaceuticals contain non-aqueous solvents.

[0096] Suitable non-aqueous solvents include polyethylene glycol, stearoyl polyoxyglycerides, medium-chain fatty acids, long-chain monoglycerides, long-chain diglycerides, medium-chain monoglycerides, medium-chain diglycerides, polyoxyethylene sorbitan fatty acid esters, caprylocaproyl polyoxyglycerides, propylene glycol monofatty acid esters, propylene glycol difatty acid esters, diethylene glycol monoethyl ethers, poloxamers, or combinations thereof.

[0097] Suitable non-aqueous solvents include polyethylene glycol, polyoxyethylene castor oil derivatives, polyoxyethylated 12-hydroxystearic acid, diethylene glycol monoethyl ether, or poloxamer, or combinations thereof.

[0098] A pharmaceutical composition for oral use is provided, preferably comprising compound I or a pharmaceutically acceptable salt thereof as the active substance: a. At least about 75% of the total amount of active substance contained in the pharmaceutical composition is released within approximately the first 45 minutes when the pharmaceutical composition is subjected to an in vitro dissolution test using 0.1 M HCl or pH 6.8 phosphate buffer as the dissolution medium, and the dissolution profile is determined at 37°C using a rotation speed of 50 rpm, as described in the United States Pharmacopeia; b. The pharmaceutical composition is semi-solid at room temperature; c. The active substance is stable in the pharmaceutical composition for at least about 2 weeks, about 1 month, about 2 months, about 3 months, about 6 months, about 12 months, or about 24 months.

[0099] A pharmaceutical composition for oral use is provided, preferably comprising compound I or a pharmaceutically acceptable salt thereof as the active substance: a. At least about 75% of the total amount of active substance contained in the pharmaceutical composition is released within approximately the first 45 minutes when the pharmaceutical composition is subjected to an in vitro dissolution test using 0.1 M HCl or pH 6.8 phosphate buffer as the dissolution medium, and the dissolution profile is determined at 37°C using a rotation speed of 50 rpm, as described in the United States Pharmacopeia; b. The pharmaceutical composition is semi-solid at room temperature; c. The pharmaceutical composition has a melting point of approximately 35°C to approximately 80°C.

[0100] A pharmaceutical composition for oral use is provided, preferably comprising compound I or a pharmaceutically acceptable salt thereof as an active substance, and a non-aqueous solvent for the active substance: a. At least about 75% of the total amount of active substance contained in the pharmaceutical composition is released within approximately the first 45 minutes when the pharmaceutical composition is subjected to an in vitro dissolution test using 0.1 M HCl or pH 6.8 phosphate buffer as the dissolution medium, and the dissolution profile is determined at 37°C using a rotation speed of 50 rpm, as described in the United States Pharmacopeia; b. The pharmaceutical composition is semi-solid at room temperature.

[0101] A pharmaceutical composition for oral use is provided, preferably comprising compound I or a pharmaceutically acceptable salt thereof as an active substance, and a non-aqueous solvent for the active substance: a. At least about 75% of the total amount of active substance contained in the pharmaceutical composition is released within approximately the first 45 minutes when the pharmaceutical composition is subjected to an in vitro dissolution test using 0.1 M HCl or pH 6.8 phosphate buffer as the dissolution medium, and the dissolution profile is determined at 37°C using a rotation speed of 50 rpm, as described in the United States Pharmacopeia; b. The pharmaceutical composition is semi-solid at room temperature; c. The active substance is homogeneously distributed throughout the non-aqueous solvent.

[0102] A further aspect of the present disclosure provides a pharmaceutical composition for oral use comprising compound I or a pharmaceutically acceptable salt thereof as an active substance and a non-aqueous solvent for the active substance, wherein the active substance is homogeneously distributed throughout the non-aqueous solvent.

[0103] Advantageously, the active substance is homogeneously dispersed within the pharmaceutical composition. This ensures that, for example, when the pharmaceutical composition is administered to a patient or used in a formulation of an immediate-release pharmaceutical product, the required amount of the active substance is present in the portion of the pharmaceutical composition. This is important from the standpoint of patient safety and efficacy.

[0104] Preferably, a pharmaceutical composition for oral use is provided, comprising compound I or a pharmaceutically acceptable salt thereof as an active substance, and a non-aqueous solvent for the active substance, wherein the active substance is homogeneously distributed throughout the non-aqueous solvent for at least about two weeks, about one month, about two months, about three months, about six months, about twelve months, or about twenty-four months.

[0105] Preferably, a pharmaceutical composition for oral use is provided, comprising compound I or a pharmaceutically acceptable salt thereof as an active substance, and a non-aqueous solvent for the active substance, wherein the active substance is homogeneously distributed throughout the non-aqueous solvent for at least about 2 weeks, about 1 month, about 2 months, about 3 months, about 6 months, about 12 months, or about 24 months after the pharmaceutical composition is stored at room temperature.

[0106] A pharmaceutical composition for oral use is provided, preferably comprising compound I or a pharmaceutically acceptable salt thereof as an active substance, and a non-aqueous solvent for the active substance: a. The active substance is homogeneously distributed throughout the non-aqueous solvent; b. The homogeneous distribution of the active substance in the non-aqueous solvent is determined by determining the weight percentage of the active substance in a portion of the pharmaceutical composition, which is ±5% of the predicted value based on the total amount of active substance added to the total amount of the pharmaceutical composition.

[0107] Preferably, a pharmaceutical composition for oral use is provided, comprising compound I or a pharmaceutically acceptable salt thereof as an active substance, and a non-aqueous solvent for the active substance, wherein the active substance is homogeneously distributed throughout the non-aqueous solvent, and the pharmaceutical composition is semi-solid at room temperature.

[0108] Preferably, a pharmaceutical composition for oral use is provided, comprising compound I or a pharmaceutically acceptable salt thereof as an active substance, and a non-aqueous solvent for the active substance, wherein the active substance is homogeneously distributed throughout the non-aqueous solvent, and the active substance is stable in the pharmaceutical composition for at least about 2 weeks, about 1 month, about 2 months, about 3 months, about 6 months, about 12 months, or about 24 months.

[0109] Suitablely, a pharmaceutical composition for oral use is provided comprising N-(2-(tert-butyl)-1-((4,4-difluorocyclohexyl)methyl)-1H-benzimidazole 5-yl)ethanesulfonamide as the active substance, or a pharmaceutically acceptable salt thereof, and a non-aqueous solvent for the active substance, wherein the active substance is homogeneously distributed throughout the non-aqueous solvent, and at least about 75% of the total amount of the active substance contained in the pharmaceutical composition is released within approximately the first 45 minutes when the pharmaceutical composition is subjected to an in vitro dissolution test using 0.1 M HCl or pH 6.8 phosphate buffer as the dissolution medium, and the dissolution profile is determined at 37°C using a rotation speed of 50 rpm as described in the United States Pharmacopeia.

[0110] Pharmaceutical preparations In one embodiment, a pharmaceutical formulation comprising a pharmaceutical composition as defined herein is provided.

[0111] In a further embodiment, an immediate-release pharmaceutical formulation for oral use is provided, comprising a pharmaceutical composition as defined herein.

[0112] Appropriately, an immediate-release pharmaceutical formulation comprises a capsule shell and a pharmaceutical composition as defined herein.

[0113] Ideally, an immediate-release pharmaceutical formulation consists of a pharmaceutical composition.

[0114] Appropriately, an immediate-release pharmaceutical formulation for oral use comprising a pharmaceutical composition as defined herein is provided, wherein the acceptable value is less than 15 when subjected to a content uniformity test as described in the European Pharmacopoeia.

[0115] Advantageously, good formulation uniformity ensures that each dosage form of an immediate-release drug formulation contains the intended amount of active ingredient. This is important from the standpoint of patient safety and efficacy.

[0116] Preferably, an immediate-release pharmaceutical formulation for oral use comprising a pharmaceutical composition as defined herein is provided, wherein the immediate-release pharmaceutical formulation is an immediate-release capsule formulation. Preferably, the immediate-release capsule formulation comprises a capsule shell.

[0117] Preferably, an immediate-release pharmaceutical formulation for oral use comprising a pharmaceutical composition as defined herein is provided, wherein the immediate-release pharmaceutical formulation is an immediate-release spray formulation.

[0118] Appropriately, immediate-release pharmaceutical formulations for oral use are provided, comprising a pharmaceutical composition as defined herein, the immediate-release formulation containing about 10 μg to about 1000 μg of the active substance, for example, about 10 μg to about 500 μg, about 20 μg to about 500 μg, about 30 μg to about 300 μg, or about 40 μg to about 250 μg.

[0119] Preferably, an immediate-release pharmaceutical formulation for oral use is provided, comprising a pharmaceutical composition as defined herein, the immediate-release formulation containing about 50 μg or about 200 μg of the active substance.

[0120] Preferably, an immediate-release pharmaceutical formulation for oral use is provided, comprising a pharmaceutical composition comprising compound I or a pharmaceutically acceptable salt thereof as an active substance, and a non-aqueous solvent for the active substance.

[0121] Preferably, an immediate-release pharmaceutical formulation for oral use comprising a pharmaceutical composition comprising compound I or a pharmaceutically acceptable salt thereof as an active substance, and a non-aqueous solvent for the active substance, and the immediate-release pharmaceutical formulation being an immediate-release capsule formulation.

[0122] Appropriately, an immediate-release pharmaceutical formulation for oral use comprising a pharmaceutical composition is provided: a. The pharmaceutical composition comprises compound I or a pharmaceutically acceptable salt thereof as the active substance, and a non-aqueous solvent for the active substance; b. Non-aqueous solvents include polyethylene glycol.

[0123] Appropriately, an immediate-release pharmaceutical formulation for oral use comprising a pharmaceutical composition is provided: a. The pharmaceutical composition comprises compound I or a pharmaceutically acceptable salt thereof as the active substance, and a non-aqueous solvent for the active substance; b. The non-aqueous solvent is polyethylene glycol, which has an average molecular weight of approximately 1000 to 6000 g / mol; c. The pharmaceutical composition contains approximately 50 to approximately 99.99% w / w of a non-aqueous solvent based on the weight of the total pharmaceutical composition; d. The pharmaceutical composition contains approximately 0.01 to approximately 0.8% w / w of the active substance relative to the total weight of the pharmaceutical composition.

[0124] Appropriately, an immediate-release pharmaceutical formulation for oral use comprising a pharmaceutical composition is provided: a. The pharmaceutical composition comprises compound I or a pharmaceutically acceptable salt thereof as the active substance, and a non-aqueous solvent for the active substance; b. The non-aqueous solvent is polyethylene glycol, which has an average molecular weight of 1000 to 6000 g / mol; c. The pharmaceutical composition contains 50-99.99% w / w of a non-aqueous solvent based on the weight of the total pharmaceutical composition; d. The pharmaceutical composition contains 0.01 to 0.8% w / w of the active substance relative to the total weight of the pharmaceutical composition.

[0125] Preferably, an immediate-release pharmaceutical formulation for oral use is provided, comprising a pharmaceutical composition comprising compound I or a pharmaceutically acceptable salt thereof as an active substance, and the pharmaceutical composition is semi-solid at room temperature.

[0126] Appropriately, an immediate-release pharmaceutical formulation for oral use comprising a pharmaceutical composition is provided: a. The pharmaceutical composition contains compound I or a pharmaceutically acceptable salt thereof as the active substance; b. The active substance is stable in the pharmaceutical composition for at least about 2 weeks, about 1 month, about 2 months, about 3 months, about 6 months, about 12 months, or about 24 months.

[0127] Appropriately, an immediate-release pharmaceutical formulation for oral use comprising a pharmaceutical composition is provided: a. The pharmaceutical composition contains compound I or a pharmaceutically acceptable salt thereof as the active substance; b. At least about 75% of the total amount of active substance contained in an immediate-release pharmaceutical formulation is released within approximately the first 45 minutes when the pharmaceutical composition is subjected to an in vitro dissolution test using 0.1 M HCl or pH 6.8 phosphate buffer as the dissolution medium, and the dissolution profile is determined at 37°C using a rotation speed of 50 rpm, as described in the United States Pharmacopeia.

[0128] Appropriately, an immediate-release pharmaceutical formulation for oral use comprising a pharmaceutical composition is provided: a. The pharmaceutical composition contains compound I or a pharmaceutically acceptable salt thereof as the active substance; b. At least about 75% of the total amount of active substance contained in the pharmaceutical composition is released within approximately the first 45 minutes when the pharmaceutical composition is subjected to an in vitro dissolution test using 0.1 M HCl or pH 6.8 phosphate buffer as the dissolution medium, and the dissolution profile is determined at 37°C using a rotation speed of 50 rpm, as described in the United States Pharmacopeia.

[0129] Appropriately, an immediate-release pharmaceutical formulation for oral use comprising a pharmaceutical composition is provided: a. The pharmaceutical composition comprises compound I or a pharmaceutically acceptable salt thereof as the active substance, and a non-aqueous solvent for the active substance; b. The active substance is homogeneously distributed throughout the non-aqueous solvent.

[0130] active substance The active substance is N-(2-(tert-butyl)-1-((4,4-difluorocyclohexyl)methyl)-1H-benzimidazole 5-yl)ethanesulfonamide (compound I) or a pharmaceutically acceptable salt thereof.

[0131] Appropriately, the pharmaceutical composition contains about 0.001 to about 0.8% w / w of the active substance based on the weight of the total pharmaceutical composition, for example, about 0.01 to about 0.8% w / w, about 0.05 to about 0.6% w / w, about 0.08 to about 0.5% w / w, or about 0.1 to about 0.4% w / w. Appropriately, the pharmaceutical composition contains 0.001 to 0.8% w / w of the active substance based on the weight of the total pharmaceutical composition, for example, 0.01 to 0.8% w / w, 0.05 to 0.6% w / w, 0.08 to 0.5% w / w, or 0.1 to 0.4% w / w.

[0132] Appropriately, the pharmaceutical composition contains about 0.1% w / w of active substance based on the total weight of the pharmaceutical composition. Appropriately, the pharmaceutical composition contains about 0.4% w / w of active substance based on the total weight of the pharmaceutical composition. Appropriately, the pharmaceutical composition contains 0.1% w / w of active substance based on the total weight of the pharmaceutical composition. Appropriately, the pharmaceutical composition contains 0.4% w / w of active substance based on the total weight of the pharmaceutical composition.

[0133] Appropriately, the pharmaceutical composition comprises about 0.001 to about 0.8% w / w of an active substance and at least about 20% w / w of a non-aqueous solvent based on the weight of the total pharmaceutical composition. Appropriately, the pharmaceutical composition comprises about 0.001 to 0.8% w / w of an active substance and at least 20% w / w of a non-aqueous solvent based on the weight of the total pharmaceutical composition.

[0134] Appropriately, the pharmaceutical composition comprises about 0.001 to about 0.8% w / w of an active substance relative to the weight of the total pharmaceutical composition and at least about 50% w / w of a non-aqueous solvent relative to the weight of the total pharmaceutical composition. Appropriately, the pharmaceutical composition comprises about 0.001 to 0.8% w / w of an active substance relative to the weight of the total pharmaceutical composition and at least 50% w / w of a non-aqueous solvent relative to the weight of the total pharmaceutical composition.

[0135] Preferably, the pharmaceutical composition comprises about 0.01 to about 0.8% w / w of an active substance relative to the weight of the total pharmaceutical composition and at least about 50% w / w of a non-aqueous solvent relative to the weight of the total pharmaceutical composition. Preferably, the pharmaceutical composition comprises 0.01 to 0.8% w / w of an active substance relative to the weight of the total pharmaceutical composition and at least 50% w / w of a non-aqueous solvent relative to the weight of the total pharmaceutical composition.

[0136] Appropriately, the pharmaceutical composition comprises about 0.001 to about 0.8% w / w of an active substance relative to the weight of the total pharmaceutical composition and at least about 90% w / w of a non-aqueous solvent relative to the weight of the total pharmaceutical composition. Appropriately, the pharmaceutical composition comprises about 0.001 to 0.8% w / w of an active substance relative to the weight of the total pharmaceutical composition and at least 90% w / w of a non-aqueous solvent relative to the weight of the total pharmaceutical composition.

[0137] Preferably, the pharmaceutical composition comprises about 0.1 to about 0.4% w / w of an active substance relative to the weight of the total pharmaceutical composition and at least about 90% w / w of a non-aqueous solvent relative to the weight of the total pharmaceutical composition. Preferably, the pharmaceutical composition comprises 0.1 to 0.4% w / w of an active substance relative to the weight of the total pharmaceutical composition and at least 90% w / w of a non-aqueous solvent relative to the weight of the total pharmaceutical composition.

[0138] Non-aqueous solvents for active substances A pharmaceutical composition for oral use is provided, preferably comprising N-(2-(tert-butyl)-1-((4,4-difluorocyclohexyl)methyl)-1H-benzimidazole 5-yl)ethanesulfonamide as an active substance, or a pharmaceutically acceptable salt thereof, and a non-aqueous solvent for the active substance.

[0139] Suitablely, the pharmaceutical composition comprises at least one non-aqueous solvent, for example, at least two, at least three, or at least four non-aqueous solvents. Suitablely, the pharmaceutical composition comprises one non-aqueous solvent, two non-aqueous solvents, three non-aqueous solvents, or four non-aqueous solvents. Suitablely, the pharmaceutical composition comprises a mixture of non-aqueous solvents.

[0140] Suitablely, the active substance has a solubility in a non-aqueous solvent of at least about 0.1% w / w, e.g., at least about 0.2% w / w, at least about 0.5% w / w, or at least about 1.0% w / w at room temperature. Suitablely, the active substance has a solubility in a non-aqueous solvent of about 0.1% w / w to about 50% w / w, e.g., about 0.1% w / w to about 25% w / w, or about 0.1% w / w to about 10% w / w. Suitablely, the active substance has a solubility in a non-aqueous solvent of at least 0.1% w / w, e.g., at least 0.2% w / w, at least 0.5% w / w, or at least 1.0% w / w at room temperature. Ideally, the active substance has a solubility in a non-aqueous solvent of 0.1% w / w to 50% w / w, for example, 0.1% w / w to 25% w / w, or 0.1% w / w to 10% w / w.

[0141] Ideally, the active substance is dispersed in a non-aqueous solvent at room temperature.

[0142] Ideally, the active substance is dissolved in a non-aqueous solvent at room temperature.

[0143] Suitablely, at room temperature, at least about 85% by weight, for example, at least about 90% by weight, at least about 95% by weight, at least about 99% by weight, or at least about 99.9% by weight of the active substance is dissolved in a non-aqueous solvent. Suitablely, at room temperature, at least 85% by weight, for example, at least 90% by weight, at least 95% by weight, at least 99% by weight, or at least 99.9% by weight of the active substance is dissolved in a non-aqueous solvent.

[0144] Ideally, all active substances are soluble in a non-aqueous solvent at room temperature. Those skilled in the art know how to determine whether an active substance is soluble in a non-aqueous solvent, which can be determined, for example, by visual inspection or microscopic examination.

[0145] Suitable non-aqueous solvents include polyethylene glycol, propylene glycol, ethanol, glycerol, stearoyl polyoxyglyceride, polyoxyethylene stearate, long-chain triglycerides, medium-chain triglycerides, long-chain fatty acids, medium-chain fatty acids, long-chain monoglycerides, long-chain diglycerides, medium-chain monoglycerides, medium-chain diglycerides, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, polyoxyethylated 12-hydroxystearic acid, caprylocaproyl polyoxyglyceride, linoleoyl polyoxyglyceride, oleoyl polyoxyglyceride, propylene glycol monofatty acid esters, propylene glycol difatty acid esters, soybean oil, glyceryl palmitostearate, diethylene glycol monoethyl ether, sorbitan esters, poloxamer, vitamin E TPGS, or combinations thereof.

[0146] Suitable non-aqueous solvents include polyethylene glycol, propylene glycol, ethanol, glycerol, stearoyl polyoxyglyceride, polyoxyethylene stearate, long-chain triglycerides, medium-chain triglycerides, long-chain fatty acids, medium-chain fatty acids, long-chain monoglycerides, long-chain diglycerides, medium-chain monoglycerides, medium-chain diglycerides, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, polyoxyethylated 12-hydroxystearic acid, caprylocaproyl polyoxyglyceride, linoleoyl polyoxyglyceride, oleoyl polyoxyglyceride, propylene glycol monofatty acid esters, propylene glycol difatty acid esters, soybean oil, glyceryl palmitostearate, diethylene glycol monoethyl ether, sorbitan esters, poloxamers, or combinations thereof.

[0147] Suitable non-aqueous solvents include polyethylene glycol, ethanol, stearoyl polyoxyglyceride, polyoxyethylene stearate, medium-chain fatty acids, long-chain monoglycerides, long-chain diglycerides, medium-chain monoglycerides, medium-chain diglycerides, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, polyoxyethylated 12-hydroxystearic acid, caprylocaproyl polyoxyglyceride, oleoyl polyoxyglyceride, propylene glycol monofatty acid esters, propylene glycol difatty acid esters, diethylene glycol monoethyl ether, poloxamer, or vitamin E TPGS or a combination thereof. Suitable polyoxyethylene castor oil derivatives include polyoxyl 40 hydrogenated castor oil. Suitable polyoxyethylene castor oil derivatives are polyoxyl 40 hydrogenated castor oil.

[0148] Suitable non-aqueous solvents include polyethylene glycol, stearoyl polyoxyglycerides, polyoxyethylene stearate, medium-chain fatty acids, long-chain monoglycerides, long-chain diglycerides, medium-chain monoglycerides, medium-chain diglycerides, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, polyoxyethylated 12-hydroxystearic acid, caprylocaproyl polyoxyglycerides, propylene glycol monofatty acid esters, propylene glycol difatty acid esters, diethylene glycol monoethyl ether, poloxamer, vitamin E TPGS, or combinations thereof. Suitable polyoxyethylene castor oil derivatives include polyoxyl 40 hydrogenated castor oil. Suitable polyoxyethylene castor oil derivatives are polyoxyl 40 hydrogenated castor oil.

[0149] Suitablely, the non-aqueous solvent includes polyethylene glycol, stearoyl polyoxyglycerides, polyoxyethylene stearate, medium-chain fatty acids, long-chain monoglycerides, long-chain diglycerides, medium-chain monoglycerides, medium-chain diglycerides, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, polyoxyethylated 12-hydroxystearic acid, caprylocaproyl polyoxyglycerides, propylene glycol monofatty acid esters, propylene glycol difatty acid esters, diethylene glycol monoethyl ether, or poloxamers or combinations thereof, wherein the polyethylene glycol has an average molecular weight of about 400 g / mol or about 1500 g / mol and is ultra-purified as defined herein.

[0150] Suitablely, the non-aqueous solvent includes polyethylene glycol, stearoyl polyoxyglyceride, polyoxyethylene stearate, medium-chain fatty acids, long-chain monoglycerides, long-chain diglycerides, medium-chain monoglycerides, medium-chain diglycerides, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, polyoxyethylated 12-hydroxystearic acid, caprylocaproyl polyoxyglyceride, propylene glycol monofatty acid esters, propylene glycol difatty acid esters, diethylene glycol monoethyl ether, or poloxamer or a combination thereof, wherein the polyethylene glycol has an average molecular weight of about 1000 to about 25000 g / mol, for example, about 1000 to about 6000 g / mol, about 1200 to about 1800 g / mol, or about 1400 to about 1600 g / mol.

[0151] Suitablely, the non-aqueous solvent includes polyethylene glycol, stearoyl polyoxyglycerides, medium-chain fatty acids, medium-chain monoglycerides, medium-chain diglycerides, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, polyoxyethylated 12-hydroxystearic acid, propylene glycol difatty acid esters, diethylene glycol monoethyl ether, or poloxamer or a combination thereof. Suitablely, the polyoxyethylene castor oil derivative includes polyoxyl 40 hydrogenated castor oil. Suitablely, the polyoxyethylene castor oil derivative is polyoxyl 40 hydrogenated castor oil.

[0152] Suitable non-aqueous solvents include polyethylene glycol, stearoyl polyoxyglycerides, polyoxyethylene stearates, medium-chain monoglycerides, medium-chain diglycerides, polyoxyethylene sorbitan fatty acid esters, propylene glycol difatty acid esters, or combinations thereof.

[0153] Suitable non-aqueous solvents include polyethylene glycol, stearoyl polyoxyglycerides, polyoxyethylene stearate, medium-chain fatty acids, long-chain monoglycerides, long-chain diglycerides, medium-chain monoglycerides, medium-chain diglycerides, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, polyoxyethylated 12-hydroxystearic acid, caprylocaproyl polyoxyglycerides, propylene glycol monofatty acid esters, propylene glycol difatty acid esters, diethylene glycol monoethyl ethers, or poloxamers or combinations thereof.

[0154] Suitable non-aqueous solvents include polyethylene glycol, stearoyl polyoxyglycerides, medium-chain fatty acids, long-chain monoglycerides, long-chain diglycerides, medium-chain monoglycerides, medium-chain diglycerides, polyoxyethylene sorbitan fatty acid esters, caprylocaproyl polyoxyglycerides, propylene glycol monofatty acid esters, propylene glycol difatty acid esters, diethylene glycol monoethyl ethers, or poloxamers or combinations thereof.

[0155] Suitable non-aqueous solvents include polyethylene glycol, polyoxyethylene stearate, polyoxyethylene castor oil derivatives, polyoxyethylated 12-hydroxystearic acid, diethylene glycol monoethyl ether, or poloxamer, vitamin E TPGS, or combinations thereof.

[0156] Suitable non-aqueous solvents include polyethylene glycol, polyoxyethylene castor oil derivatives, polyoxyethylated 12-hydroxystearic acid, diethylene glycol monoethyl ether, or poloxamer, or combinations thereof.

[0157] Suitable non-aqueous solvents include polyethylene glycol, propylene glycol, glycerol, stearoyl polyoxyglyceride, polyoxyethylene stearate, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, polyoxyethylated 12-hydroxystearic acid, caprylocaproyl polyoxyglyceride, linoleoyl polyoxyglyceride, oleoyl polyoxyglyceride, or sorbitan esters or combinations thereof.

[0158] Suitablely, the non-aqueous solvent may include polyethylene glycol, stearoyl polyoxyglyceride, or polyoxyethylene stearate, or a combination thereof.

[0159] Properly, non-aqueous solvents are water-soluble. Solubility is determined at room temperature. In this context, water solubility is defined as at least one part of the non-aqueous solvent being soluble in 10 to 30 parts of water, for example, at least one part of the non-aqueous solvent being soluble in 1 to 10 parts of water, or at least one part of the non-aqueous solvent being soluble in less than one part of water. Slightly soluble is defined as one part of the non-aqueous solvent being soluble in 30 to 100 parts of water. Slightly soluble is defined as one part of the non-aqueous solvent being soluble in 100 to 1000 parts of water. Very slightly soluble is defined as one part of the non-aqueous solvent being soluble in 1000 to 10000 parts of water. Practically insoluble or insoluble is defined as one part of the non-aqueous solvent being soluble in more than 10000 parts of water.

[0160] Suitablely, a non-aqueous solvent is miscible with water. Miscibility is defined herein as the formation of a homogeneous mixture when a non-aqueous solvent is added to water at room temperature.

[0161] Suitable non-aqueous solvents include polyethylene glycol, propylene glycol, ethanol, glycerol, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, polyoxyethylated 12-hydroxystearic acid, or poloxamers or combinations thereof.

[0162] Ideally, the non-aqueous solvent should include polyethylene glycol.

[0163] Ideally, the non-aqueous solvent is essentially derived from polyethylene glycol.

[0164] Ideally, the non-aqueous solvent consists of polyethylene glycol.

[0165] Suitablely, polyethylene glycol has an average molecular weight of approximately 200 to 25,000 g / mol, for example, approximately 300 to 10,000 g / mol, approximately 400 to 6,000 g / mol, approximately 1,000 to 6,000 g / mol, approximately 1,200 to 1,800 g / mol, or approximately 1,400 to 1,600 g / mol. Suitablely, polyethylene glycol has an average molecular weight of approximately 200 to 25,000 g / mol, for example, 300 to 10,000 g / mol, 400 to 6,000 g / mol, 1,000 to 6,000 g / mol, 1,200 to 1,800 g / mol, or 1,400 to 1,600 g / mol.

[0166] Those skilled in the art will be able to determine the average molecular weight of polyethylene glycol. For example, a molecular weight assay analysis test is disclosed in the United States Pharmacopeia monograph relating to polyethylene glycol.

[0167] The average molecular weight of polyethylene glycol can be appropriately determined using the following assay: Phthalic acid anhydride solution: Place 49.0 g of phthalic acid anhydride in an amber bottle and dissolve in 300 mL of pyridine from a freshly opened bottle, or pyridine freshly distilled for phthalic acid anhydride. Shake vigorously until completely dissolved. Add 7 g of imidazole and stir carefully to dissolve, then let stand for 16 hours before use.

[0168] Liquid polyethylene glycol sample solution: Carefully introduce 25.0 mL of phthalic anhydride solution into a dry, heat-resistant pressure bottle. Add an amount of sample equivalent to the expected average molecular weight divided by 160. Insert a stopper into the bottle and wrap it tightly in a cloth bag.

[0169] Solid polyethylene glycol sample solution: Carefully introduce 25.0 mL of phthalic anhydride solution into a dry, heat-resistant pressure bottle. Add an amount of sample equivalent to the expected average molecular weight divided by 160; however, due to limited solubility, do not use more than 25 g. Add 25 mL of pyridine from a freshly opened bottle, or freshly distilled pyridine to the phthalic anhydride. Stir to dissolve, insert a stopper into the bottle, and wrap it tightly in a cloth bag.

[0170] Blank: Add 25.0 mL of phthalic anhydride solution + any additional pyridine to the bottle.

[0171] Analysis: Immerse the bottle in a water bath maintained at 96°C-100°C to the same depth as the mixture inside the bottle. After 5 minutes, remove the bottle from the bath and homogenize by stirring for 30 seconds without unpacking. Heat in the water bath for 30 minutes (60 minutes for polyethylene glycol with a molecular weight of 3000 or more), then remove from the bath and allow to cool to room temperature. Carefully remove the bottle cap to release the pressure, remove from the bag, add 10 mL of water, and stir thoroughly. Wait for 2 minutes, add 0.5 mL of pyridine solution of phenolphthalein (1 / 100), and titrate with 0.5 N sodium hydroxide VS until the first pink color persists for 15 seconds. Perform a blank determination.

[0172] Calculate the average molecular weight obtained: Result=(2000×W) / [(V B -V S )×N] W = Weight (g) of polyethylene glycol obtained from the sample solution V B= Volume of 0.5N sodium hydroxide consumed by the blank (mL) V S = Volume of 0.5N sodium hydroxide consumed by the sample (mL) N = Normality of sodium hydroxide solution

[0173] Suitablely, polyethylene glycol has an average molecular weight of approximately 400, approximately 1000, approximately 1500, approximately 1540, approximately 2000, approximately 3000, approximately 4000, approximately 6000, approximately 8000, or approximately 20000 g / mol. Suitablely, polyethylene glycol has an average molecular weight of 400, 1000, 1500, 1540, 2000, 3000, 4000, 6000, 8000, or 20000 g / mol.

[0174] Suitablely, polyethylene glycol has an average molecular weight of approximately 400, approximately 1500, approximately 4000, or approximately 6000 g / mol. Suitablely, polyethylene glycol has an average molecular weight of 400, 1500, 4000, or 6000 g / mol.

[0175] Appropriately, polyethylene glycol has an average molecular weight of approximately 400 g / mol. Appropriately, polyethylene glycol has an average molecular weight of approximately 1500 g / mol. Appropriately, polyethylene glycol has an average molecular weight of approximately 4000 g / mol. Appropriately, polyethylene glycol has an average molecular weight of approximately 6000 g / mol. Appropriately, polyethylene glycol has an average molecular weight of 400 g / mol. Appropriately, polyethylene glycol has an average molecular weight of 1500 g / mol. Appropriately, polyethylene glycol has an average molecular weight of 4000 g / mol. Appropriately, polyethylene glycol has an average molecular weight of 6000 g / mol.

[0176] Suitablely, the non-aqueous solvent contains polyethylene glycol with an average weight of approximately 1500 g / mol.

[0177] Ideally, the non-aqueous solvent consists essentially of polyethylene glycol with an average weight of approximately 1500 g / mol.

[0178] Ideally, the non-aqueous solvent consists of polyethylene glycol having an average weight of approximately 1500 g / mol.

[0179] Suitablely, the non-aqueous solvent contains polyethylene glycol with an average weight of approximately 4000 g / mol.

[0180] Ideally, the non-aqueous solvent consists essentially of polyethylene glycol with an average weight of approximately 4000 g / mol.

[0181] Ideally, the non-aqueous solvent consists of polyethylene glycol having an average weight of approximately 4000 g / mol.

[0182] Suitablely, the non-aqueous solvent contains polyethylene glycol with an average weight of approximately 6000 g / mol.

[0183] Ideally, the non-aqueous solvent consists essentially of polyethylene glycol with an average weight of approximately 6000 g / mol.

[0184] Ideally, the non-aqueous solvent consists of polyethylene glycol having an average weight of approximately 6000 g / mol.

[0185] Suitablely, the non-aqueous solvent contains polyethylene glycol with an average weight of approximately 400 g / mol.

[0186] Ideally, the non-aqueous solvent consists essentially of polyethylene glycol with an average weight of approximately 400 g / mol.

[0187] Ideally, the non-aqueous solvent consists of polyethylene glycol with an average weight of approximately 400 g / mol.

[0188] Suitablely, polyethylene glycol is ultra-purified polyethylene glycol. Suitablely, ultra-purified polyethylene glycol has an average molecular weight of approximately 200 to 25,000 g / mol, for example, approximately 300 to 10,000 g / mol, approximately 400 to 6,000 g / mol, approximately 1,000 to 6,000 g / mol, approximately 1,200 to 1,800 g / mol, approximately 1,400 to 1,600 g / mol, approximately 350 to 450 g / mol, or approximately 380 to 420 g / mol. Suitablely, ultra-purified polyethylene glycol has an average molecular weight of approximately 400 g / mol.

[0189] Ideally, ultra-refined polyethylene glycol is: (a) Having a pH of 4.5 to 7.5, for example, 4.0 to 7.0; (b) Containing 0 to 10 ppm, for example, 0 to 1 ppm of ethylene oxide; (c) Contains 0-10 ppm of dioxane; (d) Contains 0.0 to 0.4%, for example, 0.00 to 0.25%, of ethylene glycol; (e) Contains 0.0 to 0.4%, for example 0.00 to 0.25%, for example 0.062% or less of diethylene glycol; (f) Contains a combination of ethylene glycol and diethylene glycol in an amount of 0.25% or less; (g) Contains formaldehyde at a concentration of 30 ppm or less, for example, 15 ppm or less; (h) Contains 0.0-2.0% water, for example, 1.0% or less; (i) containing 0.5% or less acetic acid; and / or (j) Has a peroxide value of 0.0 to 5.0 meqO2 / kg.

[0190] Suitablely, the non-aqueous solvent comprises two different polyethylene glycols, the first polyethylene glycol having an average weight of less than about 1000 g / mol, for example less than about 800 g / mol, or for example less than about 600 g / mol, and the second polyethylene glycol having an average weight of at least about 1000 g / mol, for example at least about 1200 g / mol, or for example at least about 1400 g / mol.

[0191] Suitablely, the non-aqueous solvent contains two different polyethylene glycols, where the first polyethylene glycol has an average weight of 200-999 g / mol, for example, 400-800 g / mol, and the second polyethylene glycol has an average weight of 1000-25000 g / mol, for example, 1200-10000 g / mol, for example, 1200-6000 g / mol.

[0192] Suitablely, the non-aqueous solvent contains two different polyethylene glycols, the first polyethylene glycol having an average weight of approximately 400 g / mol, and the second polyethylene glycol having an average weight of approximately 1500, 4000, or 6000 g / mol.

[0193] Ideally, the weight ratio of the first polyethylene glycol to the second polyethylene glycol is 1:20 to 20:1, for example, 1:10 to 10:1, or for example, 1:9 to 9:1.

[0194] Ideally, the first polyethylene glycol is ultra-refined polyethylene glycol.

[0195] Preferably, the pharmaceutical composition comprises two non-aqueous solvents, the first of which is vitamin E TPGS, and the second non-aqueous solvent is polyethylene glycol. Preferably, the polyethylene glycol has an average weight of at least about 1000 g / mol, for example, at least about 1200 g / mol, or for example, at least about 1400 g / mol. Preferably, the polyethylene glycol has an average weight of 1000 to 25000 g / mol, for example, 1200 to 10000 g / mol, or for example, 1200 to 6000 g / mol. Preferably, the polyethylene glycol has an average weight of about 1500, 4000, or 6000 g / mol. Preferably, the weight ratio of polyethylene glycol to vitamin E TPGS is 1:20 to 20:1, for example, 1:10 to 10:1, or for example, 1:9 to 9:1.

[0196] Ideally, polyoxyethylene stearate is PEG-32 stearate, polyethylene glycol monostearate, or a mixture thereof.

[0197] Glycerol has three hydroxyl functional groups, which can be esterified with one, two, or three fatty acids to form mono, di, or triglycerides, respectively. Mono, di, or triglycerides contain the fatty acids in a bound state.

[0198] Long-chain triglycerides are triglycerides having three fatty acids with aliphatic tails of 13 to 21 carbon atoms. Specifically, long-chain triglycerides contain fatty acids with aliphatic tails of 13 to 21 carbon atoms. Specifically, long-chain triglycerides contain fatty acids with aliphatic tails of 16 to 20 carbon atoms. Specifically, long-chain triglycerides contain oleic acid. Specifically, long-chain triglycerides are selected from corn oil and soybean oil.

[0199] Medium-chain triglycerides are triglycerides having three fatty acids with aliphatic tails of 6 to 12 carbon atoms. More precisely, medium-chain triglycerides contain fatty acids with aliphatic tails of 6 to 12 carbon atoms. More precisely, medium-chain triglycerides contain caprylic acid or capric acid or a mixture thereof.

[0200] A long-chain monoglyceride is a monoglyceride having one fatty acid with an aliphatic tail of 13 to 21 carbon atoms. More precisely, a long-chain monoglyceride contains a fatty acid with an aliphatic tail of 13 to 21 carbon atoms. More precisely, a long-chain monoglyceride contains a fatty acid with an aliphatic tail of 16 to 20 carbon atoms. More precisely, a long-chain monoglyceride is a glyceryl monooleate.

[0201] Medium-chain monoglycerides are monoglycerides having one fatty acid with an aliphatic tail of 6 to 12 carbon atoms. More precisely, medium-chain monoglycerides contain a fatty acid with an aliphatic tail of 6 to 12 carbon atoms. More precisely, medium-chain monoglycerides contain a fatty acid with an aliphatic tail of 8 to 12 carbon atoms. More precisely, medium-chain monoglycerides are glyceryl monocaprylate.

[0202] Long-chain fatty acids are free fatty acids (i.e., not bonded to another molecule, e.g., a mono, di, or triglyceride glycerol molecule) having an aliphatic tail of at least 13 carbon atoms, preferably 13 to 21 carbon atoms. Suitablely, long-chain fatty acids have a fatty chain containing 13 to 21 carbon atoms. Suitablely, long-chain fatty acids have a fatty chain containing 16 to 20 carbon atoms. Suitablely, long-chain fatty acids are very long-chain fatty acids. Suitablely, long-chain fatty acids are free fatty acids having an aliphatic tail of at least 22 carbon atoms. Suitablely, long-chain fatty acids are saturated long-chain fatty acids. Suitablely, long-chain fatty acids are unsaturated long-chain fatty acids. Suitablely, long-chain fatty acids are oleic acid, palmitic acid, stearic acid, arachidic acid, palmitoleic acid, nervonic acid, linoleic acid, alpha-linolenic acid, arachidonic acid, or eicosapentaenoic acid.

[0203] Medium-chain fatty acids are free fatty acids (i.e., not bonded to another molecule, such as a mono, di, or triglyceride glycerol molecule) having an aliphatic tail of 6 to 12 carbon atoms. Appropriately, medium-chain fatty acids have a fatty chain containing 6 to 12 carbon atoms. Appropriately, medium-chain fatty acids have a fatty chain containing 6 to 10 carbon atoms. Appropriately, medium-chain fatty acids are saturated medium-chain fatty acids. Appropriately, medium-chain fatty acids are unsaturated medium-chain fatty acids. Appropriately, medium-chain fatty acids are caprylic acid, capric acid, or lauric acid.

[0204] Polyoxyethylene castor oil derivatives are obtained by reacting varying amounts of ethylene oxide with either castor oil or hydrogenated castor oil. Preferably, polyoxyethylene castor oil derivatives include polyoxyl 40 hydrogenated castor oil, polyoxyl 35 castor oil, or mixtures thereof. Preferably, polyoxyethylene castor oil derivatives are polyoxyl 40 hydrogenated castor oil, polyoxyl 35 castor oil, or mixtures thereof. Preferably, polyoxyethylene castor oil derivatives include polyoxyl 40 hydrogenated castor oil. Preferably, polyoxyethylene castor oil derivatives are polyoxyl 40 hydrogenated castor oil.

[0205] Suitablely, the polyoxyethylene sorbitan fatty acid ester is polysorbate 20, polysorbate 80, or a mixture thereof. Suitablely, the polyoxyethylene sorbitan fatty acid is polysorbate 20.

[0206] More precisely, propylene glycol monofatty acid esters are propylene glycol monocaprylates.

[0207] More precisely, propylene glycol difatty acid ester is propylene glycol dilaurate.

[0208] Poloxamers are nonionic triblock copolymers composed of two hydrophilic polyoxyethylene (poly(ethylene oxide)) chains adjacent to a central hydrophobic polyoxypropylene (poly(propylene oxide)) chain. More specifically, poloxamers include poloxamer 124, poloxamer 188, poloxamer 237, poloxamer 338, or poloxamer 407.

[0209] Ideally, the non-aqueous solvent comprises two or more non-aqueous solvents, for example, two, three, or four non-aqueous solvents.

[0210] Appropriately, the pharmaceutical composition contains at least about 20% w / w of a non-aqueous solvent based on the weight of the total pharmaceutical composition, for example, at least about 30% w / w, at least about 40% w / w, at least about 50% w / w, at least about 60% w / w, at least about 70% w / w, at least about 80% w / w, at least about 90% w / w, at least about 95% w / w, at least about 96% w / w, at least about 97% w / w, at least about 98% w / w, at least about 99% w / w, at least about 99.2% w / w, or at least about 99.5% w / w. Preferably, the pharmaceutical composition contains at least 20% w / w of a non-aqueous solvent, for example, at least 30% w / w, at least 40% w / w, at least 50% w / w, at least 60% w / w, at least 70% w / w, at least 80% w / w, at least 90% w / w, at least 95% w / w, at least 96% w / w, at least 97% w / w, at least 98% w / w, at least 99% w / w, at least 99.2% w / w, or at least 99.5% w / w, based on the weight of the total pharmaceutical composition.

[0211] Appropriately, the pharmaceutical composition should be approximately 20 to approximately 99.99% w / w of the total weight of the pharmaceutical composition, for example, approximately 30 to approximately 99.99% w / w, approximately 40 to approximately 99.99% w / w, approximately 50 to approximately 99.99% w / w, approximately 60 to approximately 99.99% w / w, approximately 70 to approximately 99.99% w / w, approximately 80 to approximately 99.99% w / w, approximately 90 to approximately 99.99% w / w, approximately 95 to approximately 99.99% w / w, approximately 96 to approximately 99.99% w / w, approximately 97 to approximately 99.99% w / w, approximately 98 to approximately 99.99% w / w, approximately 99 to approximately 99.99% w / w, approximately 99.2 to approximately 99.99% w / w, or approximately 99.5 to approximately 99.99% The pharmaceutical composition contains a non-aqueous solvent in w / w amounts. Preferably, the pharmaceutical composition contains a non-aqueous solvent in an amount of 20-99.99% w / w, for example, 30-99.99% w / w, 40-99.99% w / w, 50-99.99% w / w, 60-99.99% w / w, 70-99.99% w / w, 80-99.99% w / w, 90-99.99% w / w, 95-99.99% w / w, 96-99.99% w / w, 97-99.99% w / w, 98-99.99% w / w, 99-99.99% w / w, 99.2-99.99% w / w, or 99.5-99.99% w / w amounts of the non-aqueous solvent based on the weight of the total pharmaceutical composition.

[0212] Suitablely, the pharmaceutical composition contains approximately 99.6% w / w of a non-aqueous solvent based on the weight of the total pharmaceutical composition. Suitablely, the pharmaceutical composition contains approximately 99.9% w / w of a non-aqueous solvent based on the weight of the total pharmaceutical composition.

[0213] Ideally, a non-aqueous solvent is semi-solid at room temperature. A semi-solid is any material that is solid at room temperature and liquid at temperatures above room temperature.

[0214] Suitablely, the non-aqueous solvent has a melting point of at least 30°C, for example, at least 35°C, or at least 40°C. Suitablely, the non-aqueous solvent has a melting point of at least about 30°C, for example, at least about 35°C, or at least about 40°C.

[0215] Suitablely, non-aqueous solvents have a melting point of about 35°C to about 80°C, for example, about 35°C to about 70°C, about 35°C to about 60°C, about 35°C to about 50°C, or about 40°C to about 50°C. Suitablely, non-aqueous solvents have a melting point of 35°C to 80°C, for example, 35°C to 70°C, 35°C to 60°C, 35°C to 50°C, or 40°C to 50°C.

[0216] Further excipients in pharmaceutical compositions Depending on the circumstances, further excipients may be included in the pharmaceutical composition according to this disclosure.

[0217] The pharmaceutical composition may further contain vitamin E TPGS or lauroyl polyoxyglyceride.

[0218] Ideally, the weight ratio of non-aqueous solvent to vitamin E TPGS should be 1:20 to 20:1, for example, 1:10 to 10:1, or for example, 1:9 to 9:1.

[0219] Preferably, the pharmaceutical composition comprises a non-aqueous solvent and vitamin E TPGS, the non-aqueous solvent comprising polyethylene glycol. Preferably, the polyethylene glycol has an average weight of at least about 1000 g / mol, for example, at least about 1200 g / mol, or for example, at least about 1400 g / mol. Preferably, the polyethylene glycol has an average weight of 1000 to 25000 g / mol, for example, 1200 to 10000 g / mol, or for example, 1200 to 6000 g / mol. Preferably, the polyethylene glycol has an average weight of about 1500, 4000, or 6000 g / mol. Preferably, the weight ratio of polyethylene glycol to vitamin E TPGS is 1:20 to 20:1, for example, 1:10 to 10:1, or for example, 1:9 to 9:1.

[0220] Appropriately, the pharmaceutical composition further includes viscosity modifiers, opacifiers, colorants, sweeteners, and / or preservatives, such as antioxidants.

[0221] Viscosity modifiers are excipients that adjust the viscosity of a pharmaceutical composition to impart appropriate viscosity properties to the pharmaceutical composition, enabling consistent manufacturing, for example, to ensure that the pharmaceutical composition has desired flow properties and that a desired volume of the pharmaceutical composition is dispensed during manufacturing. Preferably, the viscosity modifier is a liquid at room temperature. Preferably, the viscosity modifier is vitamin E TPGS and / or polyethylene glycol having an average weight of less than 1000 g / mol, e.g., less than 600 g / mol. Preferably, the polyethylene glycol has an average weight of about 200 to about 1000 g / mol, e.g., about 300 to 500 g / mol. Preferably, the polyethylene glycol has an average weight of about 400 g / mol.

[0222] Opaque agents are excipients that make pharmaceutical compositions opaque.

[0223] Suitable antioxidants include butylated hydroxyanisole, butylated hydroxytoluene, ascorbic acid, or α-tocopherol.

[0224] Semi-solid pharmaceutical composition Ideally, a pharmaceutical composition is semi-solid at room temperature. A semi-solid is any material that is solid at room temperature and liquid at temperatures above room temperature.

[0225] Preferably, the pharmaceutical composition has a melting point of at least about 30°C, for example, at least about 35°C, or at least about 40°C. Preferably, the pharmaceutical composition has a melting point of at least 30°C, for example, at least 35°C, or at least 40°C.

[0226] Preferably, the pharmaceutical composition has a melting point of about 35°C to about 80°C, for example, about 35°C to about 70°C, about 35°C to about 60°C, about 35°C to about 50°C, or about 40°C to about 50°C. Preferably, the pharmaceutical composition has a melting point of 35°C to 80°C, for example, 35°C to 70°C, 35°C to 60°C, 35°C to 50°C, or 40°C to 50°C.

[0227] Advantageously, having a pharmaceutical composition that is semi-solid at room temperature and has a melting point of 35°C to 80°C means that the active substance is not exposed to high temperatures during manufacturing, thereby minimizing the decomposition of the active substance during manufacturing. Furthermore, a pharmaceutical composition that can be melted facilitates the transfer of a desired amount of the pharmaceutical composition into, for example, a capsule shell.

[0228] Stability of pharmaceutical compositions Appropriately, the active substance is stable in the pharmaceutical composition. Appropriately, the active substance is stable in the pharmaceutical composition for at least about two weeks, about one month, about two months, about three months, about six months, about twelve months, or about twenty-four months. Appropriately, the active substance is stable in the pharmaceutical composition for at least two weeks, one, two, three, six, twelve, or twenty-four months.

[0229] Appropriately, the active substance is chemically stable in the pharmaceutical composition for at least about two weeks, about one month, about two months, about three months, about six months, about twelve months, or about twenty-four months. Appropriately, the active substance is chemically stable in the pharmaceutical composition for at least two weeks, one, two, three, six, twelve, or twenty-four months.

[0230] Advantageously, the active substance remains stable in the pharmaceutical composition throughout its lifespan, for example, during its manufacture, and at least until the pharmaceutical composition is administered to a patient. Stability is a crucial safety aspect of a pharmaceutical composition because it ensures consistent assays of the active substance over time and, consequently, consistent administration of the active substance to the patient. Thus, the desired dose is administered to the patient. Furthermore, degradation products of the active substance in a stable pharmaceutical composition are at minimal levels, ensuring that end-users, such as patients, are not administered degradation products of the active substance. The stability of the active ingredient in a pharmaceutical composition is important from the perspective of patient safety and efficacy.

[0231] Appropriately, the active substance is stable in the pharmaceutical composition for at least about two weeks, about one month, about two months, about three months, about six months, about twelve months, or about twenty-four months when the pharmaceutical composition is stored at 25°C / 60%RH and / or 40°C / 75%RH. Appropriately, the active substance is stable in the pharmaceutical composition for at least two weeks, one, two, three, six, twelve, or twenty-four months when the pharmaceutical composition is stored at 25°C / 60%RH and / or 40°C / 75%RH.

[0232] Appropriately, the active substance is stable in the pharmaceutical composition for at least about two weeks, about one month, about two months, about three months, about six months, about twelve months, or about twenty-four months when the pharmaceutical composition is stored at 25°C / 60%RH and / or 40°C / 75%RH. Appropriately, the active substance is stable in the pharmaceutical composition for two weeks, one, two, three, six, twelve, or twenty-four months when the pharmaceutical composition is stored at 25°C / 60%RH and / or 40°C / 75%RH.

[0233] Appropriately, the total amount of degradation products of the active substance is less than or equal to about 4 area % as determined by chromatography when the pharmaceutical composition is stored at 25°C / 60%RH and / or 40°C / 75%RH for at least about 2 weeks, about 1 month, about 2 months, about 3 months, about 6 months, about 12 months, or about 24 months. Appropriately, the total amount of degradation products of the active substance is less than or equal to about 4 area % as determined by chromatography when the pharmaceutical composition is stored at 25°C / 60%RH and / or 40°C / 75%RH for 2 weeks, 1, 2, 3, 6, 12, or 24 months.

[0234] Appropriately, the total amount of degradation products of the active substance is less than or equal to about 3 area % as determined by chromatography when the pharmaceutical composition is stored at 25°C / 60%RH and / or 40°C / 75%RH for at least about 2 weeks, about 1 month, about 2 months, about 3 months, about 6 months, about 12 months, or about 24 months. Appropriately, the total amount of degradation products of the active substance is less than or equal to 3 area % as determined by chromatography when the pharmaceutical composition is stored at 25°C / 60%RH and / or 40°C / 75%RH for 2 weeks, 1, 2, 3, 6, 12, or 24 months.

[0235] Appropriately, the total amount of degradation products of the active substance is less than or equal to about 2 area % as determined by chromatography when the pharmaceutical composition is stored at 25°C / 60%RH and / or 40°C / 75%RH for at least about 2 weeks, about 1 month, about 2 months, about 3 months, about 6 months, about 12 months, or about 24 months. Appropriately, the total amount of degradation products of the active substance is less than or equal to 2 area % as determined by chromatography when the pharmaceutical composition is stored at 25°C / 60%RH and / or 40°C / 75%RH for 2 weeks, 1, 2, 3, 6, 12, or 24 months.

[0236] Appropriately, a pharmaceutical composition shall not contain more than 1 area percent of a single degradation product of the active substance, as measured by chromatography, when the pharmaceutical composition is stored at 25°C / 60%RH and / or 40°C / 75%RH for at least about 2 weeks, about 1 month, about 2 months, about 3 months, about 6 months, about 12 months, or about 24 months. Appropriately, a pharmaceutical composition shall not contain more than 1 area percent of a single degradation product of the active substance, as measured by chromatography, when the pharmaceutical composition is stored at 25°C / 60%RH and / or 40°C / 75%RH for 2 weeks, 1, 2, 3, 6, 12, or 24 months.

[0237] Decomposition products of active substances are impurities that form after the storage of the active substance (or during the manufacture of a pharmaceutical composition). Decomposition products can be formed by exposure of the active substance to water, oxygen, peroxides, or UV light.

[0238] Appropriately, the assay of the active substance is determined by chromatography to be approximately 90-110% of the nominal value when the pharmaceutical composition is stored at 25°C / 60%RH and / or 40°C / 75%RH for at least about 2 weeks, about 1 month, about 2 months, about 3 months, about 6 months, about 12 months, or about 24 months. Appropriately, the assay of the active substance is determined by chromatography to be approximately 90-110% of the nominal value when the pharmaceutical composition is stored at 25°C / 60%RH and / or 40°C / 75%RH for 2 weeks, 1, 2, 3, 6, 12, or 24 months.

[0239] Appropriately, the assay of the active substance is determined by chromatography to be approximately 95-105% of the nominal value when the pharmaceutical composition is stored at 25°C / 60%RH and / or 40°C / 75%RH for at least about 2 weeks, about 1 month, about 2 months, about 3 months, about 6 months, about 12 months, or about 24 months. Appropriately, the assay of the active substance is determined by chromatography to be approximately 95-105% of the nominal value when the pharmaceutical composition is stored at 25°C / 60%RH and / or 40°C / 75%RH for 2 weeks, 1, 2, 3, 6, 12, or 24 months.

[0240] Appropriately, the assay of the active substance is determined by chromatography to be approximately 98-102% of the nominal value when the pharmaceutical composition is stored at 25°C / 60%RH and / or 40°C / 75%RH for at least about 2 weeks, about 1 month, about 2 months, about 3 months, about 6 months, about 12 months, or about 24 months. Appropriately, the assay of the active substance is determined by chromatography to be approximately 98-102% of the nominal value when the pharmaceutical composition is stored at 25°C / 60%RH and / or 40°C / 75%RH for 2 weeks, 1, 2, 3, 6, 12, or 24 months.

[0241] Appropriately, the total amount of degradation products of the active substance is less than or equal to about 4 area % as determined by chromatography, and the assay of the active substance is about 90-110% of the nominal value as determined by chromatography when the pharmaceutical composition is stored at 25°C / 60%RH and / or 40°C / 75%RH for at least about 2 weeks, about 1 month, about 2 months, about 3 months, about 6 months, about 12 months, or about 24 months. Appropriately, the total amount of degradation products of the active substance is less than or equal to 4 area % when the pharmaceutical composition is stored at 25°C / 60%RH and / or 40°C / 75%RH for 2 weeks, 1, 2, 3, 6, 12, or 24 months, and the assay of the active substance is about 90-110% of the nominal value as determined by chromatography.

[0242] Suitably, the active substance is stable in the pharmaceutical composition for at least about 2 weeks, about 1 month, about 2 months, about 3 months, about 6 months, about 12 months, or about 24 months, when the pharmaceutical composition is protected from light, suitably UV radiation. Suitably, the active substance is stable in the pharmaceutical composition for at least 2 weeks, 1, 2, 3, 6, 12, or 24 months, when the pharmaceutical composition is protected from light, suitably UV radiation.

[0243] Suitably, the chromatography method is an HPLC method. HPLC in this context includes UPLC.

[0244] Suitably, the HPLC method comprises a UV detector. Suitably, the UV detector measures the assay of the active substance and / or degradation products at about 256 nm.

[0245] Suitably, the HPLC method is a reversed-phase HPLC method. Suitably, the reversed-phase HPLC method comprises two eluents, and the ratio of the two eluents changes during the course of the HPLC analysis. Suitably, the first eluent comprises water and the second eluent comprises acetonitrile. Suitably, the first eluent comprises water and ammonium acetate, and the second eluent comprises acetonitrile. Suitably, the first eluent comprises water and 10 mM ammonium acetate, and the second eluent comprises acetonitrile.

[0246] Suitably, the reversed-phase HPLC method comprises an HPLC column. Suitably, the HPLC column comprises a C18 stationary phase. Suitably, the HPLC column temperature is about 40°C.

[0247] Suitably, the eluent flows through the HPLC column at about 0.3 mL / min.

[0248] Suitably, the chromatography method is a reversed-phase HPLC method, and the reversed-phase HPLC method is: a. a UV detector; b. an HPLC column; and c. comprises two eluents, and the ratio of the two eluents changes during the course of the HPLC analysis.

[0249] Release rate of active substances from pharmaceutical compositions Appropriately, at least about 75% of the total amount of active substance contained in the pharmaceutical composition is released within approximately the first 45 minutes when the pharmaceutical composition is subjected to an in vitro dissolution test using 0.1 M HCl or pH 6.8 phosphate buffer as the dissolution medium, and the dissolution profile is determined at approximately 37°C using a rotation speed of approximately 50 rpm. Appropriately, at least 75% of the total amount of active substance contained in the pharmaceutical composition is released within the first 45 minutes when the pharmaceutical composition is subjected to an in vitro dissolution test using 0.1 M HCl or pH 6.8 phosphate buffer as the dissolution medium, and the dissolution profile is determined at 37°C using a rotation speed of 50 rpm.

[0250] Advantageously, such a release profile provides optimal absorption of the active substance when administered to the patient.

[0251] Appropriately, at least about 75% of the total amount of active substance contained in the pharmaceutical composition is released within approximately the first 30 minutes when the pharmaceutical composition is subjected to an in vitro dissolution test using 0.1 M HCl or pH 6.8 phosphate buffer as the dissolution medium, and the dissolution profile is determined at approximately 37°C using a rotation speed of approximately 50 rpm. Appropriately, at least 75% of the total amount of active substance contained in the pharmaceutical composition is released within the first 30 minutes when the pharmaceutical composition is subjected to an in vitro dissolution test using 0.1 M HCl or pH 6.8 phosphate buffer as the dissolution medium, and the dissolution profile is determined at 37°C using a rotation speed of 50 rpm.

[0252] Appropriately, at least 85% of the total amount of active substance contained in the pharmaceutical composition is released within approximately the first 15 minutes when the pharmaceutical composition is subjected to an in vitro dissolution test using 0.1 M HCl or pH 6.8 phosphate buffer as the dissolution medium, and the dissolution profile is determined at approximately 37°C using a rotation speed of approximately 50 rpm. Appropriately, at least 85% of the total amount of active substance contained in the pharmaceutical composition is released within the first 15 minutes when the pharmaceutical composition is subjected to an in vitro dissolution test using 0.1 M HCl or pH 6.8 phosphate buffer as the dissolution medium, and the dissolution profile is determined at 37°C using a rotation speed of 50 rpm.

[0253] Appropriately, at least about 75% of the total amount of active substance contained in a pharmaceutical composition is released within approximately the first 45 minutes when the pharmaceutical composition is subjected to an in vitro dissolution test using 0.1 M HCl or pH 6.8 phosphate buffer as the dissolution medium, and the dissolution profile is determined at approximately 37°C using a rotation speed of approximately 50 rpm, as described in the United States Pharmacopeia. Appropriately, at least 75% of the total amount of active substance contained in a pharmaceutical composition is released within the first 45 minutes when the pharmaceutical composition is subjected to an in vitro dissolution test using 0.1 M HCl or pH 6.8 phosphate buffer as the dissolution medium, and the dissolution profile is determined at 37°C using a rotation speed of 50 rpm, as described in the United States Pharmacopeia.

[0254] Appropriately, at least about 75% of the total amount of active substance contained in a pharmaceutical composition is released within approximately the first 30 minutes when the pharmaceutical composition is subjected to an in vitro dissolution test using 0.1 M HCl or pH 6.8 phosphate buffer as the dissolution medium, and the dissolution profile is determined at approximately 37°C using a rotation speed of approximately 50 rpm, as described in the United States Pharmacopeia. Appropriately, at least 75% of the total amount of active substance contained in a pharmaceutical composition is released within the first 30 minutes when the pharmaceutical composition is subjected to an in vitro dissolution test using 0.1 M HCl or pH 6.8 phosphate buffer as the dissolution medium, and the dissolution profile is determined at 37°C using a rotation speed of 50 rpm, as described in the United States Pharmacopeia.

[0255] Appropriately, at least about 75% of the total amount of active substance contained in the pharmaceutical composition is released within approximately the first 15 minutes when the pharmaceutical composition is subjected to an in vitro dissolution test using 0.1 M HCl or pH 6.8 phosphate buffer as the dissolution medium, and the dissolution profile is determined at approximately 37°C using a rotation speed of approximately 50 rpm, as described in the United States Pharmacopeia. Appropriately, at least 75% of the total amount of active substance contained in the pharmaceutical composition is released within the first 15 minutes when the pharmaceutical composition is subjected to an in vitro dissolution test using 0.1 M HCl or pH 6.8 phosphate buffer as the dissolution medium, and the dissolution profile is determined at 37°C using a rotation speed of 50 rpm, as described in the United States Pharmacopeia.

[0256] Appropriately, at least about 85% of the total amount of active substance contained in a pharmaceutical composition is released within approximately the first 15 minutes when the pharmaceutical composition is subjected to an in vitro dissolution test using 0.1 M HCl or pH 6.8 phosphate buffer as the dissolution medium, and the dissolution profile is determined at approximately 37°C using a rotation speed of approximately 50 rpm, as described in the United States Pharmacopeia. Appropriately, at least 85% of the total amount of active substance contained in a pharmaceutical composition is released within the first 15 minutes when the pharmaceutical composition is subjected to an in vitro dissolution test using 0.1 M HCl or pH 6.8 phosphate buffer as the dissolution medium, and the dissolution profile is determined at 37°C using a rotation speed of 50 rpm, as described in the United States Pharmacopeia.

[0257] Appropriately, the in vitro dissolution test includes a container filled with approximately 500 mL of dissolving medium, which is 0.1 M HCl or pH 6.8 phosphate buffer. Appropriately, the in vitro dissolution test includes a container filled with 500 mL of dissolving medium, which is 0.1 M HCl or pH 6.8 phosphate buffer.

[0258] Ideally, the dissolving medium should have a temperature of approximately 37°C.

[0259] Appropriately, the in vitro dissolution test includes a container filled with approximately 500 mL of dissolving medium, which is 0.1 M HCl or pH 6.8 phosphate buffer, and the dissolution profile is determined at approximately 37°C using a rotation speed of approximately 50 rpm, as described in the United States Pharmacopeia. Appropriately, the in vitro dissolution test includes a container filled with 500 mL of dissolving medium, which is 0.1 M HCl or pH 6.8 phosphate buffer, and the dissolution profile is determined at 37°C using a rotation speed of 50 rpm, as described in the United States Pharmacopeia.

[0260] Appropriately, the in vitro dissolution test includes a container filled with approximately 500 mL of dissolving medium, the dissolving medium being 0.1 M HCl or pH 6.8 phosphate buffer, the dissolution profile being determined as described in the United States Pharmacopeia, the paddle rotating at approximately 50 rpm in the container, and the dissolving medium having a temperature of approximately 37°C. Appropriately, the in vitro dissolution test includes a container filled with 500 mL of dissolving medium, the dissolving medium being 0.1 M HCl or pH 6.8 phosphate buffer, the dissolution profile being determined as described in the United States Pharmacopeia, the paddle rotating at 50 rpm in the container, and the dissolving medium having a temperature of 37°C.

[0261] Appropriately, the in vitro dissolution test includes a container filled with approximately 500 mL of dissolving medium, the dissolving medium being 0.1 M HCl or pH 6.8 phosphate buffer, the dissolution profile being determined as described in the United States Pharmacopeia, the paddle rotating at approximately 50 rpm in the container for approximately the first 45 minutes of the test, then at approximately 200 rpm after approximately 45 minutes, and the dissolving medium having a temperature of approximately 37°C. Appropriately, the in vitro dissolution test includes a container filled with 500 mL of dissolving medium, the dissolving medium being 0.1 M HCl or pH 6.8 phosphate buffer, the dissolution profile being determined as described in the United States Pharmacopeia, the paddle rotating at 50 rpm in the container for the first 45 minutes of the test, then at 200 rpm after 45 minutes, and the dissolving medium having a temperature of 37°C.

[0262] Suitably, the in vitro dissolution test comprises a paddle, and the paddle rotates. Suitably, the in vitro dissolution test comprises a paddle, and the paddle rotates at about 50 rpm. Suitably, the in vitro dissolution test comprises a paddle, and the paddle rotates at about 50 rpm for substantially the first 45 minutes of the test, and then rotates at about 200 rpm after about 45 minutes. Suitably, the in vitro dissolution test comprises a paddle, and the paddle rotates at 50 rpm. Suitably, the in vitro dissolution test comprises a paddle, and the paddle rotates at 50 rpm for the first 45 minutes of the test, and then rotates at 200 rpm after 45 minutes.

[0263] Suitably, the in vitro dissolution test comprises a basket, and the basket rotates. Suitably, the in vitro dissolution test comprises a basket, and the basket rotates at about 50 rpm. Suitably, the in vitro dissolution test comprises a basket, and the basket rotates at about 50 rpm for substantially the first 45 minutes of the test, and then rotates at about 200 rpm after about 45 minutes. Suitably, the in vitro dissolution test comprises a basket, and the basket rotates at 50 rpm. Suitably, the in vitro dissolution test comprises a basket, and the basket rotates at 50 rpm for the first 45 minutes of the test, and then rotates at 200 rpm after 45 minutes.

[0264] Suitably, the in vitro dissolution test further comprises a sinker for the pharmaceutical composition. Suitably, the sinker is an O-ring sinker.

[0265] Suitably, the in vitro dissolution test comprises a detector. Suitably, the detector comprises a UV detector.

[0266] Suitably, when the pharmaceutical composition is subjected to an in vitro dissolution profile, the total amount of the active substance released from the pharmaceutical composition is determined by a chromatography method or UV spectroscopy. Suitably, the chromatography method is an HPLC method. Suitably, the HPLC method comprises a UV detector. Suitably, the UV detector measures the assay of the active substance at about 217 nm.

[0267] Appropriately, the HPLC method is the reversed-phase HPLC method. Appropriately, the reversed-phase HPLC method involves two eluents, the ratio of which changes during the HPLC analysis. Appropriately, the first eluent contains water and the second eluent contains acetonitrile. Appropriately, the first eluent contains water and phosphoric acid and the second eluent contains acetonitrile. Appropriately, the first eluent contains water and 0.1% phosphoric acid and the second eluent contains acetonitrile.

[0268] Ideally, the reversed-phase HPLC method includes an HPLC column. Ideally, the HPLC column includes a C18 stationary phase. Ideally, the HPLC column temperature is approximately 40°C. Ideally, the eluent flows through the HPLC column at approximately 0.5 mL / min.

[0269] More precisely, the chromatography method is reversed-phase HPLC, and reversed-phase HPLC is: a. UV detector; b. HPLC column; and c. It contains two eluents, and the ratio of the two eluents changes during the HPLC analysis.

[0270] Homogeneity of active ingredients in pharmaceutical compositions Ideally, the active substance is homogeneously distributed throughout the non-aqueous solvent. Ideally, the active substance is homogeneously distributed throughout the non-aqueous solvent at room temperature.

[0271] Advantageously, the active substance is homogeneously dispersed within the pharmaceutical composition. This ensures that, for example, when the pharmaceutical composition is administered to a patient or used in a formulation of an immediate-release pharmaceutical product, the required amount of the active substance is present in the portion of the pharmaceutical composition. This is important from the standpoint of patient safety and efficacy.

[0272] In this context, homogeneous dispersion is defined as the homogeneous distribution of the active substance throughout a non-aqueous solvent. For example, if separate parts of a pharmaceutical composition are analyzed to determine the content of the active substance in that part, there will be minimal variability in the content of the active substance determined for each part (i.e., variability of less than about 10%, e.g., less than about 8%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, less than 1%, or less than 0.5%).

[0273] Ideally, the active substance is homogeneously distributed throughout the non-aqueous solvent for at least two weeks, one month, two months, three months, six months, twelve months, or twenty-four months. Ideally, the active substance is homogeneously distributed throughout the non-aqueous solvent for at least two weeks, one, two, three, six, twelve, or twenty-four months.

[0274] Suitablely, the active substance is homogeneously distributed throughout the non-aqueous solvent for at least about two weeks, about one month, about two months, about three months, about six months, about twelve months, or about twenty-four months after the pharmaceutical composition has been stored at room temperature. Suitablely, the active substance is homogeneously distributed throughout the non-aqueous solvent for at least two weeks, one, two, three, six, twelve, or twenty-four months after the pharmaceutical composition has been stored at room temperature.

[0275] Ideally, the active substance is homogeneously distributed throughout the non-aqueous solvent for at least about two weeks, about one month, about two months, about three months, about six months, about twelve months, or about twenty-four months after the pharmaceutical composition has been stored at 25°C / 60%RH and / or 40°C / 75%RH. Ideally, the active substance is homogeneously distributed throughout the non-aqueous solvent for at least two weeks, or one, two, three, six, twelve, or twenty-four months after the pharmaceutical composition has been stored at 25°C / 60%RH and / or 40°C / 75%RH.

[0276] Ideally, the homogeneous distribution of active substances in a non-aqueous solvent is determined by the analytical method.

[0277] Appropriately, the analytical method includes determining the weight percentage of the active substance in a portion of the pharmaceutical composition.

[0278] Appropriately, the analytical method includes determining the weight percentage of the active substance in a portion of the pharmaceutical composition, where the weight percentage of the active substance in a portion of the pharmaceutical composition is within ±5% of an expected value based on the total amount of active substance added to the total amount of the pharmaceutical composition.

[0279] Appropriately, the analytical method includes determining the weight percentage of the active substance in a portion of the pharmaceutical composition, where the weight percentage of the active substance in a portion of the pharmaceutical composition is within ±2% of an expected value based on the total amount of active substance added to the total amount of the pharmaceutical composition.

[0280] Appropriately, the analytical method includes determining the weight percentage of the active substance in a portion of the pharmaceutical composition, where the weight percentage of the active substance in a portion of the pharmaceutical composition is within ±1% of an estimated value based on the total amount of active substance added to the total amount of the pharmaceutical composition.

[0281] Appropriately, the analytical method includes determining the weight percentage of the active substance in a portion of the pharmaceutical composition, where the weight percentage of the active substance in a portion of the pharmaceutical composition is ±0.5% of an expected value based on the total amount of active substance added to the total amount of the pharmaceutical composition.

[0282] Appropriately, the portion of the pharmaceutical composition shall be less than approximately 10% of the total weight of the pharmaceutical composition, for example, less than 5% by weight, 4% by weight, 3% by weight, or 2% by weight. Appropriately, the portion of the pharmaceutical composition shall be less than 10% of the total weight of the pharmaceutical composition, for example, less than 5% by weight, 4% by weight, 3% by weight, or 2% by weight.

[0283] Appropriately, the analytical method may include chromatography or spectroscopy.

[0284] More accurately, the spectroscopy method is NMR.

[0285] Appropriately, the chromatography method is HPLC or UPLC. Appropriately, the HPLC or UPLC method includes a UV detector. Appropriately, the UV detector measures the assay of the active substance at approximately 217 nm.

[0286] Appropriately, the HPLC method is a reversed-phase HPLC method. Appropriately, a reversed-phase HPLC method involves two eluents, the ratio of which changes during the HPLC analysis. Appropriately, the first eluent contains water and the second eluent contains acetonitrile. Appropriately, the first eluent contains water and phosphoric acid and the second eluent contains acetonitrile. Appropriately, the first eluent contains water and 0.1% phosphoric acid and the second eluent contains acetonitrile.

[0287] Ideally, the reversed-phase HPLC method includes an HPLC column. Ideally, the HPLC column includes a C18 stationary phase. Ideally, the HPLC column temperature is approximately 40°C. Ideally, the eluent flows through the HPLC column at approximately 0.5 mL / min.

[0288] More precisely, the chromatography method is reversed-phase HPLC, and reversed-phase HPLC is: a. UV detector; b. HPLC column; and c. It contains two eluents, and the ratio of the two eluents changes during the HPLC analysis.

[0289] Pharmaceutical preparations Appropriately, immediate-release pharmaceutical formulations for oral use are provided, comprising a pharmaceutical composition as defined herein.

[0290] Appropriately, immediate-release pharmaceutical formulations may be in a form suitable for oral use (e.g., hard or soft capsules, turbidiforms, emulsions, syrups or elixirs, or sprays).

[0291] Appropriately, immediate-release drug formulations have an acceptable tolerance of less than 15 when subjected to formulation uniformity testing as described in the European Pharmacopoeia. Appropriately, immediate-release drug formulations have an acceptable tolerance of 10 when subjected to formulation uniformity testing as described in the European Pharmacopoeia. Appropriately, formulation uniformity testing includes chromatographic assays of immediate-release drug formulations. Appropriately, chromatographic assays include HPLC. In this context, HPLC includes ULC.

[0292] Advantageously, the active substance in the pharmaceutical composition is homogeneously distributed and meets regulatory requirements. This ensures that the correct dose of the active substance is present in each drug dosage unit. This is important from the standpoint of patient safety and efficacy.

[0293] The appropriate European Pharmacopoeia uniformity test is 2.9.40.

[0294] Appropriately, formulation uniformity testing includes determining the amount of active substance in an immediate-release pharmaceutical formulation. Appropriately, the amount of active substance in an immediate-release pharmaceutical formulation is determined by chromatography. Appropriately, the chromatography method is HPLC. Appropriately, the HPLC method includes a UV detector. Appropriately, the UV detector measures the assay for the active substance at approximately 217 nm.

[0295] Appropriately, the HPLC method is a reversed-phase HPLC method. Appropriately, a reversed-phase HPLC method involves two eluents, the ratio of which changes during the HPLC analysis. Appropriately, the first eluent contains water and the second eluent contains acetonitrile. Appropriately, the first eluent contains water and phosphoric acid and the second eluent contains acetonitrile. Appropriately, the first eluent contains water and 0.1% phosphoric acid and the second eluent contains acetonitrile.

[0296] Ideally, the reversed-phase HPLC method includes an HPLC column. Ideally, the HPLC column includes a C18 stationary phase. Ideally, the HPLC column is at approximately 40°C. Ideally, the eluent flows through the HPLC column at approximately 0.5 mL / min.

[0297] More precisely, the chromatography method is reversed-phase HPLC, and reversed-phase HPLC is: a. UV detector; b. HPLC column; and c. It contains two eluents, and the ratio of the two eluents changes during the HPLC analysis.

[0298] Ideally, the immediate-release drug formulation is added to the diluent, dissolving the active substance in the diluent. Ideally, the diluent is 90:10 v / v 0.1M HCl:acetonitrile.

[0299] The appropriate tolerance is determined using the following formula: AV=|MX|+ks During the ceremony: X = the average of the individual content amounts (x1, x2...x3) expressed as a percentage of the stated quantity; k = tolerance constant. For n=10, k=2.4; for n=30, k=2.0 (n = sample size); s = sample standard deviation; M = reference value, where: Example 1, when T ≤ 101.5: If 98.5% ≤ X ≤ 101.5%, then M = X (and therefore AV = ks). If X < 98.5%, then M = 98.5% (and therefore AV = 98.5 - X + ks). If X > 101.5%, then M = 101.5% (and therefore AV = X - 101.5 + ks). Example 2, when T > 101.5: If 98.5% ≤ X ≤ T, then M = X (and therefore AV = ks). If X < 98.5%, then M = 98.5% (and therefore AV = 98.5 - X + ks). If X > T, then M = T % (and therefore AV = X - T + ks); and T = Amount of target test sample during manufacturing.

[0300] More precisely, an immediate-release pharmaceutical formulation is an immediate-release capsule formulation containing a capsule shell.

[0301] Ideally, the capsule shell should contain gelatin or HPMC.

[0302] Ideally, the capsule shell contains gelatin, such as firm gelatin.

[0303] Ideally, the capsule shell is a capsule shell of size 2, 3, or 4.

[0304] Ideally, immediate-release pharmaceutical formulations are in the form of sprays.

[0305] Appropriately, immediate-release formulations contain approximately 10 to 1000 μg of active substance. Appropriately, immediate-release formulations contain 10 to 1000 μg of active substance. Appropriately, immediate-release pharmaceutical formulations contain approximately 10 to 650 μg of active substance. Appropriately, immediate-release pharmaceutical formulations contain 10 to 650 μg of active substance. Appropriately, immediate-release pharmaceutical formulations contain approximately 50 to 200 μg of active substance. Appropriately, immediate-release pharmaceutical formulations contain 50 to 200 μg of active substance. Appropriately, immediate-release pharmaceutical formulations contain approximately 100 to 650 μg of active substance. Appropriately, immediate-release pharmaceutical formulations contain 100 to 650 μg of active substance. Immediate-release pharmaceutical formulations contain 25 to 75 μg of active substance. Appropriately, immediate-release pharmaceutical formulations contain approximately 150 to 250 μg of active substance.

[0306] Ideally, immediate-release pharmaceutical formulations contain approximately 50 μg of active substance.

[0307] Ideally, immediate-release pharmaceutical formulations contain approximately 200 μg of active ingredient.

[0308] Ideally, immediate-release pharmaceutical formulations contain approximately 650 μg of active ingredient.

[0309] Manufacturing process In a further embodiment, there exists a method for producing the pharmaceutical composition described herein, which includes the step of mixing compound I or a pharmaceutically acceptable salt thereof as an active substance in a non-aqueous solvent.

[0310] Ideally, the non-aqueous solvent is the liquid in the mixing process.

[0311] Preferably, the step of mixing the active substance in a non-aqueous solvent is carried out at a temperature above room temperature, for example, about 35°C to about 80°C, about 40°C to about 80°C, about 50°C to about 80°C, or about 60°C to about 80°C. Preferably, the step of mixing the active substance in a non-aqueous solvent is carried out at a temperature above room temperature, for example, 35°C to 80°C, 40°C to 80°C, 50°C to 80°C, or 60°C to 80°C.

[0312] Ideally, the step of mixing the active substance into a non-aqueous solvent should be carried out at a temperature higher than the melting point of the non-aqueous solvent.

[0313] Ideally, the step of mixing the active substance in a non-aqueous solvent is carried out under an inert atmosphere. Ideally, the inert atmosphere is a nitrogen atmosphere.

[0314] Preferably, the step of mixing the active substance in a non-aqueous solvent includes protecting the active substance from light. Preferably, the step of mixing the active substance in a non-aqueous solvent is carried out in a dark room. Preferably, the step of mixing the active substance in a non-aqueous solvent includes the use of a container for mixing the active substance and the non-aqueous solvent, the container protecting the contents of the container from light.

[0315] Advantageously, performing the mixing process under low light and / or an inert atmosphere minimizes the number of degradation products formed during and / or after the manufacture of the pharmaceutical composition.

[0316] Therapeutic use and application This disclosure provides pharmaceutical compositions as defined herein, or immediate-release pharmaceutical formulations as defined herein, for use as pharmaceuticals.

[0317] This disclosure provides pharmaceutical compositions as defined herein, or immediate-release pharmaceutical formulations as defined herein, for use in therapeutic purposes.

[0318] This disclosure provides pharmaceutical compositions as defined herein, or immediate-release pharmaceutical formulations as defined herein, for use in disease conditions or disorders in which dysfunction of CB1 and / or CB2 receptors is present or involved.

[0319] This disclosure provides pharmaceutical compositions or immediate-release pharmaceutical formulations, as defined herein, for use in the treatment of anorexia-related conditions; cachexia-related conditions; or nervous anorexia.

[0320] Appropriately, loss of appetite-related conditions include loss of appetite associated with cancer, loss of appetite associated with HIV (human immunodeficiency virus), loss of appetite associated with chronic kidney disease, loss of appetite associated with dementia, or loss of appetite associated with chronic congestive heart failure.

[0321] More precisely, the loss of appetite-related condition is cancer-related loss of appetite.

[0322] Appropriately, cachexia-related conditions include cancer-related cachexia, HIV-related cachexia, chronic kidney disease-related cachexia, dementia-related cachexia, or chronic congestive heart failure-related cachexia.

[0323] This disclosure provides pharmaceutical compositions or immediate-release pharmaceutical formulations as defined herein for use in the treatment of pain conditions. Specifically, pain conditions include cancer pain, acute pain, chronic pain, neuropathic pain, back pain, cancer pain, visceral pain, pain caused by rheumatoid arthritis, and migraines. Specifically, cancer pain is cancer pain associated with reduced opioid use in cancer patients and reduced nausea and / or vomiting.

[0324] This disclosure provides pharmaceutical compositions as defined herein, or immediate-release pharmaceutical formulations as defined herein, for use in the treatment of anxiety disorders, cancer, multiple sclerosis, Parkinson's disease, Huntington's disease, Alzheimer's disease, AIDS (acquired immunodeficiency syndrome), amyotrophic lateral sclerosis, gastrointestinal disorders, cardiovascular disorders, or insomnia.

[0325] This disclosure provides pharmaceutical compositions as defined herein, or immediate-release pharmaceutical formulations as defined herein, for use as immunomodulators. Preferably, the pharmaceutical compositions or immediate-release pharmaceutical formulations as defined herein are for use in the treatment of autoimmune diseases such as arthritis, collagen diseases, or allergies. Preferably, the pharmaceutical compositions or immediate-release pharmaceutical formulations as defined herein are for use in skin grafting, organ transplantation, and other surgical needs. Preferably, the pharmaceutical compositions or immediate-release pharmaceutical formulations as defined herein are for use as antitumor agents or antiviral agents.

[0326] This disclosure provides pharmaceutical compositions as defined herein, or immediate-release pharmaceutical formulations as defined herein, for use in the treatment of diarrhea; depression; anxiety and stress-related disorders, such as post-traumatic stress disorder, panic disorder, generalized anxiety disorder, social phobia, and obsessive-compulsive disorder; urinary incontinence; premature ejaculation; various mental disorders; cough; pulmonary edema; various gastrointestinal disorders, such as constipation, irritable bowel syndrome, and functional gastrointestinal disorders such as functional dyspepsia; Parkinson's disease and other motor disorders; traumatic brain injury; stroke; cardioprotection after myocardial infarction; spinal cord injury and drug addiction (including treatment of alcohol, nicotine, opioid and other drug abuse); and disorders of the sympathetic nervous system, such as hypertension.

[0327] This disclosure provides pharmaceutical compositions as defined herein, or immediate-release pharmaceutical formulations as defined herein, for use as analgesics, for example, for use during general anesthesia and monitored anesthesia care. Combinations of drugs with different properties are often used to achieve a balance of effects necessary for maintaining an anesthetic state (e.g., amnesia, analgesia, muscle relaxation, and sedation). These combinations include inhaled anesthetics, hypnotics, anxiolytics, neuromuscular blockers, and opioids.

[0328] Accordingly, this disclosure provides a method for activating CB1 and / or CB2 receptors in vitro or in vivo, the method comprising contacting cells with an effective amount of a pharmaceutical composition as defined herein or an immediate-release pharmaceutical formulation as defined herein.

[0329] This disclosure also provides a method for treating a disease or disorder involving dysfunction of CB1 and / or CB2 receptors in a patient requiring such treatment, the method comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition as defined herein or an immediate-release pharmaceutical formulation as defined herein.

[0330] The therapeutically effective amount of a pharmaceutical composition or immediate-release pharmaceutical formulation containing the active substance of this disclosure for use in treatment is the amount that achieves a specific biological or therapeutic outcome, including but not limited to the biological or therapeutic outcomes disclosed, described or illustrated herein. For example, treating or preventing a disease or condition referred to herein means slowing its progression and / or reducing symptoms associated with the condition and / or disease.

[0331] The amount of active substance combined with one or more excipients to manufacture a pharmaceutical composition or immediate-release pharmaceutical formulation will inevitably vary depending on the individual being treated and the specific route of administration. An immediate-release formulation intended for oral administration to humans generally contains, for example, about 10 μg to about 1000 μg of active substance (e.g., about 10 μg to about 650 μg) combined with appropriate and convenient amounts of excipients, which can vary by about 0.01 to about 99.99 weight percent of the total pharmaceutical composition or immediate-release pharmaceutical formulation.

[0332] The size of the therapeutic or prophylactic dose of an active substance will naturally vary according to well-known medical principles, depending on the nature and severity of the condition, the age and sex of the animal or patient, and the route of administration.

[0333] This disclosure provides a method for treating anorexia-related conditions, cachexia-related conditions, or nervous anorexia, the method comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition as defined herein or an immediate-release pharmaceutical formulation as defined herein.

[0334] Appropriately, loss of appetite-related conditions include loss of appetite associated with cancer, loss of appetite associated with HIV, loss of appetite associated with chronic kidney disease, loss of appetite associated with cancer dementia, or loss of appetite associated with chronic congestive heart failure.

[0335] More precisely, the loss of appetite-related condition is cancer-related loss of appetite.

[0336] Appropriately, cachexia-related conditions include cancer-related cachexia, HIV-related cachexia, chronic kidney disease-related cachexia, dementia-related cachexia, or chronic congestive heart failure-related cachexia.

[0337] This disclosure provides a method for treating a pain condition in a patient requiring such treatment, the method comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition as defined herein or an immediate-release pharmaceutical formulation as defined herein. Preferably, the pain condition is a cancer pain condition, acute pain, chronic pain, neuropathic pain, back pain, cancer pain, visceral pain, pain caused by rheumatoid arthritis, or migraine. Preferably, the cancer pain condition is a cancer pain condition associated with reduced opiate use in cancer patients, and associated with reduced nausea and / or vomiting.

[0338] This disclosure provides a method for treating anxiety disorders, cancer, multiple sclerosis, Parkinson's disease, Huntington's disease, Alzheimer's disease, AIDS, amyotrophic lateral sclerosis, gastrointestinal disorders, cardiovascular disorders, or insomnia, the method comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition as defined herein or an immediate-release pharmaceutical formulation as defined herein.

[0339] This disclosure provides a method for treating autoimmune diseases such as arthritis, collagen disease, or allergy, the method comprising administering a therapeutically effective amount of a pharmaceutical composition or immediate-release pharmaceutical formulation as defined herein to the patient. This disclosure also provides a method for treating skin grafting, organ transplantation, and other surgical needs, the method comprising administering a therapeutically effective amount of a pharmaceutical composition or immediate-release pharmaceutical formulation as defined herein to the patient.

[0340] This disclosure provides a method for treating, for example, hypertension, for diarrhea; depression; anxiety and stress-related disorders, such as post-traumatic stress disorder, panic disorder, generalized anxiety disorder, social phobia, and obsessive-compulsive disorder; urinary incontinence; premature ejaculation; various mental disorders; cough; pulmonary edema; various gastrointestinal disorders, such as constipation, irritable bowel syndrome, and functional gastrointestinal disorders such as functional dyspepsia; Parkinson's disease and other motor disorders; traumatic brain injury; stroke; cardioprotection after myocardial infarction; spinal cord injury and drug addiction (including treatment of alcohol, nicotine, opioid and other drug abuse); and disorders of the sympathetic nervous system, the method comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition as defined herein or an immediate-release pharmaceutical formulation as defined herein.

[0341] This disclosure provides a method for providing analgesic effects for use, for example, during general anesthesia and monitored anesthesia care, the method comprising administering a therapeutically effective amount of a pharmaceutical composition as defined herein or an immediate-release pharmaceutical formulation as defined herein to the patient. Combinations of drugs having different properties are often used to achieve a balance of effects necessary for maintaining an anesthetic state (e.g., amnesia, analgesia, muscle relaxation, and sedation). These combinations include inhaled anesthetics, hypnotics, anxiolytics, neuromuscular blockers, and opioids.

[0342] This disclosure provides the use of a pharmaceutical composition as defined herein or an immediate-release pharmaceutical formulation as defined herein for use in the manufacture of pharmaceuticals.

[0343] This disclosure provides pharmaceutical compositions or immediate-release pharmaceutical formulations as defined herein for use in the manufacture of pharmaceuticals for use in disease conditions or disorders in which dysfunction of CB1 and / or CB2 receptors is present or involved.

[0344] This disclosure provides pharmaceutical compositions or immediate-release pharmaceutical formulations as defined herein for use in the manufacture of pharmaceuticals for the treatment of anorexia-related conditions; cachexia-related conditions; or nervous anorexia.

[0345] Appropriately, loss of appetite-related conditions include loss of appetite associated with cancer, loss of appetite associated with HIV, loss of appetite associated with chronic kidney disease, loss of appetite associated with dementia, or loss of appetite associated with chronic congestive heart failure.

[0346] More precisely, the loss of appetite-related condition is cancer-related loss of appetite.

[0347] Appropriately, cachexia-related conditions include cancer-related cachexia, HIV-related cachexia, chronic kidney disease-related cachexia, dementia-related cachexia, or chronic congestive heart failure-related cachexia.

[0348] This disclosure provides the use of a pharmaceutical composition as defined herein or an immediate-release pharmaceutical formulation as defined herein for use in the manufacture of a pharmaceutical for the treatment of a pain condition. Preferably, the pain condition is a cancer pain condition, acute pain, chronic pain, neuropathic pain, back pain, cancer pain, visceral pain, pain caused by rheumatoid arthritis, or migraine. Preferably, the cancer pain condition is a cancer pain condition associated with reduced opiate use in cancer patients, and with reduced nausea and / or vomiting.

[0349] This disclosure provides the use of pharmaceutical compositions as defined herein or immediate-release pharmaceutical formulations as defined herein for use in the manufacture of pharmaceuticals for the treatment of anxiety disorders, cancer, multiple sclerosis, Parkinson's disease, Huntington's disease, Alzheimer's disease, AIDS, amyotrophic lateral sclerosis, gastrointestinal disorders, cardiovascular disorders, or insomnia.

[0350] This disclosure provides the use of a pharmaceutical composition or immediate-release pharmaceutical formulation as defined herein for use in the manufacture of a pharmaceutical for use as an immunomodulator. This disclosure provides the use of a pharmaceutical composition or immediate-release pharmaceutical formulation as defined herein for use in the manufacture of a pharmaceutical for the treatment of autoimmune diseases such as arthritis, collagen disease, or allergy. This disclosure provides the use of a pharmaceutical composition or immediate-release pharmaceutical formulation as defined herein for use in the manufacture of a pharmaceutical for use in skin grafting, organ transplanting, and other surgical needs. This disclosure provides the use of a pharmaceutical composition or immediate-release pharmaceutical formulation as defined herein for use in the manufacture of a pharmaceutical for use as an antitumor or antiviral agent.

[0351] This disclosure provides the use of pharmaceutical compositions or immediate-release pharmaceutical formulations as defined herein for use in the manufacture of pharmaceuticals

[0352] This disclosure provides the use of pharmaceutical compositions or immediate-release pharmaceutical formulations as defined herein for use in the manufacture of pharmaceuticals for use as analgesics, for example, for use during general anesthesia and monitored anesthesia care. Combinations of drugs with different properties are often used to achieve a balance of effects necessary for maintaining an anesthetic state (e.g., amnesia, analgesia, muscle relaxation, and sedation). These combinations include inhaled anesthetics, hypnotics, anxiolytics, neuromuscular blockers, and opioids.

[0353] In one embodiment, compound I is administered to the patient at a dose of approximately 25 to approximately 700 μg / day, for example, approximately 50 to approximately 650 μg / day. Preferably, compound I is administered to the patient at a dose of approximately 50, 150, 250, 400, or 650 μg / day.

[0354] Route of administration The pharmaceutical compositions or immediate-release pharmaceutical formulations of this disclosure can be administered to subjects by any convenient route of oral administration (for example, by oral ingestion).

[0355] Combination therapy The pharmaceutical compositions and / or pharmaceutical formulations of this disclosure are useful for treating conditions in which treatment with CB1 and / or CB2 agonists is beneficial. Examples of such conditions are outlined in the therapeutic use section above of this disclosure.

[0356] The pharmaceutical compositions and pharmaceutical formulations of this disclosure can be used in combination with one or more further therapeutic agents for the treatment of the condition in question.

[0357] Further therapeutic agents may be incorporated into the pharmaceutical compositions or pharmaceutical preparations of this disclosure having compound I as defined herein or a pharmaceutically acceptable salt thereof, or alternatively, they may be administered separately at the same time as, or before or after, the pharmaceutical compositions or pharmaceutical preparations of this disclosure.

[0358] Accordingly, according to further aspects of the present disclosure, a combination product is provided comprising a pharmaceutical composition and / or pharmaceutical preparation of the present disclosure and a pharmaceutical composition comprising a further therapeutic agent useful in the treatment or prevention of any one of the therapeutic conditions referred to herein, wherein the pharmaceutical composition and / or pharmaceutical preparation of the present disclosure and the pharmaceutical composition comprising the further therapeutic agent are administered simultaneously, sequentially, or separately.

[0359] According to this aspect of the Disclosure, a combination is provided for use in the treatment of a disease or condition in which treatment with a CB1 and / or CB2 agonist is beneficial (e.g., cancer anorexia), the combination comprising a pharmaceutical composition or pharmaceutical preparation of the Disclosure as previously defined herein, and one or more further therapeutic agents.

[0360] The Disclosure also provides pharmaceutical compositions and / or pharmaceutical formulations and one or more further therapeutic agents for use in the treatment of anorexia, particularly cancer anorexia, the pharmaceutical compositions and / or formulations and further therapeutic agents of the Disclosure which may be administered simultaneously, sequentially, or separately.

[0361] In certain embodiments, the pharmaceutical compositions and / or pharmaceutical formulations of this disclosure can be used to treat cancer-related anorexia in patients undergoing cancer treatment. Cancer treatment may take the form of radiotherapy, surgery, chemotherapy, immunotherapy, or a combination thereof.

[0362] In this specification, where the term “combination” is used, it should be understood that it refers to simultaneous, separate, or sequential administration. In one aspect of the present invention, “combination” refers to simultaneous administration. In another aspect of the present invention, “combination” refers to separate administration. According to a further aspect of the present invention, “combination” refers to sequential administration. When administration is sequential or separate, delays in the administration of the second component should not impair the beneficial effect of the combination.

[0363] As described above, combination therapies of the present disclosure can be achieved by simultaneous, sequential, or separate administration of the individual components of the treatment. Such combination products use the compositions and formulations of the present disclosure within the dosage ranges previously described herein, and one or more additional pharmaceutically active agents, each of which is used within its approved dosage range.

[0364] Specific aspects and embodiments of this disclosure The following numbered paragraphs further define specific aspects and embodiments of this disclosure.

[0365] (1) A pharmaceutical composition for oral use comprising compound I or a pharmaceutically acceptable salt thereof as an active substance, and a non-aqueous solvent for the active substance.

[0366] (2) A pharmaceutical composition according to paragraph (1), wherein the active substance has a solubility in a non-aqueous solvent at a concentration of at least about 0.1% w / w at room temperature.

[0367] (3) A pharmaceutical composition according to paragraph (1) or (2), wherein the active substance is dissolved in a non-aqueous solvent.

[0368] (4) A pharmaceutical composition according to paragraphs (1) to (3), wherein the non-aqueous solvent is water-soluble.

[0369] (5) A pharmaceutical composition according to any of paragraphs (1) to (4), wherein the pharmaceutical composition contains at least about 20% w / w of a non-aqueous solvent relative to the weight of the total pharmaceutical composition.

[0370] (6) A pharmaceutical composition according to paragraphs (1) to (5), comprising at least two non-aqueous solvents for the active substance.

[0371] (7) A pharmaceutical composition according to paragraphs (1) to (6), wherein the non-aqueous solvent comprises polyethylene glycol, propylene glycol, ethanol, glycerol, stearoyl polyoxyglyceride, polyoxyethylene stearate, long-chain triglycerides, medium-chain triglycerides, long-chain fatty acids, medium-chain fatty acids, long-chain monoglycerides, long-chain diglycerides, medium-chain monoglycerides, medium-chain diglycerides, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, polyoxyethylated 12-hydroxystearic acid, caprylocaproyl polyoxyglyceride, linoleoyl polyoxyglyceride, oleoyl polyoxyglyceride, propylene glycol monofatty acid esters, propylene glycol difatty acid esters, soybean oil, glyceryl palmitostearate, diethylene glycol monoethyl ether, sorbitan esters, poloxamer, or vitamin E TPGS or a combination thereof.

[0372] (8) A pharmaceutical composition according to paragraphs (1) to (7), wherein the non-aqueous solvent comprises polyethylene glycol, ethanol, stearoyl polyoxyglyceride, polyoxyethylene stearate, medium-chain fatty acids, long-chain monoglycerides, long-chain diglycerides, medium-chain monoglycerides, medium-chain diglycerides, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, polyoxyethylated 12-hydroxystearic acid, caprylocaproyl polyoxyglyceride, oleoyl polyoxyglyceride, propylene glycol monofatty acid esters, propylene glycol difatty acid esters, diethylene glycol monoethyl ether, poloxamer, or vitamin E TPGS or a combination thereof.

[0373] (9) A pharmaceutical composition according to paragraphs (1) to (8), wherein the non-aqueous solvent comprises polyethylene glycol, stearoyl polyoxyglyceride, polyoxyethylene stearate, medium-chain fatty acids, long-chain monoglycerides, long-chain diglycerides, medium-chain monoglycerides, medium-chain diglycerides, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, polyoxyethylated 12-hydroxystearic acid, caprylocaproyl polyoxyglyceride, propylene glycol monofatty acid esters, propylene glycol difatty acid esters, diethylene glycol monoethyl ether, poloxamer, vitamin E TPGS, or a combination thereof.

[0374] (10) A pharmaceutical composition according to paragraphs (1) to (9), wherein the non-aqueous solvent comprises polyethylene glycol, propylene glycol, glycerol, stearoyl polyoxyglyceride, polyoxyethylene stearate, polyoxyethylene castor oil derivative, polyoxyethylene sorbitan fatty acid ester, polyoxyethylated 12-hydroxystearic acid, caprylocaproyl polyoxyglyceride, linoleoyl polyoxyglyceride, oleoyl polyoxyglyceride, or sorbitan ester or a combination thereof.

[0375] (11) A pharmaceutical composition according to paragraphs (1) to (10), wherein the non-aqueous solvent comprises polyethylene glycol, stearoyl polyoxyglyceride, or polyoxyethylene stearate or a combination thereof.

[0376] (12) A pharmaceutical composition according to paragraphs (1) to (11), wherein the non-aqueous solvent comprises polyethylene glycol.

[0377] (13) A pharmaceutical composition according to paragraphs (1) to (12), wherein the non-aqueous solvent is essentially made from polyethylene glycol.

[0378] (14) A pharmaceutical composition according to paragraphs (1) to (13), wherein the non-aqueous solvent is polyethylene glycol.

[0379] (15) A pharmaceutical composition according to paragraphs (7) to (14), wherein polyethylene glycol has an average molecular weight of approximately 200 to approximately 25,000 g / mol, approximately 300 to approximately 10,000 g / mol, approximately 400 to approximately 6,000 g / mol, or approximately 1,000 to approximately 6,000 g / mol.

[0380] (16) A pharmaceutical composition according to paragraphs (7) to (15), wherein polyethylene glycol has an average molecular weight of about 400, about 1000, about 1500, about 1540, about 2000, about 3000, about 4000, about 6000, about 8000, or about 20000 g / mol.

[0381] (17) A pharmaceutical composition according to paragraphs (7) to (16), wherein polyethylene glycol has an average molecular weight of about 400, about 1500, about 4000, or about 6000 g / mol.

[0382] (18) A pharmaceutical composition according to paragraphs (7) to (17), wherein polyethylene glycol has an average molecular weight of approximately 1500 g / mol.

[0383] (19) A pharmaceutical composition according to paragraphs (7) to (11), wherein the polyoxyethylene stearate is PEG-32 stearate or polyethylene glycol monostearate or a mixture thereof.

[0384] (20) A pharmaceutical composition according to paragraph (7), wherein the long-chain triglyceride is selected from corn oil and soybean oil.

[0385] (21) A pharmaceutical composition according to paragraph (7), comprising a medium-chain triglyceride, caprylic acid, capric acid, or a mixture thereof.

[0386] (22) A pharmaceutical composition according to paragraph (7), wherein the long-chain fatty acid is oleic acid, palmitic acid, stearic acid, arachidic acid, palmitoleic acid, nervonic acid, linoleic acid, alpha-linolenic acid, arachidonic acid, or eicosapentaenoic acid.

[0387] (23) A pharmaceutical composition according to paragraphs (7) to (9), wherein the medium-chain fatty acid is caprylic acid, capric acid, or lauric acid.

[0388] (24) A pharmaceutical composition according to paragraphs (7) to (9), wherein the long-chain monoglyceride is glyceryl monooleate.

[0389] (25) A pharmaceutical composition according to paragraphs (7) to (9), wherein the medium-chain monoglyceride is glyceryl monocaprylate.

[0390] (26) A pharmaceutical composition according to paragraphs (7) to (10), wherein the polyoxyethylene castor oil derivative is polyoxyl 40 hydrogenated castor oil, polyoxyl 35 castor oil, or a mixture thereof.

[0391] (27) A pharmaceutical composition according to paragraph (26), wherein the polyoxyethylene castor oil derivative is polyoxyl 40 hydrogenated castor oil.

[0392] (28) A pharmaceutical composition according to paragraphs (7) to (10), wherein the polyoxyethylene sorbitan fatty acid ester is polysorbate 20, polysorbate 80, or a mixture thereof.

[0393] (29) A pharmaceutical composition according to paragraph (28), wherein the polyoxyethylene sorbitan fatty acid ester is polysorbate 20.

[0394] (30) A pharmaceutical composition according to paragraphs (7) to (9), wherein the propylene glycol monofatty acid ester is propylene glycol monocaprylate.

[0395] (31) A pharmaceutical composition according to paragraphs (7) to (9), wherein the propylene glycol difatty acid ester is propylene glycol dilaurate.

[0396] (32) A pharmaceutical composition according to any of paragraphs (1) to (31), further comprising vitamin E TPGS or lauroyl polyoxyglyceride.

[0397] (33) A pharmaceutical composition according to paragraphs (1) to (32), wherein the non-aqueous solvent is semi-solid at room temperature.

[0398] (34) A pharmaceutical composition according to paragraph (33), wherein the non-aqueous solvent has a melting point of approximately 35°C to approximately 80°C.

[0399] (35) A pharmaceutical composition according to any of paragraphs (1) to (34), wherein the pharmaceutical composition contains an active substance in an amount of approximately 0.001 to approximately 0.8% w / w relative to the weight of the entire pharmaceutical composition, or an active substance in an amount of approximately 0.1 to approximately 0.4% w / w relative to the weight of the entire pharmaceutical composition.

[0400] (36) A pharmaceutical composition according to any of paragraphs (1) to (35), further comprising a viscosity modifier, a coloring agent, an opacifying agent, a sweetener or flavoring agent, and / or a preservative, such as an antioxidant.

[0401] (37) A pharmaceutical composition according to paragraph (36), wherein the antioxidant comprises butylated hydroxyanisole, butylated hydroxytoluene, ascorbic acid, or α-tocopherol.

[0402] (38) A pharmaceutical composition according to any of paragraphs (1) to (37), wherein the pharmaceutical composition is semi-solid at room temperature.

[0403] (39) A pharmaceutical composition according to paragraph (38), wherein the pharmaceutical composition has a melting point of approximately 35°C to approximately 80°C.

[0404] (40) A pharmaceutical composition according to any of paragraphs (1) to (39), wherein the active substance is stable in the pharmaceutical composition for at least about two weeks, about one month, about two months, about three months, about six months, about twelve months, or about twenty-four months.

[0405] (41) a. The total amount of degradation products of the active substance is less than or equal to about 4 area % as determined by chromatography when the pharmaceutical composition is stored at 25°C / 60%RH and / or 40°C / 75%RH for at least about 2 weeks, about 1 month, about 2 months, about 3 months, about 6 months, about 12 months, or about 24 months; and / or b. The assay for the active substance is determined by chromatography when the pharmaceutical composition is stored at 25°C / 60%RH and / or 40°C / 75%RH for at least about 2 weeks, about 1 month, about 2 months, about 3 months, about 6 months, about 12 months, or about 24 months, and the value is about 90-110% of the nominal value. A pharmaceutical composition according to paragraph (40).

[0406] (42) A pharmaceutical composition according to paragraph (41), wherein the chromatography method is HPLC.

[0407] (43) A pharmaceutical composition according to paragraph (42), wherein the HPLC method is reversed-phase HPLC.

[0408] (44) A pharmaceutical composition according to any of paragraphs (1) to (43), wherein at least about 75% of the total amount of active substance contained in the pharmaceutical composition is released within approximately the first 45 minutes when the pharmaceutical composition is subjected to an in vitro dissolution test using 0.1 M HCl or pH 6.8 phosphate buffer as the dissolution medium, and the dissolution profile is determined at about 37°C using a rotation speed of about 50 rpm as described in the United States Pharmacopeia.

[0409] (45) A pharmaceutical composition according to paragraph (44), wherein at least about 75% of the total amount of active substances contained in the pharmaceutical composition is released within approximately the first 30 minutes when the pharmaceutical composition is subjected to an in vitro dissolution test.

[0410] (46) A pharmaceutical composition according to paragraph (44) or (45), wherein at least 85% of the total amount of active substances contained in the pharmaceutical composition is released within approximately the first 15 minutes when the pharmaceutical composition is subjected to an in vitro dissolution test.

[0411] (47) A pharmaceutical composition according to any of paragraphs (1) to (46), wherein the active substance is homogeneously distributed throughout the non-aqueous solvent.

[0412] (48) A pharmaceutical composition according to paragraph (47), wherein the active substance is homogeneously distributed throughout a non-aqueous solvent for at least about two weeks, about one month, about two months, about three months, about six months, about twelve months, or about twenty-four months.

[0413] (49) A pharmaceutical composition according to paragraph (47) or (48), wherein the active substance is homogeneously distributed throughout the non-aqueous solvent for at least about two weeks, about one month, about two months, about three months, about six months, about twelve months, or about twenty-four months after the pharmaceutical composition has been stored at room temperature.

[0414] (50) The homogeneous distribution of the active substance in a non-aqueous solvent is determined by an analytical method, which comprises determining the weight percentage of the active substance in a portion of the pharmaceutical composition, the weight percentage of the active substance in a portion of the pharmaceutical composition being ±5% of an expected value based on the total amount of the active substance added to the total amount of the pharmaceutical composition, according to paragraphs (47) to (49).

[0415] (51) A pharmaceutical composition comprising compound I or a pharmaceutically acceptable salt thereof as an active substance, wherein the pharmaceutical composition is semi-solid at room temperature.

[0416] (52) A pharmaceutical composition according to paragraph (51), wherein the pharmaceutical composition has a melting point of approximately 35°C to approximately 80°C.

[0417] (53) A pharmaceutical composition according to paragraph (51) or (52), wherein the pharmaceutical composition comprises a non-aqueous solvent for the active substance.

[0418] (54) A pharmaceutical composition according to paragraph (53), wherein the non-aqueous solvent for the active substance is semi-solid at room temperature.

[0419] (55) A pharmaceutical composition according to paragraph (54), wherein the non-aqueous solvent has a melting point of approximately 35°C to approximately 80°C.

[0420] (56) A pharmaceutical composition according to paragraphs (53) to (55), wherein the active substance has a solubility in a non-aqueous solvent of at least about 0.1% w / w.

[0421] (57) A pharmaceutical composition according to paragraphs (53) to (56), wherein the active substance is dissolved in a non-aqueous solvent.

[0422] (58) A pharmaceutical composition according to paragraphs (53) to (57), wherein the non-aqueous solvent is water-soluble.

[0423] (59) A pharmaceutical composition according to paragraphs (53) to (58), wherein the pharmaceutical composition contains at least about 20% w / w of a non-aqueous solvent relative to the weight of the total pharmaceutical composition.

[0424] (60) A pharmaceutical composition according to paragraphs (53) to (59), wherein the pharmaceutical composition comprises at least two non-aqueous solvents for the active substance.

[0425] (61) A pharmaceutical composition according to paragraphs (53) to (60), wherein the non-aqueous solvent comprises polyethylene glycol, propylene glycol, ethanol, glycerol, stearoyl polyoxyglyceride, polyoxyethylene stearate, long-chain triglycerides, medium-chain triglycerides, medium-chain fatty acids, long-chain monoglycerides, long-chain diglycerides, medium-chain monoglycerides, medium-chain diglycerides, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, polyoxyethylated 12-hydroxystearic acid, caprylocaproyl polyoxyglyceride, linoleoyl polyoxyglyceride, oleoyl polyoxyglyceride, propylene glycol monofatty acid esters, propylene glycol difatty acid esters, soybean oil, glyceryl palmitostearate, diethylene glycol monoethyl ether, sorbitan esters, poloxamer, or vitamin E TPGS or a combination thereof.

[0426] (62) A pharmaceutical composition according to paragraphs (53) to (61), wherein the non-aqueous solvent comprises polyethylene glycol, ethanol, stearoyl polyoxyglyceride, polyoxyethylene stearate, medium-chain fatty acids, long-chain monoglycerides, long-chain diglycerides, medium-chain monoglycerides, medium-chain diglycerides, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, polyoxyethylated 12-hydroxystearic acid, caprylocaproyl polyoxyglyceride, oleoyl polyoxyglyceride, propylene glycol monofatty acid esters, propylene glycol difatty acid esters, diethylene glycol monoethyl ether, poloxamer, or vitamin E TPGS or a combination thereof.

[0427] (63) Pharmaceutical compositions according to paragraphs (53) to (62), wherein the non-aqueous solvent comprises polyethylene glycol, stearoyl polyoxyglyceride, polyoxyethylene stearate, medium-chain fatty acids, long-chain monoglycerides, long-chain diglycerides, medium-chain monoglycerides, medium-chain diglycerides, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, polyoxyethylated 12-hydroxystearic acid, caprylocaproyl polyoxyglyceride, propylene glycol monofatty acid esters, propylene glycol difatty acid esters, diethylene glycol monoethyl ether, poloxamer, vitamin E TPGS, or a combination thereof.

[0428] (64) A pharmaceutical composition according to paragraphs (53) to (63), wherein the non-aqueous solvent comprises polyethylene glycol, propylene glycol, glycerol, stearoyl polyoxyglyceride, polyoxyethylene stearate, polyoxyethylene castor oil derivative, polyoxyethylene sorbitan fatty acid ester, polyoxyethylated 12-hydroxystearic acid, caprylocaproyl polyoxyglyceride, linoleoyl polyoxyglyceride, oleoyl polyoxyglyceride, or sorbitan ester or a combination thereof.

[0429] (65) A pharmaceutical composition according to paragraphs (53) to (64), wherein the non-aqueous solvent comprises polyethylene glycol, stearoyl polyoxyglyceride, or polyoxyethylene stearate or a combination thereof.

[0430] (66) A pharmaceutical composition according to paragraphs (53) to (65), wherein the non-aqueous solvent comprises polyethylene glycol.

[0431] (67) A pharmaceutical composition according to paragraphs (53) to (66), wherein the non-aqueous solvent is essentially made from polyethylene glycol.

[0432] (68) A pharmaceutical composition according to paragraphs (53) to (67), wherein the non-aqueous solvent is polyethylene glycol.

[0433] (69) A pharmaceutical composition according to paragraphs (61) to (68), wherein polyethylene glycol has an average molecular weight of approximately 200 to approximately 25,000 g / mol, approximately 300 to approximately 10,000 g / mol, approximately 400 to approximately 6,000 g / mol, or approximately 1,000 to approximately 6,000 g / mol.

[0434] (70) A pharmaceutical composition according to paragraphs (61) to (69), wherein polyethylene glycol has an average molecular weight of about 400, about 1000, about 1500, about 1540, about 2000, about 3000, about 4000, about 6000, about 8000, or about 20000 g / mol.

[0435] (71) A pharmaceutical composition according to paragraphs (61) to (70), wherein polyethylene glycol has an average molecular weight of about 400, about 1500, about 4000, or about 6000 g / mol.

[0436] (72) A pharmaceutical composition according to paragraphs (61) to (71), wherein polyethylene glycol has an average molecular weight of approximately 1500 g / mol.

[0437] (73) A pharmaceutical composition according to paragraphs (51) to (72), further comprising vitamin E TPGS or lauroyl polyoxyl 32-glyceride.

[0438] (74) A pharmaceutical composition according to paragraphs (51) to (73), wherein the pharmaceutical composition contains an active substance in an amount of approximately 0.001 to approximately 0.8% w / w relative to the weight of the total pharmaceutical composition.

[0439] (75) A pharmaceutical composition according to paragraphs (51) to (74), further comprising a viscosity modifier, a coloring agent, an opacifying agent, a sweetener or flavoring agent, and / or a preservative, such as an antioxidant.

[0440] (76) A pharmaceutical composition according to paragraphs (51) to (75), wherein the active substance is stable in the pharmaceutical composition for at least about two weeks, about one month, about two months, about three months, about six months, about twelve months, or about twenty-four months.

[0441] (77) a. The total amount of degradation products of the active substance is less than or equal to about 4 area % as determined by chromatography when the pharmaceutical composition is stored at 25°C / 60%RH and / or 40°C / 75%RH for at least about 2 weeks, about 1 month, about 2 months, about 3 months, about 6 months, about 12 months, or about 24 months; and / or b. The assay of the active substance of the pharmaceutical composition is determined by chromatography to be approximately 90-110% of the nominal value when the pharmaceutical composition is stored at 25°C / 60%RH and / or 40°C / 75%RH for at least approximately 2 weeks, approximately 1 month, approximately 2 months, approximately 3 months, approximately 6 months, approximately 12 months, or approximately 24 months, according to paragraph (76).

[0442] (78) A pharmaceutical composition according to paragraph (77), wherein the chromatography method is HPLC.

[0443] (79) A pharmaceutical composition according to paragraph (78), wherein the HPLC method is reversed-phase HPLC.

[0444] (80) A pharmaceutical composition according to paragraphs (51) to (79), wherein at least about 75% of the total amount of active substance contained in the pharmaceutical composition is released within approximately the first 45 minutes when the pharmaceutical composition is subjected to an in vitro dissolution test using 0.1 M HCl or pH 6.8 phosphate buffer as the dissolution medium, and the dissolution profile is determined at 37°C using a rotation speed of 50 rpm as described in the United States Pharmacopeia.

[0445] (81) A pharmaceutical composition according to paragraph (80), wherein at least about 75% of the total amount of active substances contained in the pharmaceutical composition is released within approximately the first 30 minutes when the pharmaceutical composition is subjected to an in vitro dissolution test.

[0446] (82) A pharmaceutical composition according to paragraphs (80) to (81), wherein at least 85% of the total amount of active substances contained in the pharmaceutical composition is released within approximately the first 15 minutes when the pharmaceutical composition is subjected to an in vitro dissolution test.

[0447] (83) A pharmaceutical composition according to paragraphs (51) to (82), wherein the active substance is homogeneously distributed throughout the non-aqueous solvent.

[0448] (84) A pharmaceutical composition according to paragraph (83), wherein the active substance is homogeneously distributed throughout a non-aqueous solvent for at least about two weeks, about one month, about two months, about three months, about six months, about twelve months, or about twenty-four months.

[0449] (85) A pharmaceutical composition according to paragraph (83) or (84), wherein the active substance is homogeneously distributed throughout a non-aqueous solvent for at least about two weeks, about one month, about two months, about three months, about six months, about twelve months, or about twenty-four months.

[0450] (86) The homogeneous distribution of the active substance in a non-aqueous solvent is determined by an analytical method, which comprises determining the weight percentage of the active substance in a portion of the pharmaceutical composition, the weight percentage of the active substance in a portion of the pharmaceutical composition being ±5% of an expected value based on the total amount of the active substance added to the total amount of the pharmaceutical composition, according to paragraphs (83) to (85).

[0451] (87) A pharmaceutical composition comprising compound I or a pharmaceutically acceptable salt thereof as an active substance, wherein the active substance is stable in the pharmaceutical composition for at least about two weeks, about one month, about two months, about three months, about six months, about twelve months, or about twenty-four months.

[0452] (88) a. The total amount of degradation products of the active substance is less than or equal to about 4 area % as determined by chromatography when the pharmaceutical composition is stored at 25°C / 60%RH and / or 40°C / 75%RH for at least about 2 weeks, about 1 month, about 2 months, about 3 months, about 6 months, about 12 months, or about 24 months; and / or b. The assay for the active substance is determined by chromatography when the pharmaceutical composition is stored at 25°C / 60%RH and / or 40°C / 75%RH for at least about 2 weeks, about 1 month, about 2 months, about 3 months, about 6 months, about 12 months, or about 24 months, and the value is about 90-110% of the nominal value. A pharmaceutical composition according to paragraph (87).

[0453] (89) A pharmaceutical composition according to paragraph (88), wherein the chromatography method is HPLC.

[0454] (90) A pharmaceutical composition according to paragraph (89), wherein the HPLC method is reversed-phase HPLC.

[0455] (91) A pharmaceutical composition according to paragraphs (87) to (90), wherein the pharmaceutical composition is semi-solid at room temperature.

[0456] (92) A pharmaceutical composition according to paragraph (91), wherein the pharmaceutical composition has a melting point of approximately 35°C to approximately 80°C.

[0457] (93) A pharmaceutical composition according to paragraphs (87) to (92), wherein the pharmaceutical composition comprises a non-aqueous solvent for the active substance.

[0458] (94) A pharmaceutical composition according to paragraph (93), wherein the active substance has solubility in a non-aqueous solvent of at least about 0.1% w / w.

[0459] (95) A pharmaceutical composition according to paragraphs (93) to (94), wherein the active substance is dissolved in a non-aqueous solvent.

[0460] (96) A pharmaceutical composition according to paragraphs (93) to (95), wherein the non-aqueous solvent is water-soluble.

[0461] (97) A pharmaceutical composition according to paragraphs (93) to (96), wherein the pharmaceutical composition contains at least about 20% w / w of a nonaqueous solvent relative to the weight of the total pharmaceutical composition.

[0462] (98) A pharmaceutical composition according to paragraphs (93) to (97), wherein the pharmaceutical composition comprises at least one non-aqueous solvent for the active substance.

[0463] (99) A pharmaceutical composition according to paragraphs (93) to (98), wherein the non-aqueous solvent is semi-solid at room temperature.

[0464] (100) A pharmaceutical composition according to paragraph (99), wherein the non-aqueous solvent has a melting point of 35°C to 80°C.

[0465] (101) A pharmaceutical composition according to paragraphs (93) to (100), wherein the non-aqueous solvent comprises polyethylene glycol, propylene glycol, ethanol, glycerol, stearoyl polyoxyglyceride, polyoxyethylene stearate, long-chain triglycerides, medium-chain triglycerides, long-chain fatty acids, medium-chain fatty acids, long-chain monoglycerides, long-chain diglycerides, medium-chain monoglycerides, medium-chain diglycerides, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, polyoxyethylated 12-hydroxystearic acid, caprylocaproyl polyoxyglyceride, linoleoyl polyoxyglyceride, oleoyl polyoxyglyceride, propylene glycol monofatty acid esters, propylene glycol difatty acid esters, soybean oil, glyceryl palmitostearate, diethylene glycol monoethyl ether, sorbitan esters, poloxamer, or vitamin E TPGS or a combination thereof.

[0466] (102) A pharmaceutical composition according to paragraphs (93) to (101), wherein the non-aqueous solvent comprises polyethylene glycol, stearoyl polyoxyglyceride, long-chain fatty acid, medium-chain fatty acid, medium-chain monoglyceride, medium-chain diglyceride, polyoxyethylene castor oil derivative, polyoxyethylene sorbitan fatty acid ester, polyoxyethylated 12-hydroxystearic acid, propylene glycol difatty acid ester, diethylene glycol monoethyl ether, or poloxamer or a combination thereof. Preferably, the polyoxyethylene castor oil derivative comprises polyoxyl 40 hydrogenated castor oil. Preferably, the polyoxyethylene castor oil derivative is polyoxyl 40 hydrogenated castor oil.

[0467] (103) A pharmaceutical composition according to paragraphs (93) to (102), wherein the non-aqueous solvent comprises polyethylene glycol, stearoyl polyoxyglyceride, polyoxyethylene stearate, medium-chain monoglyceride, medium-chain diglyceride, polyoxyethylene sorbitan fatty acid ester, propylene glycol difatty acid ester, or a combination thereof.

[0468] (104) A pharmaceutical composition according to paragraphs (93) to (103), wherein the non-aqueous solvent comprises polyethylene glycol, propylene glycol, glycerol, stearoyl polyoxyglyceride, polyoxyethylene stearate, polyoxyethylene castor oil derivative, polyoxyethylene sorbitan fatty acid ester, polyoxyethylated 12-hydroxystearic acid, caprylocaproyl polyoxyglyceride, linoleoyl polyoxyglyceride, oleoyl polyoxyglyceride, or sorbitan ester or a combination thereof.

[0469] (105) A pharmaceutical composition according to paragraphs (93) to (104) wherein the non-aqueous solvent comprises polyethylene glycol, stearoyl polyoxyglyceride, or polyoxyethylene stearate or a combination thereof.

[0470] (106) A pharmaceutical composition according to paragraphs (101) to (105), wherein the non-aqueous solvent comprises polyethylene glycol.

[0471] (107) A pharmaceutical composition according to paragraphs (101) to (106), wherein the non-aqueous solvent is essentially made from polyethylene glycol.

[0472] (108) A pharmaceutical composition according to paragraphs (101) to (107), wherein the non-aqueous solvent is polyethylene glycol.

[0473] (109) A pharmaceutical composition according to paragraphs (101) to (108), wherein polyethylene glycol has an average molecular weight of approximately 200 to approximately 25,000 g / mol, approximately 300 to approximately 10,000 g / mol, approximately 400 to approximately 6,000 g / mol, or approximately 1,000 to approximately 6,000 g / mol.

[0474] (110) A pharmaceutical composition according to paragraphs (101) to (109), wherein polyethylene glycol has an average molecular weight of about 400, about 1000, about 1500, about 1540, about 2000, about 3000, about 4000, about 6000, about 8000, or about 20000 g / mol.

[0475] (111) A pharmaceutical composition according to paragraphs (101) to (110), wherein polyethylene glycol has an average molecular weight of about 400, about 1500, about 4000, or about 6000 g / mol.

[0476] (112) A pharmaceutical composition according to paragraphs (101) to (111), wherein polyethylene glycol has an average molecular weight of approximately 1500 g / mol.

[0477] (113) A pharmaceutical composition according to paragraphs (87) to (112), further comprising vitamin E TPGS or lauroyl polyoxyl 32-glyceride.

[0478] (114) A pharmaceutical composition according to paragraphs (87) to (113), further comprising a viscosity modifier, a coloring agent, an opacifying agent, a sweetener or flavoring agent, and / or a preservative, such as an antioxidant.

[0479] (115) A pharmaceutical composition according to paragraphs (87) to (114), wherein the pharmaceutical composition contains approximately 0.001 to approximately 0.8% w / w of the active substance relative to the weight of the total pharmaceutical composition.

[0480] (116) A pharmaceutical composition according to paragraphs (87) to (115), wherein at least about 75% of the total amount of active substance contained in the pharmaceutical composition is released within approximately the first 45 minutes when the pharmaceutical composition is subjected to an in vitro dissolution test using 0.1 M HCl or pH 6.8 phosphate buffer as the dissolution medium, and the dissolution profile is determined at 37°C using a rotation speed of 50 rpm as described in the United States Pharmacopeia.

[0481] (117) At least about 75% of the total amount of active substances contained in the pharmaceutical composition is released within approximately the first 30 minutes when the pharmaceutical composition is subjected to an in vitro dissolution test. Pharmaceutical composition according to paragraph (116).

[0482] (118) A pharmaceutical composition according to paragraph (116) or (117), wherein at least 85% of the total amount of active substances contained in the pharmaceutical composition is released within approximately the first 15 minutes when the pharmaceutical composition is subjected to an in vitro dissolution test.

[0483] (119) A pharmaceutical composition according to paragraphs (93) to (118), wherein the active substance is homogeneously distributed throughout the non-aqueous solvent.

[0484] (120) A pharmaceutical composition according to paragraph (119), wherein the active substance is homogeneously distributed throughout a non-aqueous solvent for at least about two weeks, about one month, about two months, about three months, about six months, about twelve months, or about twenty-four months.

[0485] (121) A pharmaceutical composition according to paragraph (119) or (120), wherein the active substance is homogeneously distributed throughout the non-aqueous solvent for at least about two weeks, about one month, about two months, about three months, about six months, about twelve months, or about twenty-four months after the pharmaceutical composition has been stored at room temperature.

[0486] (122) The homogeneous distribution of the active substance in a non-aqueous solvent is determined by an analytical method, which comprises determining the weight percentage of the active substance in a portion of the pharmaceutical composition, wherein the weight percentage of the active substance in a portion of the pharmaceutical composition is ±5% of an expected value based on the total amount of the active substance added to the total amount of the pharmaceutical composition, according to paragraphs (119) to (121).

[0487] (123) A pharmaceutical composition comprising compound I or a pharmaceutically acceptable salt thereof as an active substance: 1) At least about 75% of the total amount of active substance contained in the pharmaceutical composition is released within approximately the first 45 minutes when the pharmaceutical composition is subjected to an in vitro dissolution test using 0.1 M HCl or pH 6.8 phosphate buffer as the dissolution medium, and the dissolution profile is determined at 37°C using a rotation speed of 50 rpm, as described in the United States Pharmacopeia; 2) The pharmaceutical composition is semi-solid at room temperature. Pharmaceutical composition.

[0488] (124) The pharmaceutical composition of paragraph (123), wherein at least about 75% of the total amount of active substance contained in the pharmaceutical composition is released within approximately the first 30 minutes when the pharmaceutical composition is subjected to an in vitro dissolution test.

[0489] (125) A pharmaceutical composition of paragraph (123) or (124) wherein at least 85% of the total amount of active substances contained in the pharmaceutical composition is released within approximately the first 15 minutes when the pharmaceutical composition is subjected to an in vitro dissolution test.

[0490] (126) A pharmaceutical composition according to paragraphs (123) to (125), wherein the active substance is stable in the pharmaceutical for at least about two weeks, about one month, about two months, about three months, about six months, about twelve months, or about twenty-four months.

[0491] (127) a. The total amount of degradation products of the active substance is less than or equal to about 4 area % as determined by chromatography when the pharmaceutical composition is stored at 25°C / 60%RH and / or 40°C / 75%RH for at least about 2 weeks, about 1 month, about 2 months, about 3 months, about 6 months, about 12 months, or about 24 months; and / or b. The assay of the active substance is determined by chromatography when the pharmaceutical composition is stored at 25°C / 60%RH and / or 40°C / 75%RH for at least about 2 weeks, about 1 month, about 2 months, about 3 months, about 6 months, about 12 months, or about 24 months, and is approximately 90-110% of the nominal value. A pharmaceutical composition according to paragraph (126).

[0492] (128) A pharmaceutical composition according to paragraph (127), wherein the chromatography method is HPLC.

[0493] (129) A pharmaceutical composition according to paragraph (128), wherein the HPLC method is reversed-phase HPLC.

[0494] (130) A pharmaceutical composition according to paragraphs (123) to (129), wherein the pharmaceutical composition has a melting point of approximately 35°C to approximately 80°C.

[0495] (131) A pharmaceutical composition according to paragraphs (123) to (130), wherein the pharmaceutical composition comprises a non-aqueous solvent for the active substance.

[0496] (132) A pharmaceutical composition according to paragraph (131), wherein the active substance has a solubility in a non-aqueous solvent of at least about 0.1% w / w.

[0497] (133) A pharmaceutical composition according to paragraph (131) or (132), wherein the active substance is dissolved in a non-aqueous solvent.

[0498] (134) A pharmaceutical composition according to paragraphs (131) to (133), wherein the non-aqueous solvent for the active substance is semi-solid at room temperature.

[0499] (135) A pharmaceutical composition according to paragraph (134), wherein the non-aqueous solvent has a melting point of approximately 35°C to approximately 80°C.

[0500] (136) A pharmaceutical composition according to paragraphs (131) to (135), wherein the non-aqueous solvent is water-soluble.

[0501] (137) A pharmaceutical composition according to paragraphs (131) to (136), wherein the pharmaceutical composition contains at least about 20% w / w of a non-aqueous solvent relative to the weight of the total pharmaceutical composition.

[0502] (138) A pharmaceutical composition according to paragraphs (131) to (137), wherein the pharmaceutical composition comprises at least two non-aqueous solvents for the active substance.

[0503] (139) Pharmaceutical compositions according to paragraphs (131) to (138), wherein the non-aqueous solvent comprises polyethylene glycol, propylene glycol, ethanol, glycerol, stearoyl polyoxyglyceride, polyoxyethylene stearate, long-chain triglycerides, medium-chain triglycerides, long-chain fatty acids, medium-chain fatty acids, long-chain monoglycerides, long-chain diglycerides, medium-chain monoglycerides, medium-chain diglycerides, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, polyoxyethylated 12-hydroxystearic acid, caprylocaproyl polyoxyglyceride, linoleoyl polyoxyglyceride, oleoyl polyoxyglyceride, propylene glycol monofatty acid esters, propylene glycol difatty acid esters, soybean oil, glyceryl palmitostearate, diethylene glycol monoethyl ether, sorbitan esters, poloxamer, or vitamin E TPGS or a combination thereof.

[0504] (140) A pharmaceutical composition according to paragraphs (131) to (139), wherein the non-aqueous solvent comprises polyethylene glycol, stearoyl polyoxyglyceride, polyoxyethylene stearate, medium-chain fatty acids, long-chain monoglycerides, long-chain diglycerides, medium-chain monoglycerides, medium-chain diglycerides, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, polyoxyethylated 12-hydroxystearic acid, caprylocaproyl polyoxyglyceride, propylene glycol monofatty acid esters, propylene glycol difatty acid esters, diethylene glycol monoethyl ether, or poloxamer or a combination thereof.

[0505] (141) A pharmaceutical composition according to paragraphs (131) to (140), wherein the non-aqueous solvent comprises polyethylene glycol, stearoyl polyoxyglyceride, medium-chain fatty acid, long-chain monoglyceride, long-chain diglyceride, medium-chain monoglyceride, medium-chain diglyceride, polyoxyethylene sorbitan fatty acid ester, caprylocaproyl polyoxyglyceride, propylene glycol mono fatty acid ester, propylene glycol di fatty acid ester, diethylene glycol monoethyl ether, or poloxamer or a combination thereof.

[0506] (142) A pharmaceutical composition according to paragraphs (131) to (141), wherein the non-aqueous solvent comprises polyethylene glycol, polyoxyethylene stearate, polyoxyethylene castor oil derivative, polyoxyethylated 12-hydroxystearic acid, diethylene glycol monoethyl ether, or poloxamer, vitamin E TPGS, or a combination thereof.

[0507] (143) A pharmaceutical composition according to paragraphs (131) to (142), wherein the non-aqueous solvent comprises polyethylene glycol, a polyoxyethylene castor oil derivative, polyoxyethylated 12-hydroxystearic acid, diethylene glycol monoethyl ether, or poloxamer, or a combination thereof.

[0508] (144) A pharmaceutical composition according to paragraphs (131) to (143), wherein the non-aqueous solvent comprises polyethylene glycol, propylene glycol, glycerol, stearoyl polyoxyglyceride, polyoxyethylene stearate, polyoxyethylene castor oil derivative, polyoxyethylene sorbitan fatty acid ester, polyoxyethylated 12-hydroxystearic acid, caprylocaproyl polyoxyglyceride, linoleoyl polyoxyglyceride, oleoyl polyoxyglyceride, or sorbitan ester or a combination thereof.

[0509] (145) A pharmaceutical composition according to paragraphs (131) to (144), wherein the non-aqueous solvent comprises polyethylene glycol, stearoyl polyoxyglyceride, or polyoxyethylene stearate or a combination thereof.

[0510] (146) A pharmaceutical composition according to paragraphs (131) to (145), wherein the non-aqueous solvent comprises polyethylene glycol.

[0511] (147) A pharmaceutical composition according to paragraphs (131) to (146), wherein the non-aqueous solvent is essentially made from polyethylene glycol.

[0512] (148) A pharmaceutical composition according to paragraphs (131) to (147), wherein the non-aqueous solvent is polyethylene glycol.

[0513] (149) A pharmaceutical composition according to paragraphs (139) to (148), wherein polyethylene glycol has an average molecular weight of approximately 200 to approximately 25,000 g / mol, approximately 300 to approximately 10,000 g / mol, approximately 400 to approximately 6,000 g / mol, or approximately 1,000 to approximately 6,000 g / mol.

[0514] (150) A pharmaceutical composition according to paragraphs (139) to (149), wherein polyethylene glycol has an average molecular weight of about 400, about 1000, about 1500, about 1540, about 2000, about 3000, about 4000, about 6000, about 8000, or about 20000 g / mol.

[0515] (151) A pharmaceutical composition according to paragraphs (139) to (150), wherein polyethylene glycol has an average molecular weight of about 400, about 1500, about 4000, or about 6000 g / mol.

[0516] (152) A pharmaceutical composition according to paragraphs (139) to (151), wherein polyethylene glycol has an average molecular weight of approximately 1500 g / mol.

[0517] (153) A pharmaceutical composition according to paragraphs (123) to (152), wherein the pharmaceutical composition contains approximately 0.001 to approximately 0.8% w / w of the active substance relative to the weight of the total pharmaceutical composition.

[0518] (154) A pharmaceutical composition according to paragraphs (123) to (153), further comprising vitamin E TPGS or lauroyl polyoxyl 32-glyceride.

[0519] (155) A pharmaceutical composition according to paragraphs (123) to (154), further comprising a viscosity modifier, a coloring agent, an opacifying agent, a sweetener or flavoring agent, and / or a preservative, such as an antioxidant.

[0520] (156) A pharmaceutical composition according to paragraphs (131) to (155), wherein the active substance is homogeneously distributed throughout the non-aqueous solvent.

[0521] (157) A pharmaceutical composition according to paragraph (156), wherein the active substance is homogeneously distributed throughout a non-aqueous solvent for at least about two weeks, about one month, about two months, about three months, about six months, about twelve months, or about twenty-four months.

[0522] (158) A pharmaceutical composition according to paragraph (156) or (157), wherein the active substance is homogeneously distributed throughout the non-aqueous solvent for at least about two weeks, about one month, about two months, about three months, about six months, about twelve months, or about twenty-four months after the pharmaceutical composition has been stored at room temperature.

[0523] (159) The homogeneous distribution of the active substance in a non-aqueous solvent is determined by an analytical method, which comprises determining the weight percentage of the active substance in a portion of the pharmaceutical composition, the weight percentage of the active substance in a portion of the pharmaceutical composition being ±5% of an expected value based on the total amount of the active substance added to the total amount of the pharmaceutical composition, according to paragraphs (156) to (158).

[0524] (160) A pharmaceutical composition for oral use comprising compound I or a pharmaceutically acceptable salt thereof as an active substance, and a non-aqueous solvent for the active substance, wherein the active substance is homogeneously distributed throughout the non-aqueous solvent.

[0525] (161) A pharmaceutical composition according to paragraph (160), wherein the active substance is homogeneously distributed throughout a non-aqueous solvent for at least about two weeks, about one month, about two months, about three months, about six months, about twelve months, or about twenty-four months.

[0526] (162) A pharmaceutical composition according to paragraph (160) or (161), wherein the active substance is homogeneously distributed throughout the non-aqueous solvent for at least about two weeks, about one month, about two months, about three months, about six months, about twelve months, or about twenty-four months after the pharmaceutical composition has been stored at room temperature.

[0527] (163) A pharmaceutical composition according to paragraphs (160) to (162), wherein the homogeneous distribution of the active substance in a non-aqueous solvent is determined by an analytical method.

[0528] (164) A pharmaceutical composition according to paragraph (163), wherein the analytical method comprises determining the weight percentage of the active substance in a portion of the pharmaceutical composition.

[0529] (165) A pharmaceutical composition according to paragraphs (163) to (164), wherein the analytical method comprises determining the weight percentage of the active substance in a portion of the pharmaceutical composition, the weight percentage of the active substance in a portion of the pharmaceutical composition being ±5% of an expected value based on the total amount of the active substance added to the total amount of the pharmaceutical composition.

[0530] (166) A pharmaceutical composition according to paragraphs (163) to (165), wherein the analytical method comprises determining the weight percentage of the active substance in a portion of the pharmaceutical composition, the weight percentage of the active substance in a portion of the pharmaceutical composition being ±2% of an expected value based on the total amount of the active substance added to the total amount of the pharmaceutical composition.

[0531] (167) A pharmaceutical composition according to paragraphs (163) to (166), wherein the analytical method comprises determining the weight percentage of the active substance in a portion of the pharmaceutical composition, the weight percentage of the active substance in a portion of the pharmaceutical composition being ±1% of an expected value based on the total amount of the active substance added to the total amount of the pharmaceutical composition.

[0532] (168) A pharmaceutical composition according to paragraphs (163) to (167), wherein the analytical method includes chromatography or spectroscopy.

[0533] (169) A pharmaceutical composition according to paragraph (168), wherein the chromatography method is HPLC.

[0534] (170) A pharmaceutical composition according to paragraphs (160) to (169), wherein the pharmaceutical composition is semi-solid at room temperature.

[0535] (171) A pharmaceutical composition according to paragraph (170), wherein the pharmaceutical composition has a melting point of approximately 35°C to approximately 80°C.

[0536] (172) A pharmaceutical composition according to paragraphs (160) to (171), wherein the non-aqueous solvent for the active substance is semi-solid at room temperature.

[0537] (173) A pharmaceutical composition according to paragraph (172), wherein the non-aqueous solvent has a melting point of approximately 35°C to approximately 80°C.

[0538] (174) A pharmaceutical composition according to paragraphs (160) to (173), wherein the active substance has solubility in a non-aqueous solvent of at least about 0.1% w / w.

[0539] (175) A pharmaceutical composition according to paragraphs (160) to (174), wherein the active substance is dissolved in a non-aqueous solvent.

[0540] (176) A pharmaceutical composition according to paragraphs (160) to (175), wherein the non-aqueous solvent is water-soluble.

[0541] (177) A pharmaceutical composition according to paragraphs (160) to (176), wherein the pharmaceutical composition contains at least about 20% w / w of a non-aqueous solvent relative to the weight of the total pharmaceutical composition.

[0542] (178) A pharmaceutical composition according to paragraphs (160) to (177), wherein the pharmaceutical composition comprises at least two non-aqueous solvents for the active substance.

[0543] (179) A pharmaceutical composition according to paragraphs (160) to (178), wherein the non-aqueous solvent comprises polyethylene glycol, propylene glycol, ethanol, glycerol, stearoyl polyoxyglyceride, polyoxyethylene stearate, long-chain triglycerides, medium-chain triglycerides, long-chain fatty acids, medium-chain fatty acids, long-chain monoglycerides, long-chain diglycerides, medium-chain monoglycerides, medium-chain diglycerides, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, polyoxyethylated 12-hydroxystearic acid, caprylocaproyl polyoxyglyceride, linoleoyl polyoxyglyceride, oleoyl polyoxyglyceride, propylene glycol monofatty acid esters, propylene glycol difatty acid esters, soybean oil, glyceryl palmitostearate, diethylene glycol monoethyl ether, sorbitan esters, poloxamer, or vitamin E TPGS or a combination thereof.

[0544] (180) A pharmaceutical composition according to paragraphs (160) to (179), wherein the non-aqueous solvent comprises polyethylene glycol, ethanol, stearoyl polyoxyglyceride, polyoxyethylene stearate, medium-chain fatty acids, long-chain monoglycerides, long-chain diglycerides, medium-chain monoglycerides, medium-chain diglycerides, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, polyoxyethylated 12-hydroxystearic acid, caprylocaproyl polyoxyglyceride, oleoyl polyoxyglyceride, propylene glycol monofatty acid esters, propylene glycol difatty acid esters, diethylene glycol monoethyl ether, poloxamer, or vitamin E TPGS or a combination thereof.

[0545] (181) A pharmaceutical composition according to paragraphs (160) to (180), wherein the non-aqueous solvent comprises polyethylene glycol, stearoyl polyoxyglyceride, polyoxyethylene stearate, medium-chain fatty acids, long-chain monoglycerides, long-chain diglycerides, medium-chain monoglycerides, medium-chain diglycerides, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, polyoxyethylated 12-hydroxystearic acid, caprylocaproyl polyoxyglyceride, propylene glycol monofatty acid esters, propylene glycol difatty acid esters, diethylene glycol monoethyl ether, poloxamer, vitamin E TPGS, or a combination thereof.

[0546] (182) A pharmaceutical composition according to paragraphs (160) to (181), wherein the non-aqueous solvent comprises polyethylene glycol, propylene glycol, glycerol, stearoyl polyoxyglyceride, polyoxyethylene stearate, polyoxyethylene castor oil derivative, polyoxyethylene sorbitan fatty acid ester, polyoxyethylated 12-hydroxystearic acid, caprylocaproyl polyoxyglyceride, linoleoyl polyoxyglyceride, oleoyl polyoxyglyceride, or sorbitan ester or a combination thereof.

[0547] (183) A pharmaceutical composition according to paragraphs (160) to (182), wherein the non-aqueous solvent comprises polyethylene glycol, stearoyl polyoxyglyceride, or polyoxyethylene stearate or a combination thereof.

[0548] (184) A pharmaceutical composition according to paragraphs (160) to (183), wherein the non-aqueous solvent contains polyethylene glycol.

[0549] (185) A pharmaceutical composition according to paragraphs (160) to (184), wherein the non-aqueous solvent is essentially made from polyethylene glycol.

[0550] (186) A pharmaceutical composition according to paragraphs (160) to (185), wherein the non-aqueous solvent is polyethylene glycol.

[0551] (187) A pharmaceutical composition according to paragraphs (179) to (186), wherein polyethylene glycol has an average molecular weight of approximately 200 to approximately 25,000 g / mol, approximately 300 to approximately 10,000 g / mol, approximately 400 to approximately 6,000 g / mol, or approximately 1,000 to approximately 6,000 g / mol.

[0552] (188) A pharmaceutical composition according to paragraphs (179) to (187), wherein polyethylene glycol has an average molecular weight of about 400, about 1000, about 1500, about 1540, about 2000, about 3000, about 4000, about 6000, about 8000, or about 20000 g / mol.

[0553] (189) A pharmaceutical composition according to paragraphs (179) to (188), wherein polyethylene glycol has an average molecular weight of about 400, about 1500, about 4000, or about 6000 g / mol.

[0554] (190) A pharmaceutical composition according to paragraphs (179) to (189), wherein polyethylene glycol has an average molecular weight of approximately 1500 g / mol.

[0555] (191) A pharmaceutical composition according to paragraphs (160) to (190), further comprising vitamin E TPGS or lauroyl polyoxyl 32-glyceride.

[0556] (192) A pharmaceutical composition according to paragraphs (160) to (191), wherein the pharmaceutical composition contains approximately 0.001 to approximately 0.8% w / w of the active substance relative to the weight of the total pharmaceutical composition.

[0557] (193) A pharmaceutical composition according to paragraphs (160) to (192), further comprising a viscosity modifier, a coloring agent, an opacifying agent, a sweetener or flavoring agent, and / or a preservative, such as an antioxidant.

[0558] (194) A pharmaceutical composition according to paragraphs (160) to (193), wherein the active substance is stable in the pharmaceutical composition for at least about two weeks, about one month, about two months, about three months, about six months, about twelve months, or about twenty-four months.

[0559] (195) a. The total amount of degradation products of the active substance is less than or equal to about 4 area % as determined by chromatography when the pharmaceutical composition is stored at 25°C / 60%RH and / or 40°C / 75%RH for at least about 2 weeks, about 1 month, about 2 months, about 3 months, about 6 months, about 12 months, or about 24 months; and / or b. The assay for the active substance is determined by chromatography when the pharmaceutical composition is stored at 25°C / 60%RH and / or 40°C / 75%RH for at least about 2 weeks, about 1 month, about 2 months, about 3 months, about 6 months, about 12 months, or about 24 months, and the value is 90-110% of the nominal value. A pharmaceutical composition according to paragraph (194).

[0560] (196) A pharmaceutical composition according to paragraph (195), wherein the chromatography method is HPLC.

[0561] (197) A pharmaceutical composition according to paragraph (196), wherein the HPLC method is reversed-phase HPLC.

[0562] (198) At least about 75% of the total amount of active substance contained in the pharmaceutical composition is released within approximately the first 45 minutes when the pharmaceutical composition is subjected to an in vitro dissolution test using 0.1 M HCl or pH 6.8 phosphate buffer as the dissolution medium, and the dissolution profile is determined at 37°C using a rotation speed of 50 rpm as described in the United States Pharmacopeia, according to paragraphs (160) to (197).

[0563] (199) A pharmaceutical composition according to paragraph (198), wherein at least about 75% of the total amount of active substances contained in the pharmaceutical composition is released within approximately the first 30 minutes when the pharmaceutical composition is subjected to an in vitro dissolution test.

[0564] (200) A pharmaceutical composition according to paragraph (198) or (199), wherein at least 85% of the total amount of active substances contained in the pharmaceutical composition is released within approximately the first 15 minutes when the pharmaceutical composition is subjected to an in vitro dissolution test.

[0565] (201) A pharmaceutical composition according to paragraphs (1) to (200), comprising two non-aqueous solvents for the active substance.

[0566] (202) A pharmaceutical composition according to paragraph (201), wherein the first non-aqueous solvent comprises polyethylene glycol or vitamin E TPGS.

[0567] (203) A pharmaceutical composition according to paragraph (202), wherein the first non-aqueous solvent comprises polyethylene glycol having an average molecular weight of less than 1000 g / mol.

[0568] (204) A pharmaceutical composition according to paragraphs (201) to (203), wherein the first non-aqueous solvent comprises polyethylene glycol having an average molecular weight of about 400 g / mol.

[0569] (205) A pharmaceutical composition according to paragraphs (201) to (204), wherein the second nonaqueous solvent comprises polyethylene glycol having an average molecular weight of at least about 1000 g / mol.

[0570] (206) A pharmaceutical composition according to paragraphs (201) to (205), wherein the weight ratio of the first non-aqueous solvent to the second non-aqueous solvent is about 1:20 to about 20:1, for example about 1:10 to about 10:1, for example about 1:9 to about 9:1.

[0571] (207) Pharmaceutical compositions according to paragraphs (61)-(65), (73)-(86), (101)-(105), (113)-(122), (139)-(142), (144)-(145), (153)-(159), (179)-(183), (191)-(204) and (206), wherein the polyoxyethylene stearate is PEG-32 stearate or polyethylene glycol monostearate or a mixture thereof.

[0572] (208) A pharmaceutical composition according to paragraph (207), wherein the polyoxyethylene stearate is polyethylene glycol monostearate.

[0573] (209) Pharmaceutical compositions according to paragraphs (61)-(63), (73)-(86), (101)-(102), (113)-(122), (139)-(141), (153)-(159), (179)-(181), (191-204) and (206), wherein the medium-chain fatty acid is caprylic acid, capric acid, or lauric acid.

[0574] (210) Pharmaceutical compositions according to paragraphs (61)-(63), (73)-(86), (101), (113)-(122), (139)-(141), (153)-(159), (179)-(181), (191-204) and (206), wherein the long-chain monoglyceride is glyceryl monooleate.

[0575] (211) Pharmaceutical compositions according to paragraphs (61)-(63), (73)-(86), (101)-(103), (113)-(122), (139)-(141), (153)-(159), (179)-(181), (191-204) and (206), wherein the medium-chain monoglyceride is glyceryl monocaprylate.

[0576] (212) A pharmaceutical composition according to paragraphs (61)-(64), (73)-(86), (101)-(104), (113)-(122), (139)-(144), (153)-(159), (179)-(182), (191-204) and (206), wherein the polyoxyethylene castor oil derivative is polyoxyl 40 hydrogenated castor oil, polyoxyl 35 castor oil, or a mixture thereof.

[0577] (213) A pharmaceutical composition according to paragraph (212), wherein the polyoxyethylene castor oil derivative is polyoxyl 40 hydrogenated castor oil.

[0578] (214) Pharmaceutical compositions according to paragraphs (61)-(64), (73)-(86), (101)-(104), (113)-(122), (139)-(141), (153)-(159), (179)-(182), (191-204) and (206), wherein the polyoxyethylene sorbitan fatty acid ester is polysorbate 20, polysorbate 80, or a mixture thereof.

[0579] (215) A pharmaceutical composition according to paragraph (214), wherein the polyoxyethylene sorbitan fatty acid ester is polysorbate 20.

[0580] (216) Pharmaceutical compositions according to paragraphs (61)-(63), (73)-(86), (101), (113)-(122), (139)-(141), (153)-(159), (179)-(181), (191-204) and (206), wherein the propylene glycol monofatty acid ester is propylene glycol monocaprylate.

[0581] (217) Pharmaceutical compositions according to paragraphs (61)-(63), (73)-(86), (101)-(103), (113)-(122), (139)-(141), (153)-(159), (179)-(181), (191-204) and (206), wherein the propylene glycol di fatty acid ester is propylene glycol dilaurate.

[0582] (218) A pharmaceutical composition according to any of paragraphs (1) to (217), further comprising vitamin E TPGS or lauroyl polyoxyglyceride.

[0583] (219) An immediate-release pharmaceutical formulation for oral use comprising the pharmaceutical composition according to paragraphs (1) to (218).

[0584] (220) An immediate-release drug formulation, when subjected to the formulation uniformity test described in the European Pharmacopoeia, has an acceptable value of less than 15, as described in paragraph (219).

[0585] (221) An immediate-release pharmaceutical formulation according to paragraph (220), wherein the acceptable value is less than 10.

[0586] (222) An immediate-release pharmaceutical formulation, wherein the formulation uniformity test includes a chromatographic assay of the immediate-release pharmaceutical formulation, according to paragraph (220) or (221).

[0587] (223) An immediate-release drug formulation according to paragraphs (219) to (222), wherein the immediate-release drug formulation is an immediate-release capsule formulation.

[0588] (224) An immediate-release pharmaceutical formulation according to paragraph (223), comprising a capsule shell, wherein the capsule shell comprises gelatin or HPMC.

[0589] (225) An immediate-release pharmaceutical formulation according to paragraph (224), wherein the capsule shell contains gelatin.

[0590] (226) An immediate-release pharmaceutical formulation according to paragraph (219), wherein the immediate-release pharmaceutical formulation is a spray.

[0591] (227) An immediate-release pharmaceutical formulation according to paragraphs (219) to (226), wherein the immediate-release formulation contains approximately 10 to approximately 1000 μg, approximately 10 to approximately 650 μg, or approximately 100 to approximately 650 μg of the active substance.

[0592] (228) An immediate-release pharmaceutical formulation according to paragraphs (219) to (227), wherein the immediate-release formulation contains approximately 50 μg of the active substance.

[0593] (229) An immediate-release pharmaceutical formulation according to paragraphs (219) to (227), wherein the immediate-release formulation contains approximately 200 μg of the active substance.

[0594] (230) Pharmaceutical compositions according to paragraphs (1) to (218) or immediate-release pharmaceutical preparations according to paragraphs (219) to (229) for use as pharmaceuticals.

[0595] (231) Pharmaceutical compositions according to paragraphs (1) to (218) or immediate-release pharmaceutical formulations according to paragraphs (219) to (229) for use in disease conditions or disorders in which dysfunction of CB1 and / or CB2 receptors is present or involved.

[0596] (232) Conditions related to loss of appetite; conditions related to cachexia; anorexia nervosa; pain conditions; anxiety disorders; cancer; multiple sclerosis; Parkinson's disease; Huntington's disease; Alzheimer's disease; AIDS; amyotrophic lateral sclerosis; gastrointestinal disorders; cardiovascular disorders; insomnia; autoimmune diseases such as arthritis, collagen disease, or allergies; diarrhea; depression; anxiety and stress-related disorders, such as post-traumatic stress disorder, panic disorder, generalized anxiety disorder, social phobia, and obsessive-compulsive disorder; urinary incontinence; premature ejaculation; various mental illnesses Pharmaceutical compositions according to paragraphs (1) to (218) or immediate-release pharmaceutical formulations according to paragraphs (219) to (229) for use in the treatment of sympathetic nervous system disorders, such as cough; pulmonary edema; various gastrointestinal disorders, such as constipation, irritable bowel syndrome and functional gastrointestinal disorders such as functional dyspepsia; Parkinson's disease and other motor disorders; traumatic brain injury; stroke; cardioprotection after myocardial infarction; spinal cord injury and drug addiction (including treatment of alcohol, nicotine, opioid and other drug abuse); and disorders of the sympathetic nervous system, such as hypertension.

[0597] (233) A pharmaceutical composition or immediate-release pharmaceutical preparation according to paragraph (232) for use in the treatment of conditions related to loss of appetite; conditions related to cachexia; or anorexia nervosa.

[0598] (234) A pharmaceutical composition or immediate-release pharmaceutical preparation according to paragraph (232) or (233), wherein the loss of appetite-related condition is cancer-related loss of appetite, HIV-related loss of appetite, chronic kidney disease-related loss of appetite, dementia-related loss of appetite, or chronic congestive heart failure-related loss of appetite.

[0599] (235) A pharmaceutical composition or immediate-release pharmaceutical preparation according to paragraphs (232) to (234), wherein the loss of appetite-related condition is cancer-related loss of appetite.

[0600] (236) A pharmaceutical composition or immediate-release pharmaceutical preparation according to paragraph (232) or (233), wherein the cachexia-related condition is cancer-related cachexia, HIV-related cachexia, chronic kidney disease-related cachexia, dementia-related cachexia, or chronic congestive heart failure-related cachexia.

[0601] (237) A pharmaceutical composition or immediate-release pharmaceutical preparation according to paragraph (232) wherein the pain condition is a cancer pain condition, acute pain, chronic pain, neuropathic pain, back pain, cancer pain, visceral pain, pain caused by rheumatoid arthritis, or migraine.

[0602] (238) A pharmaceutical composition or immediate-release pharmaceutical preparation according to paragraph (237) wherein the pain state in cancer is a pain state in cancer associated with a reduction in nausea and / or vomiting associated with a reduction in opiate use in cancer patients.

[0603] (239) Pharmaceutical compositions according to paragraphs (1) to (218) or immediate-release pharmaceutical preparations according to paragraphs (219) to (229) for use during general anesthesia and surveillance anesthesia.

[0604] (240) A pharmaceutical composition according to paragraphs (1) to (218) or an immediate-release pharmaceutical preparation according to paragraphs (219) to (229) for use as an analgesic. [Examples]

[0605] In the examples, the following abbreviations were used: The API (Active Pharmaceutical Ingredient) is, in this example, N-(2-(tert-butyl)-1-((4,4-difluorocyclohexyl)methyl)-1H-benzimidazole-5-yl)ethanesulfonamide (compound I). AV tolerance HPMC (Hydroxypropyl Methylcellulose) n / a Not applicable NMT or less PEG polyethylene glycol Vitamin E TPGS D-α-Tocopherol Polyethylene Glycol Succinate

[0606] Example 1 - Study of forced decomposition of N-(2-(tert-butyl)-1-((4,4-difluorocyclohexyl)methyl)-1H-benzimidazole-5-yl)ethanesulfonamide The N-(2-(tert-butyl)-1-((4,4-difluorocyclohexyl)methyl)-1H-benzimidazole-5-yl)ethanesulfonamide study (active substance) underwent forced decomposition for up to 13 days under various stress conditions. The active substance was shown to be stable against decomposition as a solution at room temperature, as a solid at 100°C, under 1M acidic conditions at room temperature and 60°C, under 0.5M basic conditions at room temperature and 60°C, as a solution heated to 60°C, and as a solid under photostable conditions. The active substance showed slight decomposition when these tests were extended to 80°C under peroxide conditions, 1M acidic conditions, and 0.5M basic conditions, and decomposition as a solution occurred when heated to 80°C. Major decomposition of the active substance as a solution occurred under photostable conditions.

[0607] material Active substance: N-(2-(tert-butyl)-1-((4,4-difluorocyclohexyl)methyl)-1H-benzimidazole-5-yl)ethanesulfonamide ex-OnyxScientific Ltd Batch number: CB988E LCMS Water ex-OnyxScientific Ltd N / A Acetonitrile ex-Sigma-Aldrich Lot Number: STBJ1963 Ammonium acetate ex-Fluka Lot number: - H2010 6.0M Hydrochloric Acid ex-Fluka Lot Number: - H1370 1M Sodium Hydroxide ex-Fisher Lot Number: - 1871868 30% Hydrogen Peroxide ex-Sigma-Aldrich Lot Number: MKBS2987V

[0608] analysis HPLC conditions Equipment: Agilent 1100 / 1200 Column: YMC Triart Phenyl, 4.6x150mm. Particle size 3μm (ex-YMC PNTPH12S03-1546PTH) Mobile phase: A - 10 mM ammonium acetate pH 6.0 B - Acetonitrile Flow rate: 1.0ml / min Injection volume: 5μl Detection: UV@220nm Column temperature: 30℃ Post-run: 4 minutes [Table 1]

[0609] Diluent: Acetonitrile: Deionized water (1:1) Standard solution: Prepare a 0.2 mg / ml solution. This should be freshly prepared before use at T=3 and T=7 days.

[0610] Stock solution preparation Accurately weigh 80 mg of the active substance into a 100 mL volumetric flask and dissolve it in 50 mL of diluent. Dilute the resulting solution to a specific volume with the diluent and mix thoroughly.

[0611] procedure Table 1 below details the various research tests conducted. All solution samples were prepared and stored in sealed vials. Heated samples were cooled to room temperature before sampling to prevent evaporation. Analysis was performed on the 3rd and 7th days after the start of stress application for the solutions described in Tests 1-6, and after exposure was complete for the samples described in Tests 7-10. Due to the low levels of degradation observed on day 7, Tests 3, 4, and 5 were heated at 80°C for an additional 4 days and analyzed, and Test 6 was analyzed after an additional 6 days.

[0612] The photostable samples were subjected to a total of 1.92 million lux hours and a total near-ultraviolet energy of 374.6 Whm. -2 They were exposed to it. [Table 2] [Table 3]

[0613] result observation [Table 4]

[0614] analysis [Table 5]

[0615] [Table 6]

[0616] Example 2 - Pre-preparation study - Compatibility of active ingredient with capsule shell and semi-solid excipient Pre-preparation studies were conducted to select excipients for the development of immediate-release capsules containing a low dose of N-(2-(tert-butyl)-1-((4,4-difluorocyclohexyl)methyl)-1H-benzimidazole-5-yl)ethanesulfonamide in a semi-solid carrier. The chemical stability of N-(2-(tert-butyl)-1-((4,4-difluorocyclohexyl)methyl)-1H-benzimidazole-5-yl)ethanesulfonamide in the semi-solid carrier was evaluated at 40°C and 50°C for up to 28 days.

[0617] Both types of capsule shells evaluated (HPMC and PEG softened-hardened gelatin shells) were compatible with the active ingredient. Of the three semi-solids tested, the solubility of the active ingredient was sufficiently high (>0.1% w / w), allowing for the preparation of low-dose capsules. The active ingredient showed good chemical stability in PEG and vitamin E TPGS over 28 days, but significant degradation of the active ingredient was observed in Gelucire 44 / 14 during incubation at 40°C.

[0618] methodology While suspension formulations themselves were not ruled out, solution-based formulations were preferred to maximize the opportunity to achieve uniformity of content. To deliver a dose strength of 200 μg in a size 4 capsule, a target solubility of >0.1% w / w for the active ingredient in the excipient was set (the maximum filling weight of a size 4 capsule is approximately 200 mg, 0.2 mg / 200 mg × 100 = 0.1% w / w), and the amount of excipient administered was minimized. This solubility would allow for the production of higher dose strengths in larger capsules, e.g., approximately 650 μg in a size 0 capsule, if needed as development progresses.

[0619] The chemical compatibility between the active ingredient and the excipient was evaluated.

[0620] material Active ingredient: (N-(2-(tert-butyl)-1-((4,4-difluorocyclohexyl)methyl)-1H-benzimidazole-5-yl)ethanesulfonamide) ex IPCA Supplier Lot ID JCM1019B HMPC Capsules White Capsugel VCaps Plus Size 4 Hard gelatin capsules, green / gray, Qualicaps Quali-G PEG (size 4) Vitamin E from TPGS Isochem Polyethylene glycol PEG1500, Merck Polyoxylglyceride Gelucire 44 / 14

[0621] Analysis methodology UPLC conditions Column: Waters Acquity BEH Shield 100 x 2.1 mm, 1.7 μm Column temperature: 40°C Sample manager washing solution (UPLC): Acetonitrile Sample Manager Purge (UPLC) HPLC Water:ACN 50:50% v / v Mobile phase A (for semi-solids): pH 9.2, sodium hydroxide. Mobile phase A (for capsule shell): 25% ammonia solution Mobile phase B: Acetonitrile Mobile phase C: 2-propanol Flow rate 0.3mL / min Injection volume: 10 μL (at a nominal concentration of 0.01 mg / mL) 5 μL (at a nominal concentration of 0.02 mg / mL) Wavelength 215nm Gradient program [Table 7]

[0622] Part 1 - Compatibility of the Active Ingredient with the Capsule Shell Before day 0 Preparation of a 3 mg / mL doping solution A 3 mg / mL active ingredient doping solution in ethanol was prepared by directly distributing 89.5–90.5 mg of the active ingredient into a 30 mL amber bottle (avoiding the distribution of aggregates, as this slows dissolution). A total of 30 mL of anhydrous ethanol was added to the bottle in a solvent fume cupboard. The contents of the bottle were stirred using a magnetic chisel and stirring plate until all solids were dissolved (using a backlight from outside a darkroom for a short time, ignoring fibrous materials in the bottle). The bottle was placed in the freezer until required for use.

[0623] Day 0 The following stability vials were prepared and stored according to Table 5. The two components, "dry excipients" and the active ingredient, were partitioned into vials, and 100 μL of doping solution was added. It was ensured that the doping solution made complete contact with the dry excipients upon addition to the vials. The solvent was evaporated until a white film formed. Placebo-controlled samples: A dry excipient (HPMC capsule or hard gelatin capsule) was added to the vial, but the stock solution was not applied to the vial. These served as controls to aid in HPLC peak identification. Control of active ingredient only: 100 μL of the doping solution was added to an empty vial, and the solvent was evaporated. These demonstrated the chemical stability of the active ingredient as a control.

[0624] For the vials where solvent evaporation was required, the vials were left open overnight. Once the solvent had evaporated, the vials were closed and placed in an opaque plastic storage box. [Table 8]

[0625] Once specified in Table 5, the vials were removed and placed in the freezer until the HPLC analysis was performed.

[0626] result Table 6 shows the assay results for the active ingredients in HPMC and gelatin capsules. [Table 9]

[0627] Overall, the % assays for both sample sets appear consistent across all conditions and time points, indicating no degradation of the active ingredients in either the HPMC or gelatin capsules.

[0628] The only two exceptions are the low results for one of the HPMC replicas at 25°C after 14 days, and for one of the gelatin replicas at 50°C after 28 days. These results were inconsistent with the other replicas in both cases and are therefore considered outliers.

[0629] Table 7 shows the peak areas of potential active ingredient-related substances. Since the total impurities remained below 1% without increasing with incubation time or temperature for any of the impurities, there is no evidence of active ingredient degradation in either capsule type. [Table 10]

[0630] Part 2 - Evaluation of solubility and stability of active ingredients in semi-solid excipients The solubility of up to three aliquots of the active ingredient in each semi-solid solution was evaluated using samples taken for stability assessment, as follows: 1. While melting the semi-solid at approximately 70°C, aliquot 1 of the active ingredient was added to the molten semi-solid, and then homogenized at 2000 RPM using a Silverson mixer. 2. After dissolving the first active ingredient aliquot, 10 stability and 10 "method development" samples were taken out (200 μL per vial, unweighed) and stored stably at 25 and 40°C for up to 28 days. 3. Since the active ingredients were clearly completely soluble in this experiment, aliquots 2 and 3 of the active ingredients were added and then homogenized until dissolved in the remaining solution. 4. After adding aliquots of each active ingredient, the appearance of the solution was recorded.

[0631] In step 2, the following procedure was used to determine the mass of the semi-solid material that was volume-distributed into 20 vials: 1. The group mass (mass G) of the five "method development" vials was measured. 2. The vials were washed twice with ethanol (sonicated for 10 minutes each time) and dried for 1 hour - the vials were completely clean and dry. 3. The group mass (mass T) of 5 clean vials was measured. 4. The average net weight of the semi-solid in the original vial was calculated as (GT) / 5, where G and T.

[0632] Table 8 shows the levels of the active ingredient added to three different semi-solids. [Table 11]

[0633] result All three active ingredient aliquots dissolved completely in each of the three molten semi-solids: Vitamin E TPGS, PEG1500, and Gelucire 44 / 14. Clear solutions without particles or opacity were achieved; only Vitamin E TPGS was slightly yellow, while PEG1500 and Gelucire 44 / 14 were colorless. The final concentrations of the API in each semi-solid were 0.10–0.12% w / w, consistent with the maximum dose (200 μg) being able to be filled into capsules of a preferred size (size 4).

[0634] Table 9 summarizes the assays of the active ingredient in semi-solids, sampled after only the initial aliquot addition (i.e., 0.024–5% w / w of the active ingredient, representing the highest risk of stability) following 28-day stability studies at 25 and 40°C. [Table 12]

[0635] The related substances for the three types of semi-solid excipients are shown in Tables 10, 11, and 12.

[0636] Both vitamin E TPGS and PEG1500 appear stable with no significant effect of incubation time and temperature on the assay. However, there is evidence of significant degradation of Gelucire 44 / 14 under accelerated stability conditions (40°C). [Table 13]

[0637] [Table 14]

[0638] [Table 15]

[0639] Example 3 - Preparation, stability, and solubility analysis of PEG1500 and vitamin E TPGS-based immediate-release formulations Semi-solid capsules containing the active ingredient in either vitamin E TPGS or PEG were prepared in different doses (50 and 200 μg) and sizes of hard gelatin capsules (sizes 3 and 4). The prepared capsules were subjected to stability studies at 25°C and 40°C for 4 weeks. Both types of semi-solid capsules (vitamin E TPGS and PEG) were stable under the tested conditions. The PEG1500 formulation met the European Pharmacopoeia standard for conventional immediate-release formulations (80% of the active ingredient is released within 45 minutes), but surprisingly, the vitamin E TPGS formulation did not in some cases.

[0640] methodology A batch of semi-solid capsules containing the active ingredient was prepared according to Tables 13 and 14.

[0641] In both tables, suffix codes are used to indicate the two concentrations of the active ingredient used in PEG or vitamin E TPGS solution: • L indicates a low concentration (0.1%) of the active ingredients in L-PEG and L-vitamin E TPGS solution. • H indicates a low concentration (0.4%) of the active ingredient in H-PEG and H vitamin E TPGS solution.

[0642] The batches listed in Tables 13 and 14 were prepared in batch size of approximately 80g by performing the following process in a darkroom without controlling the oxygen or RH levels: 1. Using a Silverson homogenizer, dissolve the active ingredient in molten vitamin E TPGS or PEG1500 until a clear solution is formed. 2. Fill the capsules using a manual pipette (Gilson Repetman) (the target filling weight is specified in Table 13).

[0643] The filling process worked well for vitamin E TPGS at the target temperature of 55°C throughout, but the operator noted that PEG1500 tended to coagulate (high weight variability) at this target temperature.

[0644] Weight uniformity was suboptimal for H-PEG and H-vitamin E TPGS in the analyzed capsules, but this could be improved in subsequent trials under more controlled process conditions.

[0645] In addition to capsule preparation, the active ingredient solution was held at 55°C for 24 hours to mimic a reasonable process holding step.

[0646] Because some of the dissolution profiles of Vitamin E TPGS capsules do not conform to the European Pharmacopoeia standards for conventional immediate-release dosage forms, only PEG1500 capsules were subjected to 4-week stability testing at 25°C, 40°C, and -20°C (all were analyzed together, and -20°C data was used as the initial). [Table 16]

[0647] [Table 17]

[0648] Analysis method Dissolution Device: Paddle (USP Device II) Paddle speed 50 rpm 200rpm infinite speed Dissolution medium: 0.1M hydrochloric acid / phosphate buffer, pH 6.8 Vehicle amount Dose 50μg: 500mL (nominal concentration 0.1μg / mL) Dose 200μg: 500mL (nominal concentration 0.4μg / mL) Temperature 37±0.5℃ Sinker: A band sinker with an O-ring inner diameter suitable for the capsule size being tested. Sampling filter 13mm, 0.2μm PVDF syringe filter Cannula filter, 10μm cannula filter (P / N FIL010-CA-a) Sampling times: 10, 20, 30 minutes, and 45 minutes at 50 rpm. 60 minutes (infinite speed at 200 rpm after the 45-minute mark) Detection by HPLC / UPLC

[0649] Preparation of 0.1M HCl dissolution medium Transfer 4000 mL of deionized water or HPLC water to a dissolving aspirator. Using a graduated cylinder, transfer 41 mL of concentrated HCl to the aspirator. Then transfer another 959 mL of deionized water or HPLC water to the same aspirator. Mix.

[0650] Preparation of a pH 6.8 phosphate buffer solution Dissolve 81.6±0.5g of anhydrous monopotassium phosphate (KH2PO4) in 3000mL of deionized water (Preparation 1). Dissolve 214.8±0.5g of disodium hydrogen phosphate dodecahydrate (Na2HPO4·12H2O) in 3000mL of deionized water (Preparation 2). Combine 2550mL of Preparation 1 with 2450mL of Preparation 2. Measure the pH of the solution. The pH should be pH 6.8±0.05. If necessary, adjust the pH to 6.8 using either Preparation 1 or Preparation 2 (Preparation 1 to lower the pH or Preparation 2 to raise the pH).

[0651] Dissolution HPLC / UPLC Column: Halo C18 2.7μm 3.0x50mm Column temperature: 40°C Sample Manager Washing Solution (UPLC) HPLC Water:ACN 50:50% v / v Needle washing solution (HPLC): HPLC water:ACN 50:50% v / v Sample Manager Purge (UPLC) HPLC: Water + 0.1% Phosphate Mobile phase A: HPLC water + 0.1% phosphate Mobile phase B: 100% acetonitrile [Table 18]

[0652] Flow rate 0.5mL / min Injection volume 10μL (dose 200μg) 25μL (dose 50μg) Wavelength 217nm

[0653] Standard preparations for HPLC / UPLC The active ingredient is photosensitive and requires protection from light. High dose calibration standard: 0.1M HCl Prepare a 0.4 μg / mL active ingredient standard in 90:10 v / v 0.1 M HCl:acetonitrile. Low dose calibration standard: 0.1M HCl: Prepare a 0.1 μg / mL active ingredient standard in 90:10 v / v 0.1 M HCl:acetonitrile. High-dose calibration standard: pH 6.8 phosphate buffer Prepare a 0.4 μg / mL active ingredient standard in a pH 6.8 90:10 v / v phosphate buffer:acetonitrile solution. Low-dose calibration standard: pH 6.8 phosphate buffer Prepare a 0.1 μg / mL active ingredient standard in a pH 6.8 90:10 v / v phosphate buffer:acetonitrile solution.

[0654] Content uniformity Weigh and record the mass of each capsule. Add each capsule dropwise to a separate 500 mL amber volumetric flask. Add approximately 200 mL of 90:10 v / v 0.1 M HCl:acetonitrile. Place on an orbital shaker set to approximately 200 rpm and stir thoroughly for 2 hours. Confirm that the capsules have disintegrated. Equilibrate to room temperature and add 90:10 v / v 0.1 M HCl:acetonitrile to a constant volume. Seal the flask and invert 15 times to ensure competitive mixing. Take a portion of the sample and place it in an 8 mL amber vial. Centrifuge each sample at 4200 rpm for 30 minutes, or until a clear supernatant is formed. Transfer 1.5 mL of the clear supernatant to an amber HPLC vial for analysis (see Example 3 "Dissolution HPLC / UPLC" above). Calculate the acceptable value (AV) using the following formula according to Ph.Eur.2.9.40: AV=|MX|+ks During the ceremony X = the average of the individual content values ​​(x1, x2...x3) expressed as a percentage of the stated quantity. k = receptor constant. When n = 10, k = 2.4, and when n = 30, k = 2.0, where n = sample size. s = standard deviation of the sample M = reference value. Case 1, when T ≤ 101.5: If 98.5% ≤ X ≤ 101.5%, then M = X (and therefore AV = ks). If X < 98.5%, then M = 98.5% (therefore, AV = 98.5 - X + ks). If X > 101.5%, then M = 101.5% (therefore, AV = X - 101.5 + ks). Case 2, when T > 101.5: If 98.5% ≤ X ≤ T, then M = X (and therefore AV = ks). If X < 98.5%, then M = 98.5% (therefore, AV = 98.5 - X + ks). If X > T, then M = T % (therefore, AV = X - T + ks). T = Target test sample quantity during manufacturing

[0655] result Dissolution Dissolution results were obtained from various capsules in 0.1 M HCl (pH approximately 1) and pH 6.8 phosphate buffered media (see Figures 1-12). PEG1500-based formulations exhibited faster dissolution profiles for each dose in both media. Furthermore, the filling weight appeared to affect the release rate of the active ingredient from the TPGS-containing capsules in 0.1 M HCl. Release from some vitamin E TPGS formulations in specific media did not meet the European Pharmacopoeia standards for conventional immediate-release formulations (typically 80% release of the active ingredient within 45 minutes).

[0656] stability Since only some of the vitamin E TPGS formulations conform to the European Pharmacopoeia standards for conventional immediate-release formulations in specific dissolving media, only the PEG formulations were stabilized and analyzed.

[0657] The assay results for the PEG formulations are shown in Table 15. The assay results for the PEG-based capsules were all below nominal (approximately 90% of the target) throughout the stability studies, likely due to the method used, which involved scraping the semi-solid plug from the shell for analysis. However, there were no clear trends in the assay or impurity peak area, or any changes from the 24-28 hour retention of the API, at storage temperatures (-20°C vs. 25°C for 28 days). Based on these results, there are no stability concerns. [Table 19]

[0658] Content uniformity The results for content uniformity across all tested capsules showed an acceptable value (AV) < 15 (see Table 16). [Table 20]

[0659] Example 4 - Preparation and analysis of a stability batch of PEG1500 immediate-release capsules Semi-solid capsules containing the active ingredient in PEG1500 were prepared in different doses (50 and 200 μg) and sizes of hard gelatin capsules (sizes 2 and 4). The prepared capsules were subjected to stability studies at 25°C and 40°C, and stability has been demonstrated at the time of analysis to date. The formulations conform to the European Pharmacopoeia standards for conventional immediate-release dosage forms (80% of the active ingredient is released within 45 minutes) and exhibit good uniformity of content.

[0660] methodology material Active substance: (N-(2-(tert-butyl)-1-((4,4-difluorocyclohexyl)methyl)-1H-benzimidazole-5-yl)ethanesulfonamide) Onyx (Lot: JCM1019B) Polyethylene glycol PEG1500 Merck, Lot: K51120505 950 Gelatin capsules, green / gray, size 4, Quali G capsules, Qualicaps (ARE) Gelatin capsules, white, size 2, Quali G capsules, Qualicaps (ARE) HPMC Capsules, Red, Size 4, Quali V Capsules, Qualicaps (ARE) HPMC Capsules, White, Size 2, Quali V Capsules, Qualicaps (ARE)

[0661] Pharmaceutical composition The prepared compositions are summarized in Table 17. [Table 21]

[0662] Two doses (50 μg and 200 μg) were prepared by melting PEG1500. All preparations were carried out in a dark room under nitrogen (≤2% oxygen) as follows: PEG1500 was melted using a glycerol bath on a hot plate, and the temperature was maintained at 60-66°C throughout the distribution and encapsulation process. • The placebo formulation was prepared by melting PEG1500 alone and distributing it into capsules. Regarding the active ingredient, the active substance was gradually added once the target temperature for PEG1500 was reached. The active ingredients were mixed using a magnetic chisel until completely dissolved. A spatula was needed to break up the aggregates of the active ingredients. The Repetman pipette was set to dispense 50 mg of the filling solution. Each formulation was filled into the capsule shells listed in Table 17. • Quali-V capsules were excluded from further study (due to interference issues in the assay and related substances from HPMC). Only Quali-G PEG QC capsules were tested at T=0 and kept stable.

[0663] Analysis methodology Dissolution The dissolution method described in Example 3 was followed. The HPLC / UPLC dissolution method used was the same as described in Example 3.

[0664] Content uniformity The method for determining the uniformity of the content described in Example 3 was followed.

[0665] UPLC / HPLC parameters used for analysis and testing of related substances Column: Halo C18 2.7μm 3.0x50mm Column temperature: 40°C Sample Manager Washing Solution (UPLC) HPLC Water:ACN 50:50% v / v Sample Manager Purge (UPLC) HPLC Water:ACN 50:50% v / v Mobile phase A: 10 mM ammonium acetate, pH 7.0 Mobile phase B: 100% acetonitrile [Table 22]

[0666] Flow rate 0.3mL / min Injection volume: 12 or 38 μL Wavelength 256nm Diluent: Acetonitrile Sample preparation: Assay analysis: Nominal concentration 0.01 g / mL Related substance: Nominal concentration 0.025 mg / mL

[0667] Long term stability study The PEG1500 active substance and placebo batches were stabilized as shown in Table 18. [Table 23]

[0668] result Manufacturing process evaluation Four batches, two active formulations (200 μg and 50 μg), and two corresponding placebos, as shown in Table 17, were successfully manufactured. The following challenges were observed during manufacturing: I. Aggregation of the active substance upon addition to molten PEG (even when added gradually). Aggregation was more pronounced when more active substance was added (i.e., at higher doses). To aid in the dispersion of the active substance and thus increase its solubility, the aggregates were broken down using a spatula. The total time required for complete dissolution of the API was 1 hour 17 minutes and 1 hour 40 minutes for low and high doses, respectively. II. Rapid solidification of the molten preparation was observed at the pipette tip or on the outer surface of the pipette tip. Therefore, distribution had to be carried out quickly.

[0669] The process parameters for blend preparation and capsule filling are summarized in Table 19. [Table 24]

[0670] Content uniformity The results for 50 μg and 200 μg gelatin capsules (green / gray size 4 Quali-G PEG and white size 2 Quali-G PEG, respectively) are shown in Tables 20 and 21. The acceptable values ​​determined for both sets of capsules demonstrate good uniformity of content. [Table 25]

[0671] [Table 26]

[0672] Related substance analysis Ten red size 4 Quali-V (HPMC) capsules containing 50 μg of the active substance and ten green / gray size 4 Quali-G (PEG) capsules containing 50 μg of the active substance were analyzed by HPLC / UPLC according to the methodology described above. The HPMC capsule shells (Quali-V) were observed to produce chromatographic peaks with the same relative retention time as the potential peroxide degradation peaks. Strong peaks from the HPMC capsules (including the placebo capsules) were observed to dissolve at approximately 1 to 4 minutes, thus potentially interfering with the detection of these potential degradation products. It is noteworthy that the gelatin capsules did not cause any interference at approximately 3.5 minutes (or at any actual dissolution time).

[0673] Furthermore, a new peak was detected in the active HPMC capsule after approximately 12 minutes of retention, but not in the placebo capsule. The concern is that this peak may increase further with storage. Therefore, the HPMC capsules were not tested further (i.e., they were not tested at the initial stage or were left in a stable state).

[0674] When capsules incubated at 60°C were incubated, a new peak in the chromatogram was observed at RRT 1.35. This peak was not observed during development or forced degradation studies and appeared to increase when capsules were incubated at 60°C in air or a nitrogen atmosphere. This peak was not present in capsules or vial samples not incubated at 60°C. The increase in this peak is shown in Figure 13 – the area increases with increasing incubation time and increases in air compared to nitrogen (<1% O2). This suggests that processing batches under nitrogen may help reduce the chemical degradation of the batch.

[0675] Stability study results Stability study results are shown in Tables 22, 23, 24, and 25. The dissolution profiles at the initial time point are shown in Figures 14 and 15; determined by dissolution in 0.1 M HCl and pH 6.8 phosphate buffer, all capsules released 85% of the active material by 15 minutes. [Table 27]

[0676] [Table 28]

[0677] [Table 29]

[0678] [Table 30]

[0679] Example 5 - Solubility Study The purpose of this study was to evaluate the solubility of N-(2-(tert-butyl)-1-((4,4-difluorocyclohexyl)methyl)-1H-benzimidazole-5-yl)ethanesulfonamide in many different excipients. Excipients in which the active ingredient was solubilized at ≥0.0125% w / w were evaluated for their compatibility with the active ingredient (see Example 6) and their solubility (see Example 7).

[0680] material The materials used in this study are summarized in Table 26. [Table 31]

[0681] methodology Preparation of a two-component semi-solid composition Two-component semi-solid compositions are summarized in Table 27.

[0682] A two-component semi-solid composition mixture was prepared as follows: I. After partitioning the semi-solid, it was melted overnight at approximately 60°C (PEG1500 and vitamin E TPGS) or approximately 80°C (PEG 6000). II.PEG 400 was added the following day as needed (when all semi-solids had melted). III. A two-component solvent mixture containing PEG 6000 was mixed at approximately 80°C, and the remaining two components were mixed at approximately 70°C until homogeneous. [Table 32]

[0683] Methodology for evaluating solubility: Table 28 summarizes the amounts of APIs and solvents used in the solubility studies (Parts 1 and 2). [Table 33]

[0684] If necessary, the semi-solid was melted overnight before use. The solubility of the API in the selected solvent was evaluated in two parts (Part 1 and Part 2 studies) as follows: i. Solvent aliquots were added to the pre-distributed API while mixing using a magnetic chisel and a stirrer. ii. The solvent temperature was maintained as follows: a. Single-component liquid: Room temperature (ambient) b. TPGS and PEG1500: Approximately 60°C c. Two-component solvent mixture containing PEG 6000 and PEG 6000: approximately 80°C iii. The solvent was mixed for a maximum of 1 hour between each aliquot addition. iv. The solvent was carefully visually inspected between aliquots. v. The addition of solvent was stopped in the following cases: a. If the API is completely dissolved, add aliquot 2 - (even if the API dissolves after aliquot 1, add aliquot 2) b. After adding all the solvent aliquots from Table 28 vi. The number of solvent aliquots added and the mixing time are summarized in Table 29. [Table 34] [Table 35]

[0685] result: Single-component liquid: Table 30 shows the liquid solvents used in the solubility study. From Part 1 of the study, the following can be noted: API exhibited the highest solubility in diethylene glycol monoethyl ether, where it was completely dissolved after the addition of the first aliquot. PEG 400, octanoic acid, propylene glycol monocaprylate, and Labrasol ALF dissolved the API after the addition of a second solvent aliquot. Propylene glycol dilaurate, polysorbate 20, and polysorbate 80 dissolved the API, but only after the addition of a third aliquot. • The remaining solvent was unable to dissolve the API, even after the third aliquot addition.

[0686] Regarding the solubility of Part 2, the following points should be noted: As in Part 1 of the solubility study, API exhibited the highest solubility in diethylene glycol monoethyl ether, octanoic acid, and propylene glycol monocaprylate, and dissolved in aliquots of only two solvents. To dissolve the API in PEG 400, polysorbate 20, polysorbate 80, propylene glycol dilaurate, and Labrasol ALF, four solvent aliquots were required. However: ○ Propylene glycol dilaurate, polysorbate 80, and polysorbate 20 had to be mixed overnight (approximately 15 hours) to dissolve the API. Regarding Labrasol ALF, the API dissolved after the addition of the third aliquot, and the solution remained clear after the addition of the fourth aliquot. However, after standing at ambient temperature for 5 days, precipitation of the API from the solution was observed during testing. [Table 36]

[0687] Single-component semi-solid Table 31 summarizes the single-component semi-solid solvents used in Parts 1 and 2 of the solubility study. Part 1 of the study presents the following observations: API exhibited the highest solubility in PEG 4000, Kolliphor HS15, Capmul 808G, and Gelucire 48 / 16 - API completely dissolved after the addition of the first aliquot. • PEG 6000, glyceryl monooleate, Gelucire 50 / 13, and Cremophore RH40 all dissolved the API after the addition of a second solvent aliquot. However: ○ In Gelucire 50 / 13, API precipitation was observed the following day. ○ Cremophore RH40 had to be mixed overnight (approximately 15 hours) after the addition of the second aliquot to dissolve the API. The remaining solvents (sorbitan palmitate and glyceryl palmitostearate) were unable to dissolve the API even after the addition of a third aliquot.

[0688] In the second part of the study, the following observations can be presented: Unlike in Part 1 of the solubility study, API exhibited the highest solubility in PEG 6000. Furthermore, API showed higher solubility in Gelucire 50 / 13 in Part 2 compared to Part 1. The higher solubility observed in Part 2 compared to Part 1 may be due to the smaller volume of this highly viscous solvent. Using this smaller volume: • Heat is more likely to spread more evenly throughout the mixture (less chance of cold spots in a viscous fluid). • The mixing energy per unit volume is higher, allowing for improved fluid dynamics for API dissolution. When working with semi-solids that have high melting points and high viscosity, such as PEG 6000 and Gelucire 50 / 13, controlled temperature and effective mixing are extremely important. The solvents requiring two aliquots to dissolve the API were PEG 4000, Cremophore RH40, Kolliphore HS15, and glyceryl monooleate. ○ Creophor RH40 had to be mixed overnight to dissolve the API. To dissolve the API in Gelucire 50 / 13 and Capmul 808G, three aliquots of the solvent had to be added. To dissolve the API in Gelucire 48 / 16, four aliquots of the solvent were required. [Table 37]

[0689] Two-component solvent mixture Table 32 summarizes the solubility of APIs in two-component solvent mixtures. APIs showed high solubility in all two-component solvent mixtures for both Part 1 and Part 2. Except for PEG1500:TPGS(1:9) and PEG1500:PEG6000(1:9), APIs dissolved completely after the addition of the first solvent aliquot. Unexpectedly, the solubility of APIs in PEG1500:TPGS(1:9) was lower than that of all other two-component solvent mixtures. Three solvent aliquots were required to dissolve the API in Part 1, and two solvent aliquots were required in Part 2. However, the solubility of APIs in the 1:9 ratio PEG1500:TPGS solvent mixture was still acceptable. [Table 38]

[0690] conclusion In the case of semi-solid compositions, the API should have some degree of solubility in the excipients of the composition, and ideally, it should be completely soluble. Based on the expected dose of this drug, the excipients in which the API has sufficient solubility are: Octanoic acid, PEG 400, PEG 4000, PEG 6000, Cremophor RH40, Kolliphor HS15, Gelucire 50 / 13, Polysorbate 20, Gelucire 48 / 16, Polysorbate 80, Capmul 808G, Propylene glycol monocaprylate, Propylene glycol dilaurate, Diethylene glycol monoethyl, Glyceryl monooleate, PEG 400:PEG1500 (9:1), PEG 400:PEG1500 (1:1), PEG 400:PEG1500 (1:9), PEG1500:PEG 6000 (1:1), PEG1500:PEG 6000 (9:1), PEG1500:PEG These are 6000(1:9), PEG1500:TPGS(9:1), PEG1500:TPGS(1:1), and PEG1500:TPGS(1:9).

[0691] These solvent systems were further studied to determine their compatibility with APIs (see Example 6).

[0692] Example 6 - Excipient compatibility For the excipients tested in Example 5, in which the API was solubilized, samples of the excipients and API solutions were subjected to stability studies to determine whether the API was compatible with the excipients.

[0693] methodology Based on the results of Example 5, if the API was completely dissolved after the addition of aliquot 2 or 3, a sample of the API solution was taken for excipient compatibility.

[0694] Single replicas of dual-active samples and their placebo controls (without API) were placed in stations (-20°C, 25°C, and 40°C) for 14 and 28 days, respectively. The concentration of API in the excipients was 0.025% w / w. After the incubation period was complete, the samples were removed and placed in a freezer until LC testing was performed.

[0695] Conditions for the UPLC method: [Table 39]

[0696] result: Assay: The assay results are shown in Table 34. Most samples generally showed low assay values ​​of <85%, but very few samples showed even lower assay values ​​(<70%). A decrease in assay values ​​with incubation time and temperature suggests API-excipient incompatibility.

[0697] Apart from these cases, most assay values ​​remained consistently low throughout the study. This is attributed to insufficient extraction during sample preparation. The extraction method was optimized for PEG1500 and not for the other excipients studied here.

[0698] For propylene glycol monocaprylate, the API peak and the peak at RRT 0.93 were concatenated, and therefore, accurate assay results could not be determined. However, the UV spectrum of the API peak in the sample did not match that of the standard UV spectrum. Propylene glycol monocaprylate is incompatible with API.

[0699] When the solvent contained at least 50% PEG 400, PEG 400, PEG 400:PEG 1500 (9:1), and PEG 400:PEG 1500 (1:1) showed evidence of overall degradation (i.e., assay values ​​decreased significantly with time and temperature (lowest at 28 days at 40°C)).

[0700] Related substances: The related substances detected for each excipient API system are shown in Tables 35-59 below.

[0701] Due to retention time shifts during sequencing, some excipient peaks did not always perfectly align with the peaks in the active sample in the overlaid chromatogram. This is expected in excipient compatibility analysis. However, such retention time shifts were generally easily explainable.

[0702] The relevant substance peaks at RRT 0.96, 0.97, 1.02, and 1.03 / 1.04 are also present in the standard chromatogram. Each sample set is processed so that API integration matches the standard API peaks of its sequence. In some sample sets, the RRT 1.02 and / or 1.03 / 1.04 peaks are indistinguishable from the API peaks, and in some sets, the RRT 0.96 and / or 0.97 peaks are not sufficiently resolved, for example, due to interference from excipient peaks.

[0703] While all reported peaks are clearly identifiable from baseline, the reported area percentage of the relevant substance may be inaccurate if the sample has particularly low assay results (less than 50% of the nominal value), as it may not fall within the valid linearity range. This is acceptable for excipient compatibility analysis, as the results may still show a trend.

[0704] For some families, peaks were detected in samples tested at T=14 days but not at T=28 days. Since true degradation peaks are likely to show an increase in area from 14 to 28 days, these peaks are unlikely to be degradation peaks. Possible reasons for these occurrences are as follows: • Accidental contamination of vials during the LC dilution process (potentially not occurring within 28 days). • There is more baseline noise on the 28th than on the 14th. • Determine which API / excipient-related substance peaks are present at 14 and 28 days using different sequences and different placebo-control samples. For example, if an (excipient) peak is seen in the placebo-control sample at 28 days but not in the (freezing control) at 14 days, this may indicate that the excipient underwent thermal decomposition (at 40°C) on 28 days.

[0705] Conclusions regarding related substances: For polysorbate 20, Gelucire 50 / 13, Gelucire 48 / 16, Capmul 808G, propylene glycol monocaprylate, and propylene glycol dilaurate, there was no evidence of increase in the relevant substances with incubation time and temperature. However, it should be noted that all of these showed at least one peak (without clear dependence on time or temperature) that was not present in the corresponding placebo-controlled sample at the corresponding time.

[0706] When comparing the area of ​​relevant substances across all PEG grades for single-component solvents (see Tables 35-37), the following differences can be noted: PEG 400 showed several peaks that increased with incubation time and temperature: RRT 0.63, RRT 0.64, RRT 0.77, RRT 0.87, RRT 1.07, and RRT 1.08. The peaks at RRT 0.64 and RRT 0.77 had individual areas exceeding 1% after 28 days at 40°C. PEG 4000 showed the only peak (RRT 1.18) that increased with incubation time and temperature. However, this remained below 0.5% throughout. PEG 6000 showed two peaks that increased with incubation time and temperature: RRT 0.63 and RRT 1.65. However, these remained below 0.2% throughout.

[0707] For two-component samples with adjusted ratios of the two solvents, the following points can be noted: PEG1500 + Vitamin E TPGS: A faint peak (area NMT 0.3%) that increased with incubation time and temperature was detected in RRT 0.85 and RRT 0.86 / 0.87, and was observed in all of these samples stored at 25°C and 40°C for T=28 days. The area of ​​these peaks increased slightly with vitamin E TPGS content, suggesting a possible association with vitamin E TPGS. A pair of peaks were also detected between RRTs 1.61 and 1.65 (the exact RRTs for both peaks varied across the three sample families), and their area increased significantly with vitamin E TPGS content, reaching approximately 3% and 7% for the early and late elution peaks, respectively, after 28 days at 40°C for 1:9 PEG1500:TPGS, suggesting a correlation with vitamin E TPGS. Samples prepared with a 1:9 PEG1500:TPGS ratio showed additional peaks (RRT0.56, RRT0.69, RRT0.71, RRT0.82, and RRT1.20), which did not increase with time or temperature. These peaks were not observed with PEG:TPGS=9:1, suggesting they are likely related to TPGS and not to PEG1500.

[0708] PEG 400 + PEG 1500 Numerous peaks were detected (at least after 28 days at 40°C), and these increased with incubation time and temperature. See, for example, the peaks at RRT approximately 0.62, RRT approximately 0.63, RRT 0.77, RRT 0.89, RRT 1.06, and RRT 1.34. The area % of all these peaks tended to increase as the ratio of PEG 400 in the two-component mixture increased. See, for example, RRT 0.63 and 0.77.

[0709] For the PEG400:PEG1500 (9:1) and PEG400:PEG1500 (1:1) samples, the decrease in assay observed in samples stored at 40°C for 28 days appears to be related to an increase in the peaks of the relevant substances in these samples.

[0710] PEG1500 + PEG 6000 The peak in the low-area (less than 0.2% of the total) increased with incubation time and temperature in both families, but in different RRTs: In the 1:9 PEG1500:PEG 6000 ratio, the detected peaks were RRT 0.83 and RRT 0.85. In the 9:1 PEG1500:PEG 6000 assay, the detected peaks were RRT 0.61, RRT 0.62, and RRT 0.77.

[0711] Overall conclusion: For polysorbate 20, Gelucire 50 / 13, Gelucire 48 / 16, Capmul 808G, and propylene glycol dilaurate, there was no evidence of activator:API non-conformity with respect to incubation time and temperature. Consistent assays were determined for PEG 4000, PEG 6000, Cremophore RH40, Kolliphor HS15, polysorbate 80, octanoic acid, diethylene glycol monoethyl ether, PEG400:PEG1500 (1:9), PEG1500:PEG6000 (9:1), glyceryl monooleate, PEG1500:PEG6000 (1:9), PEG1500:TPGS (1:1), PEG1500:TPGS (9:1), and PEG1500:TPGS (1:9) using incubation time / temperature. The grade of PEG 400 used (alone or in combination with PEG1500 in 9:1 and 1:1 PEG400:PEG1500) resulted in decreased assay performance, and the relevant substance peaks did not conform to the API as incubation time / temperature increased. It is assumed that the grade of PEG400 used may contribute in part to the API incompatibility, and that ultra-purified grades of PEG400 may be compatible with the API, given that other PEG solvents have been demonstrated to be compatible with the API (see this example and Example 4). Using ultra-purified PEG may be advantageous for other PEGs (e.g., PEG1500, PEG4000, PEG6000), for example, by extending the shelf life of the product.

[0712] [Table 40] [Table 41]

[0713] [Table 42]

[0714] [Table 43]

[0715] [Table 44]

[0716] [Table 45]

[0717] [Table 46]

[0718] The difference in RRT 1.01 and RRT 1.04 peaks between T=initial and T=14 days, compared to T=28 days, is likely due to variations in the API peak integral between the two sequences.

[0719] [Table 47]

[0720] [Table 48]

[0721] [Table 49]

[0722] [Table 50]

[0723] Relevant substance data for both replications at 40°C and 14 days were consistent. However, significant placebo degradation was observed at T=28 days at 40°C compared to T=28 days at 25°C and T=initial. The additional peak at 40°C and 14 days is likely due to placebo degradation, but since there was no representative degraded placebo at 40°C and T=14 days, the peak could not be discounted at the time of analysis. [Table 51]

[0724] Relevant substance data for both replications at 40°C and 14 days were consistent. However, significant placebo degradation was observed at T=28 days at 40°C compared to T=28 days at 25°C and T=initial. The additional peak at 14 days at 40°C is likely due to placebo degradation, but since there was no representative degraded placebo at 40°C and T=14 days, the peak could not be discounted during analysis. [Table 52]

[0725] Table 53

[0726] Table 54

[0727] Table 55

[0728] Table 56

[0729] Table 57

[0730] Table 58

[0731] Table 59

[0732] Table 60

[0733] Table 61

[0734] Table 62

[0735] [Table 63]

[0736] [Table 64]

[0737] [Table 65]

[0738] [Table 66]

[0739] The first replication, performed at 25°C for 28 days, showed more peaks than the second replication, but fewer than the replication performed at 40°C for 28 days.

[0740] Example 7 - Capsule dissolution test Numerous capsules were prepared using a selection of solvents, and dissolution tests were conducted.

[0741] Part 1: Methodology: material The materials used in this study are summarized in Table 60. [Table 67]

[0742] Blend preparation The following blends were prepared: Blend A: Vitamin E 0.4% w / w API in TPGS • Blend B: 0.4% w / w API in PEG1500 • Blend C: 0.4% w / w API in PEG6000 • 0.4% w / w API in a blend of Ww:PEG1500:TPGS(1:1) • Blend Yy:PEG1500:TPGS(9:1) 0.4% w / w API • 0.4% w / w API in blend Zz:PEG1500:TPGS(1:9)

[0743] The blend composition and preparation process are summarized in Table 61. [Table 68]

[0744] API solutions Yy, Ww, and Zz were prepared as described in Example 5.

[0745] The API solution used for encapsulation was prepared as described below: I. The semi-solid was distributed as follows: a. The required amounts of PEG1500 and PEG6000 were dispensed and then melted at approximately 60°C (PEG1500) or approximately 80°C (PEG6000). b. Vitamin E TPGS was melted at approximately 60°C before dispensing the required amount. II. The API was added to the molten semi-solid and mixed until completely dissolved (approximately 60°C for PEG1500 and vitamin E TPGS, or 80°C for PEG 6000).

[0746] Encapsulation The API solution prepared above or in Example 5 was melted at 70-80°C (for the semi-solid containing PEG 6000) or 60-70°C (for the remaining semi-solid) for 30-60 minutes. The liquid solution was encapsulated at room temperature. The solution was encapsulated as follows: 1. A size 2 Profiller was loaded with 10 x size 2 Quali-G PEG capsules. 2. Using a pipette (set to dispense 0.49–0.51 g of blend), one aliquot of the molten blend was systematically filled into the capsules. 3. Next, the capsule was locked.

[0747] Analytical testing Dissolution was performed in two different dissolution media (n=2 per medium), 0.1 M HCl, and pH 6.8 phosphate buffer. For both dissolution media, the dissolution parameters were as follows: • Paddle (USP device II) · Media capacity 500mL • Paddle speed of 50 rpm and unlimited spin at 200 rpm. · Temperature 37±0.5℃ • Band sinker - O-ring inner diameter 6mm~7mm

[0748] result Blend preparation and encapsulation Three API solutions containing 0.4% w / w API were successfully prepared (in vitamin E TPGS, PEG 6000 and PEG 1500, and a mixture of vitamin E TPGS and PEG 1500). The APIs dissolved completely in the semi-solids in less than 2 hours for PEG 1500 and PEG 6000, and in less than 3 hours for vitamin E TPGS. All solutions were clear and appeared to be particle-free.

[0749] All six solutions were successfully filled into size 2 Quali-G capsules.

[0750] Melting: The dissolution data is shown in Figures 16 and 17. Figure 16 shows the raw dissolution profile data (average API dissolved from two capsules, expressed as a percentage of the nominal dose). This is then replotted as normalized data in Figure 17, where the raw data result at each sample point is expressed as a percentage of the average result at the final (60-minute) sample point.

[0751] With two exceptions, the dissolution data results at the final time (60 minutes) were within ±10% of the nominal API content of the capsule: • PEG1500 capsules in both media contained approximately 12-14% more API than the nominal amount. The capsule weight was very close to the target weight, and therefore there is no clear explanation for the higher percentage of API released. • PEG 6000 content in both media was approximately 30% lower than the nominal API content. The following are the potential causes of incomplete API release considered, followed by the conclusions of the investigation (in parentheses), and the underlying reasons for the situation: ○ Incorrect drug load in the blend (discount) - Upon checking the composition, it was found that the quantities were correct. ○ Capsule filling weight (discount) - The capsule weight was checked, and it was estimated that the filling weight was within ±10% of the target. ○ API degradation (considered highly unlikely) - PEG1500 (chemically similar to PEG 6000) was known to be compatible with APIs (see Example 4). ○ Incomplete breakdown of the PEG 6000 matrix (the only possible explanation) - PEG 6000 is likely to be translucent in the dissolution medium, making it difficult to notice any small undissolved residue in the amber dissolution container, and its high molecular weight likely slows down the breakdown of the matrix, i.e., reduces the final drug release at 60 minutes of testing.

[0752] All capsules, with the exception of PEG1500:TPGS 1:9 in a pH 6.8 medium where the released API increased by approximately 8% from 45 to 60 minutes, plateaued within ±2% of the final (60-minute) value at 45 minutes or earlier, consistent with PEG1500:TPGS 1:9 being the slowest-releasing capsule formulation.

[0753] (Based on normalized data) Capsules prepared from all API solutions showed a slower dissolution rate in pH 6.8 phosphate buffer than in 0.1 M HCl.

[0754] (Apart from the abnormality of PEG 6000 mentioned above), PEG1500:TPGS 1:9 capsules showed the slowest normalized drug release in pH 6.8 phosphate buffer, followed by TPGS capsules. This means that (apart from the abnormality of PEG 6000) the API solvent with the slowest erosion in the medium is vitamin E TPGS.

[0755] Part 2: Capsules were prepared using a variety of solvents, with concentrations of either 0.1% w / v or 0.4% w / v depending on the solubility of the API in the solvent. These capsules were analyzed by dissolution in 0.1 M HCl and pH 6.8 phosphate buffer (n=2).

[0756] Methodology: Thirteen sets of approximately 200 μg capsules, prepared with either a 0.1% or 0.4% API (dissolution), are encapsulated at a rate of one set per solvent. The blend composition is summarized in Table 62. [Table 69]

[0757] material Most of the materials required for capsule construction are already listed in Example 5. Additional materials are listed in Table 63. [Table 70]

[0758] Blend preparation The API solution was prepared as described in Example 5, and the API solution used for encapsulation was prepared as described below: I. In the case of semi-solid excipients, the API was added to the molten semi-solid and mixed until completely dissolved. II. In the case of excipients that were liquid at room temperature, the API was added at room temperature and mixed until completely dissolved.

[0759] Encapsulation API solutions were prepared as described above and in Example 5. Liquid solutions were encapsulated at room temperature, while semi-solid API solutions were melted at 70-80°C (for semi-solids containing PEG 6000) or 60-70°C (for the remaining semi-solids) for 30-60 minutes. All solutions were encapsulated as follows: a) A size 2 profiller was loaded with 10 x size 2 Quali-G PEG capsules. b) Using a pipette, one aliquot of the molten blend was systematically filled into the capsule. i) 0.245~0.255g - In the case of a 0.4% drug loading blend ii) 0.98~1.02g - In the case of a 0.1% drug challenge blend Set to distribute c) Next, the capsule was locked.

[0760] Analytical testing As in Part 1.

[0761] Results and Discussion Blend preparation and encapsulation: All solutions were clear and appeared to be particle-free. • All solutions were successfully filled into size 2 Quali-G capsules.

[0762] Melting: To facilitate comparison, we divide the dissolution profiles into two solvent groups: • Single excipient • A two-component mixture of excipients

[0763] The results were plotted as the average result of the two capsules tested for each solvent tested, and in all cases there was very good agreement between the results from the two individual capsules. Two representations of the same data are shown: • Dissolution is raw data calculated as a percentage of the nominal dose as dissolved API. • Normalized data where the results at each point in time are expressed as a percentage of the results at the end of the test (60 minutes).

[0764] The solubility profiles of single excipients are summarized in Figure 18 (raw data) and Figure 19 (normalized), and the solubility profiles of two-component mixtures are summarized in Figure 20 (raw data) and Figure 21 (normalized).

[0765] The dissolution plots are generally similar, with the following trends and differences: · All capsule batch plateaus plateaued within ±3% of their final (60-minute or 45-minute) values at or before 20 minutes. · All capsules completely disintegrated within the first 15 minutes of the dissolution test. · Gelucire 48 / 16 provided the slowest dissolution—it was the only capsule batch that did not reach its final release value at 45 minutes in both media. No slow disintegration of capsules was reported. · All capsule batches showed slower dissolution rates in pH 6.8 phosphate buffer than in 0.1 M HCl. · It might have been expected that the dissolution rate (and potentially also the disintegration rate) of API from PEG-based capsules would increase as the molecular weight of PEG decreases, that is, increase in the order of PEG 6000 < PEG 4000 < PEG 1500 < PEG 400. However, through the normalized dissolution data of the present study, no clear trend was observed between dissolution rate and any of the following: ○ Molecular weight of PEG in a single solvent system. ○ Proportion of higher molecular weight PEG in mixed solvent systems (PEG 400 + PEG 1500 or PEG 1500 + PEG 6000).

[0766] Overall conclusion: All prepared capsules released at least 75% of the API (normalized data) within 45 minutes of the dissolution test.

[0767] Example 7: Stability study of PEG 1500 in gelatin capsules containing 50 μg and 200 μg of N-(2-(tert-butyl)-1-((4,4-difluorocyclohexyl)methyl)-1H-benzimidazol-5-yl)ethanesulfonamide Capsules containing 50 μg or 200 μg of N-(2-(tert-butyl)-1-((4,4-difluorocyclohexyl)methyl)-1H-benzimidazole-5-yl)ethanesulfonamide in PEG1500 were prepared. Gelatin capsule shells were used (capsule composition and preparation according to Example 4). The capsules were stabilized at 25°C / 60%RH for 12 months and at 45°C / 75%RH for 6 months. The capsules were stored in 50 mL HDPE DUMA bottles with PP DUMA twist-off caps.

[0768] The results showed that the capsules met the specifications when stored at 25°C / 60%RH for at least 12 months.

[0769] The results also showed that the product met specifications even after being stored at 40°C / 75%RH for 3 months. Some results for the 50μg capsules at 6 months were out of specification (assay and lysis), which is thought to be due to the observation of residue on the capsules at this point.

[0770] result: exterior: [Table 71]

[0771] [Table 72]

[0772] Assay: [Table 73]

[0773] [Table 74]

[0774] Related substances: [Table 75] [Table 76]

[0775] [Table 77] [Table 78]

[0776] Melting: For dissolution plots of 50 μg and 200 μg, please refer to Figures 22-29.

[0777] Dissolve 0.1M HCl: [Table 79]

[0778] [Table 80]

[0779] Dissolved in phosphate buffer at pH 6.8 [Table 81]

[0780] [Table 82]

[0781] Uniformity of dosage units: [Table 83]

[0782] [Table 84]

[0783]

[0784] [Table 85]

[0785] Micro: [Table 86]

[0786] [Table 87]

[0787] Example 8: Clinical trial protocol: Phase 1 / 2 study of formulations containing (N-(2-(tert-butyl)-1-((4,4-difluorocyclohexyl)methyl)-1H-benzimidazole-5-yl)ethanesulfonamide (50 μg and 200 μg) in patients with cancer-related anorexia and weight loss. the purpose: Phase 1 Main purpose: • Examine the safety profile of the product in cancer patients with anorexia at different doses. • If present, measure dose-limiting toxicity within the dose range used during the first four weeks following the initial administration of the product. • Determine the most effective and safe dose to use in Phase 2 (recommended Phase 2 dose, or RP2D).

[0788] Secondary purpose: • Evaluate the product's activity in the patient population based on its effects on increasing lean body mass, weight gain, and improving loss of appetite. • Evaluate the patient's quality of life (QoL). • Determine the pharmacokinetic profile of the product in the patient population. • Evaluate changes in Karnovsky Performance Status (KPS).

[0789] Exploratory purpose: • Evaluate the anti-inflammatory and hormonal effects of the product. • Evaluate the impact on the mood of patients during clinical trials. • Assess the potential for product abuse. • Evaluate the opioid-saving effect of the product.

[0790] Phase 2 Main purpose: • Determine the point estimates of the product's activity in terms of improvement in weight gain, lean body mass, KPS, and anorexia at week 12 of RP2D.

[0791] Secondary purpose: • Continue evaluating the product's safety profile in cancer patients with anorexia. • Evaluate the patient's quality of life (QoL).

[0792] Exploratory purpose: • Evaluate the anti-inflammatory and hormonal effects of the product. • Evaluate the mood of patients during clinical trials. • Assess the potential for product abuse. • The physical activity of patients during the trial period is evaluated based on activity reported by a wearable physical activity monitor. • Evaluate the opioid-saving effect of the product.

[0793] Experimental design: Phase 1 dose escalation in Phase 1 to determine the dose for Phase 2 randomized, double-blind, placebo-controlled Phase 2 trial.

[0794] Experimental treatment: Phase 1 involved the product alone, while Phase 2 involved the product and placebo (4:1 randomization).

[0795] Dose-limiting toxicity: Dose-limiting toxicity refers to toxicity that occurs within the first four weeks of administration of the product and cannot be explained by the underlying malignancy, its treatment, comorbidities, or treatment: • Grade 3 or 4 myelotoxicity that does not decrease to grade 2 or lower within two weeks of onset, despite adequate supportive care. • Grade 3 or 4 non-hematological toxicity lasting more than 4 days despite appropriate supportive care, or failure to administer the next scheduled dose within 4 days of the scheduled date; Grade 3 fatigue must be present for more than 7 days to be considered a dose-limiting toxicity (DLT). • A single or series of adverse events of grade 2 that are unbearable in the patient's opinion. That is the case.

[0796] Phase 1 dose escalation: The dose levels are 150, 250, and 400 μg / dose / day. In the 400 μg / dose / day group, if no dose-limiting toxicity is observed over 4 weeks and a mean weight gain of at least 2% body weight is not achieved, a higher dose group up to 650 μg / dose / day can be explored in another 6 patients.

[0797] Phase 2 dosage and design: The RP2D is determined in Phase 1. Phase 2 is conducted randomized, double-blind, and placebo-controlled using the most active dose found in Phase 1. If the most active dose is not deemed safe, the next lowest dose is used. If the initial dose level exceeds the MTD, the principal investigator and medical monitor, with the sponsor's consent, may allow evaluation of lower dose levels. Assuming the minimum capsule size is limited to 50 μg, the possible dose levels are 50 or 100 μg. 25 patients will be randomized in a 4:1 (drug vs. placebo) ratio in Phase 2.

[0798] Number of patients: Assuming a screening failure rate of 15%, approximately 60 patients would agree to participate in the trial, and up to 49 evaluable patients (up to 24 in the first phase and up to 25 in the second phase) would receive the trial treatment.

[0799] Test population: Patients with certain cancers who are not receiving chemotherapy or are receiving certain treatments stably on a daily basis and have experienced a weight loss of more than 5% of their body weight in the past six months since signing the informed consent document (registration).

[0800] Selection criteria: 1. Cancer has been confirmed by pathological tissue diagnosis or cytological diagnosis (excluding cancers excluded by the exclusion criteria). 2. The person has a self-reported decrease or absence of appetite, or anorexia as determined by an aversion to food. 3. You have experienced unintentional weight loss exceeding 5% of your body weight in the past six months from the registration date. 4. The patient is in one of the following conditions: a. No chemotherapy was administered in the two weeks prior to registration, and no chemotherapy is expected for the first 12 weeks after the initial dose of the product (Phase 1), or, in Phase 2, no chemotherapy is expected after the start of product / placebo administration; or b. Stable daily administration starting two weeks prior to registration, and such treatment is expected to be given for an additional 12 weeks of hormone therapy for breast cancer, prostate cancer, or uterine cancer, or capecitabine monotherapy for breast cancer or colon cancer. 5. An estimated life expectancy of at least 12 weeks, as determined by the principal investigator based on clinical impression. It has a KPS of over 6.50. 7. Must be at least 18 years old at the time of registration. 8. Appropriate blood, renal, and hepatic function based on clinical laboratory values ​​obtained within 14 days of randomization: • Absolute neutrophil count ≥ 1.0 × 10⁹ / L · Platelets ≧75×109 / L • Serum creatinine level ≤ 1.5 times the upper limit of normal (ULN) in clinical laboratory tests. • Total serum bilirubin is ≤1.5 times the ULN (≤3.0 times the ULN if the patient is diagnosed with Gilbert's syndrome) • Aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (AP) levels were ≤2.5 times ULN. 9. For women of childbearing potential and men with childbearing potential partners, the patient must agree to use contraception during the treatment period and for six months after the last experimental treatment. 10. Before any assessment / procedure related to the examination, understand, voluntarily sign, and date the Informed Consent Document (ICD). 11. We are willing and able to comply with the test visit schedule and other protocol requirements. 12. Since the phototoxicity of the product has not been tested in animals, I intend to avoid sun exposure during treatment by using protective measures such as sunscreen, clothing, and sunglasses. 13. Known adverse events of the product include dizziness and somnolence. If an adverse event occurs, I agree not to operate or drive heavy machinery for at least the first four weeks of treatment.

[0801] Exclusion criteria: 1. Primary brain tumor or symptomatic brain metastasis. 2. Unable to swallow food or medication capsules. 3. Patients with oral mucositis or oral fungal infections that cause loss of appetite or taste disorders. 4. It causes obstruction of the gastrointestinal tract, or involves disorders that limit calorie absorption, such as intestinal obstruction or celiac disease. 5. Receiving enteral nutrition or parenteral nutrition. 6. You are taking, have taken, or are expected to take any medication that may cause loss of appetite or affect calorie intake within the four weeks prior to registration. Examples of such medications include any synthetic or natural cannabinoid (inhaled or administered by any other route) and megestrol. 7. Corticosteroids are acceptable if administered at a stable or tapering dose for two weeks prior to registration. Patients taking inhaled corticosteroids are permitted. 8. A medical history of reciprocal or illicit drug use, alcohol abuse, or other drug abuse. Current illicit drug use, or reciprocal or medicinal use of cannabinoids, is also excluded. 9. Known hypersensitivity to the API or its excipients. Provide the facility with a list of the product's ingredients before commencing Phase 1 of the protocol. Provide the facility with a list of the placebo's ingredients before commencing Phase 2. 10. Pregnant or breastfeeding. 11. Clinically significant depression requiring current use of antidepressants. 12. Non-cancerous conditions that may cause loss of appetite and / or weight loss, such as AIDS, chronic obstructive pulmonary disease, chronic kidney disease, heart failure, or pathological eating disorders. 13. Uncontrolled comorbidities, including but not limited to progressive or active infections requiring intravenous (IV) antibiotics, and mental / social conditions that limit compliance with examination requirements. 14. Major surgery performed within two weeks prior to registration. 15. A complication that, in the judgment of the principal investigator or medical monitor, impairs their ability to interpret data obtained from the trial. 16. Known human immunodeficiency virus infection, acute or chronic hepatitis B, or acute hepatitis C infection. 17. Clinically significant ascites requiring or expected to require paracentesis. 18. Corrected QT interval (QTc) interval calculated according to Fridericia's formula (QTcF) > 480ms. 19. The anticipated need for anticancer therapy in the two weeks prior to registration, the twelve weeks after the initial dose, or from the second stage product / placebo administration. (Continued use of the current daily dose anticancer therapy is permitted.) 20. The expected need for the investigational drug within 4 weeks prior to registration, or for the product, or for 12 weeks after the first dose of placebo in Phase 2. 21. The patient has received radiotherapy within two weeks of registration, or is expected to require radiotherapy within 12 weeks of registration. Short-term palliative radiotherapy for localized lesions is permitted.

[0802] Formulation: The 50 and 200 μg doses are as shown in Example 4. Summary of the evaluation: Safety is assessed based on physical examination, assessment of adverse events, vital signs, electrocardiogram, and results of hematological, chemical, and urinalysis tests. Pharmacokinetic parameters are evaluated. Activity is assessed by changes in lean body mass, body weight, body mass index, and degree of anorexia. In the second stage, physical activity is monitored using a wearable physical activity monitor. Potential drug abuse and opioid-saving effects are also assessed.

[0803] Statistical analysis: Descriptive statistics are used to describe demographics and measures of safety and efficacy for multiple dose groups and a second-stage placebo. Pharmacokinetics are described using a non-compartmental model. Comparative analysis trials conducted after trial data collection and unblinding are considered hypothesis generation studies.

[0804] Test evaluation criteria: Key evaluation criteria Safety: Analysis of the type, frequency, and severity of adverse drug reactions determined by reported adverse events (AEs), as well as evaluation of routine chemical and hematological tests, urinalysis, vital signs, and electrocardiogram. • Assessment of the type and incidence of dose-limiting toxicity (DLT). • The most effective and safe dose (RP2D) used in the second phase. Efficacy is primarily based on evaluation criteria for lean body mass and weight gain at week 4.

[0805] Secondary evaluation criteria: Activity: • Changes in body weight and lean body mass as determined by DEXA scan. • Changes in appetite as determined by a visual analog scale (VAS). • Quality of life (QoL) is assessed using the functional evaluation of the treatment for anorexia cachexia (FAACT), the patient-developed subjective global assessment (PG-SGA), the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C15-PAL, and the revised Edmonton Symptom Rating Scale (ESAS-r) questionnaire. • Changes in KPS.

[0806] Pharmacokinetics: • The pharmacokinetics of APIs in cancer-related anorexia will be determined by analyzing the blood concentrations of APIs and their metabolites over time.

[0807] Exploratory evaluation criteria: Anti-inflammatory: • Changes in sedimentation rate, C-reactive protein, and IL-6 levels. hormone: • Changes in thyroid-stimulating hormone (TSH), thyroxine (T4), luteinizing hormone (LH), and testosterone levels. feeling: • Mood changes as measured by Beck's Depression Inventory-II (BDI-II). Potential for abuse: • The potential for abuse is assessed by evaluating adverse events (AEs) that may suggest abuse, as well as by four VAS (Visual Analog Scale) scores for drug preference, euphoria, drug re-intake, and overall drug preference. Opioid-saving effect • Reduction in opioid use among patients taking opioid medications, as determined from patient diaries.

[0808] Phase 2 Key evaluation criteria Activity: • Weight and lean body mass changes determined by DEXA scan at week 12. • Changes in appetite as determined by the Visual Analog Scale (VAS) and the Facilitative Assessment of Appetite Complication (FAACT) questionnaire. • Changes in KPS.

[0809] Secondary outcome items Safety: • Evaluation of the product's safety profile by analyzing the type, frequency, and severity of adverse drug reactions, as determined by reporting of adverse events (AEs) and routine chemical and hematological tests, urinalysis, vital signs, and electrocardiogram evaluations. Quality of life: • Quality of life (QoL) is assessed using the functional assessment of the Anorexia Cachexia Therapy (FAACT), the Patient-Defined Subjective Global Assessment (PG-SGA), the EORTC QLQ-C15-PAL, and the Modified Edmonton Symptom Rating Scale (ESAS-r) questionnaire.

[0810] Exploratory evaluation items Anti-inflammatory: • Changes in sedimentation rate, C-reactive protein, and IL-6 levels. hormone: • Changes in TSH, T4, LH, and testosterone levels. feeling: • Mood changes as measured by the BDI-II. Potential for abuse • The potential...

Claims

1. A pharmaceutical composition for oral use comprising N-(2-(tert-butyl)-1-((4,4-difluorocyclohexyl)methyl)-1H-benzimidazole 5-yl)ethanesulfonamide as an active substance, or a pharmaceutically acceptable salt thereof, and a non-aqueous solvent for the active substance, (i) The pharmaceutical composition contains the active substance in an amount of about 0.001% to about 0.8% w / w relative to the weight of the total pharmaceutical composition, where the term "about" is used to include a variation of ±10% or less from a specific value. (ii) The pharmaceutical composition comprises at least 20% w / w of the non-aqueous solvent based on the weight of the total pharmaceutical composition, wherein the non-aqueous solvent comprises polyethylene glycol having an average molecular weight of 400 to 10,000 g / mol. The aforementioned pharmaceutical composition.

2. The pharmaceutical composition according to claim 1, wherein the active substance is dissolved in the non-aqueous solvent.

3. The pharmaceutical composition according to claim 1 or 2, wherein the pharmaceutical composition comprises at least two non-aqueous solvents for the active substance.

4. The pharmaceutical composition according to any one of claims 1 to 3, wherein the polyethylene glycol has an average molecular weight of 400 to 6000 g / mol, 1000 to 6000 g / mol, 1200 to 1800 g / mol, or 1400 to 1600 g / mol.

5. The pharmaceutical composition according to any one of claims 1 to 4, wherein the non-aqueous solvent is semi-solid at room temperature, and the pharmaceutical composition is semi-solid at room temperature.

6. The pharmaceutical composition according to any one of claims 1 to 5, wherein the pharmaceutical composition contains the active substance in an amount of 0.1 to 0.4% w / w relative to the weight of the entire pharmaceutical composition.

7. The pharmaceutical composition according to any one of claims 1 to 6, wherein the active substance is stable in the pharmaceutical composition for at least two weeks, one month, two months, three months, six months, twelve months, or twenty-four months.

8. The pharmaceutical composition according to any one of claims 1 to 7, wherein at least 75% of the total amount of the active substance contained in the pharmaceutical composition is released within the first 45 minutes when the pharmaceutical composition is subjected to an in vitro dissolution test using 0.1 M HCl or pH 6.8 phosphate buffer as the dissolution medium, and the dissolution profile is determined at 37°C using a rotation speed of 50 rpm as described in the United States Pharmacopeia.

9. The pharmaceutical composition according to any one of claims 1 to 8, wherein the active substance is homogeneously distributed throughout the non-aqueous solvent, and the active substance may remain homogeneously distributed throughout the non-aqueous solvent for at least two weeks, one month, two months, three months, six months, twelve months, or twenty-four months.

10. The pharmaceutical composition according to claim 9, wherein the homogeneous distribution of the active substance in the non-aqueous solvent is determined by an analytical method, the analytical method comprising determining the weight percentage of the active substance in a portion of the pharmaceutical composition, the weight percentage of the active substance in a portion of the pharmaceutical composition being ±5% of an estimated value based on the total amount of the active substance added to the total amount of the pharmaceutical composition.

11. A rapid-release pharmaceutical formulation for oral use comprising the pharmaceutical composition according to any one of claims 1 to 10.

12. When the aforementioned immediate-release pharmaceutical formulation is subjected to a uniformity test of formulation as described in the European Pharmacopoeia, the acceptable value is less than 15, and / or The aforementioned immediate-release pharmaceutical formulation is an immediate-release capsule formulation. The immediate-release pharmaceutical formulation according to claim 11.

13. A pharmaceutical composition according to any one of claims 1 to 10, or an immediate-release pharmaceutical formulation according to claim 11 or 12, for use as a pharmaceutical.

14. CB １ and / or CB ２ A pharmaceutical composition or immediate-release pharmaceutical formulation according to claim 13, for use in disease conditions or disorders in which receptor dysfunction is present or involved.

15. A pharmaceutical composition or immediate-release pharmaceutical formulation according to claim 13 or 14 for use in the treatment of conditions related to loss of appetite; conditions related to cachexia; or nervous anorexia.

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