Multiple particles

Abstract

The present disclosure relates to a plurality of granules containing 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 plurality of granules are suitable for use in a pharmaceutical composition. The pharmaceutical composition is suitable for use in the treatment of medical conditions in which treatment with an agonist of the CB1 / CB2 receptor is beneficial.

Description

【Technical Field】 【0001】 The present disclosure relates to a plurality of granules 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 plurality of granules are suitable for use in pharmaceutical compositions. The pharmaceutical compositions are suitable for use in the treatment of medical conditions where treatment with an agonist of the CB1 / CB2 receptor is beneficial. 【Background Art】 【0002】 N-(2-(tert-butyl)-1-((4,4-difluorocyclohexyl)methyl)-1H-benzimidazol-5-yl)ethanesulfonamide is a very potent, peripherally restricted synthetic dual cannabinoid agonist that targets the peripheral CB1 / CB2 receptor (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】 【0003】 Compound I and the synthetic route for preparing it were first disclosed in WO 2006 / 033631 A1 pamphlet. Compound I has been evaluated in several Phase I clinical trials as a potential treatment for pain. 【0004】 Cannabinoid agonists have potential uses in several clinical situations, including pain relief and cancer treatment (Cancer Prev Res (Phila). 2011 January;4(1):65-75). 【0005】 Furthermore, a number of cannabinoid agonists have been approved in the United States and other major markets for the treatment of cancer-related nausea and vomiting, and clinical trials are being conducted to evaluate the potential use of cannabinoids in cancer-related anorexia and cachexia. 【0006】 Compound I has been shown to stimulate appetite in a dose-dependent manner. Compound I acts peripherally on a portion of the endogenous cannabinoid system that stimulates hunger and does not produce CNS psychoactive 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 compositions that require very small amounts of the active substance can be difficult to manufacture because it can be difficult to achieve an acceptable level of uniformity of the contents. It is inevitable that the pharmaceutical composition has an acceptable uniformity of the contents in order to ensure that the patient receiving the pharmaceutical composition receives the intended dose. This is important from the perspectives of safety and efficacy. In the examples of the present invention, the minimum dose is expected to be as low as 50 μg. 【0008】 Because very small amounts of the active substance are required, problems can occur during mixing and formulation of the active substance, for example due to segregation, uniformity of the contents, and physical stability. The required small amount of the active substance must be uniformly distributed throughout the powder blend. This is particularly difficult when the active substance has poor flowability and / or is cohesive. 【0009】 In this case, an immediate-release pharmaceutical composition containing Compound I is also necessary to provide optimal absorption. 【0010】 Furthermore, Compound I is present in solution and is prone to decomposition when exposed to light. Refer to Example 1 in this specification. This poses a problem when considering a viable pharmaceutical composition of this active substance. The active substance needs to be stable during the manufacturing process of the pharmaceutical composition and preferably, the resulting composition should also be stable over a long period. 【0011】 The combination of the need for a low dose of Compound I and its instability in solution presents difficulties in developing an appropriate pharmaceutical composition. 【0012】 Therefore, an immediate-release oral dosage form of Compound I with good content uniformity and good physical and chemical stability during the manufacture of the pharmaceutical composition, preferably over a long period, is needed. 【0013】 This disclosure was devised with the above in mind. 【Summary of the Invention】 【Means for Solving the Problems】 【0014】 Disclosed herein are a number of granules comprising Compound I or a pharmaceutically acceptable salt thereof as an active substance, and a pharmaceutical composition comprising these a number of granules. 【0015】 According to a first aspect of the present disclosure, a. N-(2-(tert-butyl)-1-((4,4-difluorocyclohexyl)methyl)-1H-benzimidazol-5-yl)ethanesulfonamide or a pharmaceutically acceptable salt thereof; and b. a number of granules comprising at least one pharmaceutically acceptable excipient are provided. There is. 【0016】 According to a second aspect of the disclosure, a pharmaceutical composition comprising a number of granules as defined herein is provided. 【0017】 In a further aspect, there is a process for preparing a number of granules as defined herein, the process comprising: a. mixing a binder and a diluent together; b. injecting a primary granulation liquid into the mixture of step a and mixing until granules are formed; and c. drying the mixture of step b, wherein N-(2-(tert-butyl)-1-((4,4-difluorocyclohexyl)methyl)-1H-benzimidazol-5-yl)ethanesulfonamide or a pharmaceutically acceptable salt thereof is mixed with the binder and diluent in step a or dissolved in the primary granulation liquid. 【0018】 In a further aspect, there is provided a pharmaceutical composition as defined herein for use as a medicament. 【0019】 The preferred, suitable and, where appropriate, the features of any one particular aspect of the present disclosure are also the preferred, suitable and, where appropriate, the features of any other aspect. 【0020】 For a better understanding of the present disclosure and to show how embodiments of the present disclosure may be carried out, reference is now made, by way of example, to the following drawings. 【Brief Description of the Drawings】 【0021】 【Figure 1】 Drug release from 50 μg of HPMC capsules (Quali-V) (TRI002 / 89G50-4A vs TRI002 / 89G50-4B) in 0.1 M HCl medium. 【Figure 2】 Drug release from 50 μg of HPMC capsules (Quali-V) (TRI002 / 89G50-4A vs TRI002 / 89G50-4B) in phosphate buffer at pH 6.8. 【Figure 3】 Drug release from n = 6 50 μg capsules (TRI002 / 89G50-4H) in 0.1 M HCl medium. 【Figure 4】Drug release from 50 μg capsules (TRI002 / 89G50-4H) with n = 3 in pH 6.8 medium. 【Figure 5】 Comparison of average drug release from 50 μg capsules (TRI002 / 89G50-4H) in 0.1 M HCl medium and pH 6.8 medium. 【Figure 6】 Drug release from 200 μg capsules (TRI002 / 89G200-2H) with n = 6 in 0.1 M HCl medium. 【Figure 7】 Drug release from 200 μg capsules (TRI002 / 89G200-2H) with n = 3 in pH 6.8 medium. 【Figure 8】 Average drug release from 200 μg capsules (TRI002 / 89G200-2H) in HCl medium and pH 6.8 medium. 【Mode for Carrying Out the Invention】 【0022】 Unless otherwise specified, the following terms used in the specification and claims have the following meanings as set forth below. 【0023】 The numerous particles, compositions, manufacturing processes, and methods disclosed can be more readily understood by reference to the following detailed description in conjunction with the accompanying drawings that form a part of this disclosure. The numerous particles, compositions, manufacturing processes, and methods disclosed are not limited to the specific numerous particles, compositions, manufacturing processes, and methods described and / or shown herein, and the terms used herein are for the purpose of describing only specific embodiments by way of example and are not intended to limit the numerous particles, compositions, manufacturing processes, and methods claimed. 【0024】 References to specific numerical values include at least that specific value unless the context clearly indicates otherwise. When a range of values is expressed, other embodiments include from one specific value and / or to another specific value. Further, references to values specified in a range include any value within that range. All ranges are inclusive and combinable. 【0025】 When values are expressed as approximations using the antecedent "about", specific values are understood to form separate embodiments. 【0026】 The term "about", when used with respect to a numerical range, cutoff, or specific value, is used to indicate that the recited value can vary by up to 10% from the recited value. Since many of the numerical values used herein are experimentally determined, one of ordinary skill in the art should understand that such determined values can, in many cases, vary between different experiments. The values used herein should not be regarded as unduly limited by this inherent variability. Thus, the term "about" is used to encompass variations of less than or equal to ±10%, less than or equal to ±5%, less than or equal to ±1%, less than or equal to ±0.5%, or less than or equal to ±0.1% from a particular value. 【0027】 It should be understood that the specific features of the numerous particles, compositions, manufacturing processes, and methods disclosed herein, which are described in the context of separate embodiments for clarity, may be provided in combination in a single embodiment. Conversely, the various features of the numerous particles, compositions, manufacturing processes, and methods disclosed herein, which are described in the context of a single embodiment for brevity, may be provided separately or in any subcombination. 【0028】 As used herein, the singular forms "a", "an", and "the" include the plural. 【0029】 The active substance is N-(2-(tert-butyl)-1-((4,4-difluorocyclohexyl)methyl)-1H-benzimidazol-5-yl)ethanesulfonamide (Compound I) or a pharmaceutically acceptable salt thereof. 【0030】 Throughout this specification, unless otherwise specified, references to the amount of the active substance are understood to refer to the amount of the parent compound on a free base basis, even when the compound is present as a salt of Compound 1. 【0031】 When an item is said to contain a defined component, this is taken to include items that contain one type of defined component, or a mixture of several types of defined components. For example, the item may contain at least one type, such as at least two types, at least three types, or at least four types of defined components. Suitably, the item contains one type of defined component, two types of defined components, three types of defined components or four types of defined components. 【0032】 When an item is said to contain a defined component (optionally in a defined amount or concentration), the item may contain further components other than those optionally defined. However, in certain embodiments, an item said to contain a defined component may in fact consist essentially of, or consist of, all of the defined components. 【0033】 As used herein, when an item is said to consist essentially of a particular component, the item suitably contains at least 70% by weight of the component, suitably at least 80% by weight of the component, suitably at least 90% by weight of the component, suitably at least 95% by weight of the component, most suitably at least 99% by weight of the component. Suitably, when an item is said to consist essentially of a particular component, it consists of the component, excluding one or more trace impurities. 【0034】 Room temperature is defined herein as a temperature of from about 15°C to about 25°C, such as from about 20°C to about 25°C. Suitably, room temperature is about 20°C. Suitably, room temperature is from 15°C to 25°C, such as from 20°C to 25°C. Suitably, room temperature is 20°C. 【0035】 References to "treating" or "treatment" should be understood to include prevention and alleviation of established symptoms of a condition. Thus, "treating" a condition, disorder or state means: (1) preventing or delaying the onset of clinical symptoms of a condition, disorder or state in a human who may or is likely to develop the condition, disorder or state but has not yet experienced or exhibited clinical or subclinical symptoms of the condition, disorder or state; (2) inhibiting the condition, disorder or state, or at least one clinical or subclinical symptom thereof, i.e., preventing, reducing or delaying the onset or recurrence (in the case of maintenance therapy) of the disease; or (3) alleviating or attenuating the disease, i.e., causing regression of at least one of the condition, disorder or state or its clinical or subclinical symptoms. 【0036】 As used herein, the expression "therapeutically effective amount" refers to the amount of a pharmaceutical composition comprising an active agent as described herein that is effective to achieve a particular biological or therapeutic result, such as, but not limited to, a biological or therapeutic result disclosed, described or exemplified herein. The therapeutically effective amount can vary according to factors such as the individual's disease state, age, sex, and weight, as well as the ability of the composition to elicit the desired response in the subject. Such results include, but are not limited to, reduction, remission, and / or regression of a benign or malignant disease, or prevention of the occurrence of a benign or malignant disease, determined by any means appropriate in the art. 【0037】 As used herein, "subject" includes vertebrates; mammals such as primates, humans, dogs, cattle, and horses; or domestic animals. 【0038】 A number of granules According to a first aspect of the disclosure: a. N-(2-(tert-Butyl)-1-((4,4-difluorocyclohexyl)methyl)-1H-benzimidazol-5-yl)ethanesulfonamide or a pharmaceutically acceptable salt thereof; and b. A plurality of granules are provided, comprising at least one pharmaceutically acceptable excipient. 【0039】 Advantageously, the plurality of granules are formed using a wet granulation process (see examples). The wet granulation process facilitates the uniform distribution of the active substance throughout the plurality of granules, which is important from the perspective of patient safety to ensure that the intended amount of the active substance is present in a given portion of the plurality of granules, for example, in a pharmaceutical composition comprising a portion of the plurality of granules. 【0040】 Suitably, the pharmaceutically acceptable excipient is selected from diluents, disintegrants, and binders. 【0041】 Suitably, the plurality of granules comprise a diluent. Suitably, the plurality of granules comprise a binder. Suitably, the plurality of granules comprise a disintegrant. 【0042】 Suitably, the plurality of granules comprise a diluent and a binder. 【0043】 Suitably, the plurality of granules comprise a diluent, a binder, and a disintegrant. 【0044】 Suitably, N-(2-(tert-butyl)-1-((4,4-difluorocyclohexyl)methyl)-1H-benzimidazol-5-yl)ethanesulfonamide or a pharmaceutically acceptable salt thereof is present in the plurality of granules in an amount of less than 0.5% w / w, for example, less than 0.4% w / w, less than 0.3% w / w, less than 0.2% w / w, less than 0.15% w / w, less than 0.14% w / w, less than 0.13% w / w, less than 0.12% w / w, less than 0.11% w / w, less than 0.10% w / w, less than 0.08% w / w, less than 0.0% w / w, or less than 0.05% w / w of the total weight of the plurality of granules. 【0045】 Suitably, N-(2-(tert-butyl)-1-((4,4-difluorocyclohexyl)methyl)-1H-benzimidazol-5-yl)ethanesulfonamide or a pharmaceutically acceptable salt thereof is present in a number of granules in an amount of about 0.01% w / w to about 0.5% w / w of the total weight of the number of granules, for example, about 0.01% w / w to about 0.4% w / w, about 0.01% w / w to about 0.3% w / w, about 0.01% w / w to about 0.2% w / w, about 0.01% w / w to about 0.15% w / w, about 0.01% w / w to about 0.12% w / w, about 0.02% w / w to about 0.12% w / w, or about 0.03% w / w to about 0.10% w / w. 【0046】 Suitably, N-(2-(tert-butyl)-1-((4,4-difluorocyclohexyl)methyl)-1H-benzimidazol-5-yl)ethanesulfonamide or a pharmaceutically acceptable salt thereof is present in a number of granules in an amount of about 0.04, about 0.10, or about 0.12% w / w of the total weight of the number of granules. 【0047】 Suitably, the diluent is present in a number of granules in an amount of at least 70% w / w of the total weight of the number of granules, for example, at least 75% w / w, 80% w / w, 85% w / w, or 90% w / w. 【0048】 Suitably, the diluent is present in a number of granules in an amount of about 75% w / w to about 98% w / w of the total weight of the number of granules, for example, about 85% w / w to about 98% w / w, or about 90% w / w to about 95% w / w. 【0049】 Suitably, the diluent is present in a number of granules in an amount of about 93% w / w of the total weight of the number of granules. 【0050】 Suitably, the binder is present in a number of granules in an amount of at least 0.5% w / w of the total weight of the number of granules, for example, at least 1% w / w or 2% w / w. 【0051】 Suitably, the binder is present in the plurality of granules in an amount of from about 0.5% w / w to about 5% w / w, for example from about 1% w / w to about 4% w / w or from about 2% w / w to about 3% w / w, based on the total weight of the plurality of granules. 【0052】 Suitably, the binder is present in the plurality of granules in an amount of about 2.5% w / w, based on the total weight of the plurality of granules. 【0053】 Suitably, the disintegrant is present in the plurality of granules in an amount of at least 0.5% w / w, for example at least 1% w / w, 2% w / w, or 3% w / w, based on the total weight of the plurality of granules. 【0054】 Suitably, the disintegrant is present in the plurality of granules in an amount of from about 1% w / w to about 10% w / w, for example from about 2% w / w to about 6% w / w or from about 3% w / w to about 5% w / w, based on the total weight of the plurality of granules. 【0055】 Suitably, the disintegrant is present in the plurality of granules in an amount of about 4% w / w, based on the total weight of the plurality of granules. 【0056】 Suitably, the plurality of granules: a. less than 0.5% w / w of N-(2-(tert-butyl)-1-((4,4-difluorocyclohexyl)methyl)-1H-benzimidazol-5-yl)ethanesulfonamide or a pharmaceutically acceptable salt thereof; b. at least 70% w / w of a diluent; and c. contain at least 0.5% w / w of a binder, these weights being relative to the total weight of the plurality of granules. 【0057】 Suitably, the plurality of granules: a. less than 0.5% w / w of N-(2-(tert-butyl)-1-((4,4-difluorocyclohexyl)methyl)-1H-benzimidazol-5-yl)ethanesulfonamide or a pharmaceutically acceptable salt thereof; b. at least 70% w / w of a diluent; c. At least 0.5% w / w of a binder; and d. At least 0.5% w / w of a disintegrant, these weights being relative to the total weight of the plurality of granules. 【0058】 Suitably, the plurality of granules are: a. Less than 0.15% w / w of N-(2-(tert-butyl)-1-((4,4-difluorocyclohexyl)methyl)-1H-benzimidazol-5-yl)ethanesulfonamide or a pharmaceutically acceptable salt thereof; b. At least 70% w / w of a diluent; c. At least 0.5% w / w of a binder; and d. At least 1% w / w of a disintegrant, these weights being relative to the total weight of the plurality of granules. 【0059】 Suitably, the plurality of granules are: a. Less than 0.13% w / w of N-(2-(tert-butyl)-1-((4,4-difluorocyclohexyl)methyl)-1H-benzimidazol-5-yl)ethanesulfonamide or a pharmaceutically acceptable salt thereof; b. At least 80% w / w of a diluent; c. At least 1% w / w of a binder; and d. At least 1% w / w of a disintegrant, these weights being relative to the total weight of the plurality of granules. 【0060】 Suitably, the plurality of granules are: a. Less than 0.11% w / w of N-(2-(tert-butyl)-1-((4,4-difluorocyclohexyl)methyl)-1H-benzimidazol-5-yl)ethanesulfonamide or a pharmaceutically acceptable salt thereof; b. At least 90% w / w of a diluent; c. At least 1% w / w of a binder; and d. At least 1% w / w of a disintegrant, these weights being relative to the total weight of the plurality of granules. 【0061】 Preferably, a large number of granules are: a. N-(2-(tert-Butyl)-1-((4,4-difluorocyclohexyl)methyl)-1H-benzimidazol-5-yl)ethanesulfonamide or a pharmaceutically acceptable salt thereof at less than 0.05% w / w; b. at least 90% w / w of a diluent; c. at least 1% w / w of a binder; and d. at least 1% w / w of a disintegrant, where these weights are in weight % relative to the total weight of the large number of granules. 【0062】 Preferably, a large number of granules are: a. about 0.01% w / w to about 0.15% w / w of N-(2-(tert-Butyl)-1-((4,4-difluorocyclohexyl)methyl)-1H-benzimidazol-5-yl)ethanesulfonamide or a pharmaceutically acceptable salt thereof; b. about 85% w / w to about 98% w / w of a diluent; c. about 2% w / w to about 3% of a binder; and d. about 2% w / w to about 6% w / w of a disintegrant, where these weights are relative to the total weight of the large number of granules. 【0063】 Preferably, a large number of granules are: a. about 0.04% w / w of N-(2-(tert-Butyl)-1-((4,4-difluorocyclohexyl)methyl)-1H-benzimidazol-5-yl)ethanesulfonamide or a pharmaceutically acceptable salt thereof; b. about 93% w / w of a diluent; c. about 2.5% w / w of a binder; and d. about 4% w / w of a disintegrant, where these weights are relative to the total weight of the large number of granules. 【0064】 Preferably, a large number of granules are: a. About 0.1% w / w of N-(2-(tert-butyl)-1-((4,4-difluorocyclohexyl)methyl)-1H-benzimidazol-5-yl)ethanesulfonamide or a pharmaceutically acceptable salt thereof; b. About 93% w / w of a diluent; c. About 2.5% w / w of a binder; and d. About 4% w / w of a disintegrant, these weights being relative to the total weight of a number of granules. 【0065】 Suitably, the number of granules is: a. About 0.12% w / w of N-(2-(tert-butyl)-1-((4,4-difluorocyclohexyl)methyl)-1H-benzimidazol-5-yl)ethanesulfonamide or a pharmaceutically acceptable salt thereof; b. About 93% w / w of a diluent; c. About 2.5% w / w of a binder; and d. About 4% w / w of a disintegrant, these weights being relative to the total weight of a number of granules. 【0066】 Suitably, the number of granules is: a. N-(2-(tert-butyl)-1-((4,4-difluorocyclohexyl)methyl)-1H-benzimidazol-5-yl)ethanesulfonamide or a pharmaceutically acceptable salt thereof; b. Mannitol; c. Hydroxypropylmethylcellulose; and d. Containing low-substituted hydroxypropylcellulose. 【0067】 Suitably, the number of granules is: a. About 0.01% w / w to about 0.15% w / w of N-(2-(tert-butyl)-1-((4,4-difluorocyclohexyl)methyl)-1H-benzimidazol-5-yl)ethanesulfonamide or a pharmaceutically acceptable salt thereof; b. About 85% w / w to about 98% w / w of mannitol; c. About 2% w / w to about 3% of hydroxypropylmethylcellulose; and d. containing about 2% w / w to about 6% w / w of low-substituted hydroxypropyl cellulose, these weights being relative to the total weight of a number of granules. 【0068】 Suitably, a number of granules further contain a lubricant. 【0069】 Suitably, the lubricant is present in a number of granules in an amount of at least 0.1% w / w, for example at least 0.5% w / w or 0.8% w / w, based on the total weight of the number of granules. 【0070】 Suitably, the lubricant is present in a number of granules in an amount of about 0.1% w / w to about 2% w / w, for example about 0.5% w / w to about 1.5% w / w, based on the total weight of the number of granules. 【0071】 Suitably, the lubricant is present in a number of granules in an amount of about 1% w / w based on the total weight of the number of granules. 【0072】 Suitably, a number of granules are: a. less than 0.5% w / w of N-(2-(tert-butyl)-1-((4,4-difluorocyclohexyl)methyl)-1H-benzimidazol-5-yl)ethanesulfonamide or a pharmaceutically acceptable salt thereof; b. at least 70% w / w of a diluent; c. at least 0.5% w / w of a binder; d. at least 0.5% w / w of a disintegrant; and e. containing at least 0.1% w / w of a lubricant, these weights being relative to the total weight of a number of granules. 【0073】 Suitably, a number of granules are: a. less than 0.15% w / w of N-(2-(tert-butyl)-1-((4,4-difluorocyclohexyl)methyl)-1H-benzimidazol-5-yl)ethanesulfonamide or a pharmaceutically acceptable salt thereof; b. at least 70% w / w of a diluent; c. At least 0.5% w / w of a binder; d. At least 1% w / w of a disintegrant; and e. At least 0.5% w / w of a lubricant, where these weights are relative to the total weight of the plurality of granules. 【0074】 Suitably, the plurality of granules are: a. About 0.01% w / w to about 0.15% w / w of N-(2-(tert-butyl)-1-((4,4-difluorocyclohexyl)methyl)-1H-benzimidazol-5-yl)ethanesulfonamide or a pharmaceutically acceptable salt thereof; b. About 85% w / w to about 98% w / w of a diluent; c. About 2% w / w to about 3% of a binder; d. About 2% w / w to about 6% w / w of a disintegrant; and e. About 0.5% w / w to about 1.5% w / w of a lubricant, where these weights are relative to the total weight of the plurality of granules. 【0075】 Suitably, the plurality of granules are: a. About 0.04% w / w of N-(2-(tert-butyl)-1-((4,4-difluorocyclohexyl)methyl)-1H-benzimidazol-5-yl)ethanesulfonamide or a pharmaceutically acceptable salt thereof; b. About 93% w / w of a diluent; c. About 2.5% w / w of a binder; d. About 4% w / w of a disintegrant; and e. About 1% w / w of a lubricant, where these weights are relative to the total weight of the plurality of granules. 【0076】 Suitably, the plurality of granules are: a. About 0.1% w / w of N-(2-(tert-butyl)-1-((4,4-difluorocyclohexyl)methyl)-1H-benzimidazol-5-yl)ethanesulfonamide or a pharmaceutically acceptable salt thereof; b. About 93% w / w of a diluent; c. About 2.5% w / w of a binder; d. about 4% w / w of a disintegrant; and e. about 1% w / w of a lubricant, these weights being relative to the total weight of the plurality of granules. 【0077】 Suitably, the plurality of granules are: a. N-(2-(tert-butyl)-1-((4,4-difluorocyclohexyl)methyl)-1H-benzimidazol-5-yl)ethanesulfonamide or a pharmaceutically acceptable salt thereof; b. mannitol; c. hydroxypropylmethylcellulose; d. low-substituted hydroxypropylcellulose; and e. sodium stearyl fumarate. 【0078】 Suitably, the plurality of granules are: a. about 0.01% w / w to about 0.15% w / w of N-(2-(tert-butyl)-1-((4,4-difluorocyclohexyl)methyl)-1H-benzimidazol-5-yl)ethanesulfonamide or a pharmaceutically acceptable salt thereof; b. about 85% w / w to about 98% w / w of mannitol; c. about 2% w / w to about 3% of hydroxypropylmethylcellulose; d. about 2% w / w to about 6% w / w of low-substituted hydroxypropylcellulose; and f. about 0.5% w / w to about 1.5% w / w of sodium stearyl fumarate, these weights being relative to the total weight of the plurality of granules. 【0079】 Suitably, the plurality of granules have an average size of less than 1200 μm, preferably less than 1000 μm. 【0080】 Suitably, the plurality of granules have an average size of 800 - 1200 μm, preferably 1000 - 1200 μm. 【0081】 Suitably, a number of granules as defined herein have a bulk density of from about 0.1 to about 0.7 g / mL, such as, for example, from about 0.2 to about 0.6 g / mL, or from about 0.3 to about 0.5 g / mL. Suitably, a number of granules as defined herein have a bulk density of about 0.4 g / mL. 【0082】 Pharmaceutical composition According to a second aspect of the present disclosure, there is provided an oral pharmaceutical composition comprising a number of granules as disclosed herein. 【0083】 Preferably, the pharmaceutical composition is an immediate release pharmaceutical composition. 【0084】 Suitably, the pharmaceutical composition consists essentially of a number of granules as disclosed herein. Suitably, the pharmaceutical composition consists of a number of granules as disclosed herein. 【0085】 Suitably, the pharmaceutical composition is a capsule or a tablet. 【0086】 Preferably, the pharmaceutical composition is a capsule. Suitably, the pharmaceutical composition comprises a capsule shell and a number of granules as defined herein. 【0087】 Suitably, the capsule shell comprises hydroxypropyl methylcellulose or gelatin. Suitably, the capsule shell comprises gelatin such as hard gelatin. Suitably, the capsule shell is a size 4 capsule shell. 【0088】 Suitably, the pharmaceutical composition is a tablet. Suitably, the tablet is formed by compressing a number of granules as defined herein. 【0089】 Suitably, the pharmaceutical composition comprises a plurality of granules as defined herein, the plurality of granules comprising from about 0.001 to about 0.8% w / w, such as from about 0.01 to about 0.8% w / w, from about 0.02 to about 0.2% w / w, or from about 0.03 to about 0.15% w / w of the active substance, based on their total weight. Suitably, the pharmaceutical composition comprises a plurality of granules as defined herein, the plurality of granules comprising from 0.001 to 0.8% w / w, such as from 0.01 to 0.8% w / w, from 0.02 to 0.2% w / w, or from 0.03 to 0.15% w / w of the active substance, based on their total weight. 【0090】 Suitably, the pharmaceutical composition comprises a plurality of granules as defined herein, the plurality of granules comprising about 0.1% w / w of the active substance, based on their total weight. Suitably, the pharmaceutical composition comprises a plurality of granules as defined herein, the plurality of granules comprising about 0.4% w / w of the active substance, based on their total weight. Suitably, the pharmaceutical composition comprises a plurality of granules as defined herein, the plurality of granules comprising 0.1% w / w of the active substance, based on their total weight. Suitably, the pharmaceutical composition comprises a plurality of granules as defined herein, the plurality of granules comprising 0.4% w / w of the active substance, based on their total weight. 【0091】 Suitably, there is provided an oral pharmaceutical composition comprising a plurality of granules as defined herein, the pharmaceutical composition comprising from about 10 μg to about 1000 μg, such as from about 10 μg to about 500 μg, from about 20 μg to about 500 μg, from about 30 μg to about 300 μg, or from about 40 μg to about 250 μg of the active substance. 【0092】 Suitably, there is provided an oral pharmaceutical composition comprising a plurality of granules as defined herein, the pharmaceutical composition comprising about 50 μg or about 200 μg of the active substance. 【0093】 Suitably, the pharmaceutical composition comprises a plurality of granules as defined herein, and the plurality of granules contains a diluent. Suitably, the diluent is present in an amount of at least 70% w / w, for example, at least 75% w / w, 80% w / w, 85% w / w, or 90% w / w of the total weight of the plurality of granules. 【0094】 Suitably, the diluent is present in the plurality of granules in an amount of about 75% w / w to about 98% w / w, for example, about 85% w / w to about 98% w / w or about 90% w / w to about 95% w / w of the total weight of the plurality of granules. 【0095】 Suitably, the diluent is present in the plurality of granules in an amount of about 93% w / w of the total weight of the plurality of granules. 【0096】 Suitably, the pharmaceutical composition comprises a plurality of granules as defined herein, and the plurality of granules contains a binder. Suitably, the binder is present in the plurality of granules in an amount of at least 0.5% w / w, for example, at least 1% w / w or 2% w / w of the total weight of the plurality of granules. 【0097】 Suitably, the binder is present in the plurality of granules in an amount of about 0.5% w / w to about 5% w / w, for example, about 1% w / w to about 4% w / w or about 2% w / w to about 3% w / w of the total weight of the plurality of granules. 【0098】 Suitably, the binder is present in the plurality of granules in an amount of about 2.5% w / w of the total weight of the plurality of granules. 【0099】 Suitably, the pharmaceutical composition comprises a plurality of granules as defined herein, and the plurality of granules contains a disintegrant. Suitably, the disintegrant is present in the plurality of granules in an amount of at least 0.5% w / w, for example, at least 1% w / w, 2% w / w, or 3% w / w of the total weight of the plurality of granules. 【0100】 Suitably, the disintegrant is present in a plurality of granules in an amount of about 1% w / w to about 10% w / w, for example, about 2% w / w to about 6% w / w or about 3% w / w to about 5% w / w of the total weight of the plurality of granules. 【0101】 Suitably, the disintegrant is present in a plurality of granules in an amount of about 4% w / w of the total weight of the plurality of granules. 【0102】 Suitably, there is provided an oral pharmaceutical composition comprising a plurality of granules as defined herein, and the pharmaceutical composition further comprises a lubricant. 【0103】 Suitably, the lubricant is present in the pharmaceutical composition in an amount of at least 0.1% w / w, for example, at least 0.5% w / w or 0.8% w / w of the total weight of the pharmaceutical composition. 【0104】 Suitably, the lubricant is present in the pharmaceutical composition in an amount of about 0.1% w / w to about 2% w / w, for example, about 0.5% w / w to about 1.5% w / w of the total weight of the pharmaceutical composition. 【0105】 Suitably, the lubricant is present in the pharmaceutical composition in an amount of about 1% w / w of the total weight of the pharmaceutical composition. 【0106】 Suitably, there is provided an oral pharmaceutical composition comprising a plurality of granules as defined herein, and the plurality of granules further comprises a lubricant. 【0107】 Suitably, the lubricant is present in a plurality of granules in an amount of at least 0.1% w / w, for example, at least 0.5% w / w or 0.8% w / w of the total weight of the plurality of granules. 【0108】 Suitably, the lubricant is present in a plurality of granules in an amount of about 0.1% w / w to about 2% w / w, for example, about 0.5% w / w to about 1.5% w / w of the total weight of the plurality of granules. 【0109】 Suitably, the lubricant is present in the plurality of granules in an amount of about 1% w / w of the total weight of the plurality of granules. 【0110】 Suitably, the pharmaceutical composition comprises a plurality of granules and a plurality of placebo granules as defined herein. 【0111】 The plurality of placebo granules comprises a binder and a diluent as defined herein for the plurality of granules. The plurality of placebo granules further comprises a disintegrant as defined herein for the plurality of granules. The plurality of placebo granules may further comprise a lubricant as defined herein for the plurality of granules. 【0112】 Suitably, the plurality of placebo granules are a plurality of granules in which no active substance is present. 【0113】 Suitably, the ratio of the plurality of granules to the plurality of placebo granules in the pharmaceutical composition is from 1:10 to 10:1, suitably from 1:5 to 10:1 or from 1:3 to 7:1. 【0114】 Suitably, the pharmaceutical composition comprises a plurality of granules, which plurality of granules: a. less than 0.5% w / w of N-(2-(tert-butyl)-1-((4,4-difluorocyclohexyl)methyl)-1H-benzimidazol-5-yl)ethanesulfonamide or a pharmaceutically acceptable salt thereof; b. at least 70% w / w of a diluent; and c. at least 0.5% w / w of a binder, these weights being relative to the total weight of the plurality of granules. 【0115】 Suitably, the pharmaceutical composition comprises a plurality of granules, which plurality of granules: a. less than 0.15% w / w of N-(2-(tert-butyl)-1-((4,4-difluorocyclohexyl)methyl)-1H-benzimidazol-5-yl)ethanesulfonamide or a pharmaceutically acceptable salt thereof; b. at least 70% w / w of a diluent; c. At least 0.5% w / w of a binder; and d. At least 1% w / w of a disintegrant, these weights being relative to the total weight of the plurality of granules. 【0116】 Suitably, the pharmaceutical composition comprises a plurality of granules, which plurality of granules: a. Less than 0.13% w / w of N-(2-(tert-butyl)-1-((4,4-difluorocyclohexyl)methyl)-1H-benzimidazol-5-yl)ethanesulfonamide or a pharmaceutically acceptable salt thereof; b. At least 80% w / w of a diluent; c. At least 1% w / w of a binder; and d. At least 1% w / w of a disintegrant, these weights being relative to the total weight of the plurality of granules. 【0117】 Suitably, the pharmaceutical composition: a. Less than 0.11% w / w of N-(2-(tert-butyl)-1-((4,4-difluorocyclohexyl)methyl)-1H-benzimidazol-5-yl)ethanesulfonamide or a pharmaceutically acceptable salt thereof; b. At least 80% w / w of a diluent; c. At least 1% w / w of a binder; and d. At least 1% w / w of a disintegrant, these weights being relative to the total weight of the plurality of granules. 【0118】 Suitably, the pharmaceutical composition comprises a plurality of granules, which plurality of granules: a. Less than 0.05% w / w of N-(2-(tert-butyl)-1-((4,4-difluorocyclohexyl)methyl)-1H-benzimidazol-5-yl)ethanesulfonamide or a pharmaceutically acceptable salt thereof; b. At least 90% w / w of a diluent; c. At least 1% w / w of a binder; and d. At least 1% w / w of a disintegrant, these weights being relative to the total weight of the plurality of granules. 【0119】 Suitably, the pharmaceutical composition comprises a plurality of granules, and the plurality of granules: a. less than 0.13% w / w of N-(2-(tert-butyl)-1-((4,4-difluorocyclohexyl)methyl)-1H-benzimidazol-5-yl)ethanesulfonamide or a pharmaceutically acceptable salt thereof; b. at least 80% w / w of a diluent; c. at least 1% w / w of a binder; d. at least 1% w / w of a disintegrant; and e. at least 0.5% w / w of a lubricant, and these weights are relative to the total weight of the plurality of granules. 【0120】 Suitably, the pharmaceutical composition comprises a plurality of granules, and the plurality of granules: a. less than 0.11% w / w of N-(2-(tert-butyl)-1-((4,4-difluorocyclohexyl)methyl)-1H-benzimidazol-5-yl)ethanesulfonamide or a pharmaceutically acceptable salt thereof; b. at least 80% w / w of a diluent; c. at least 1% w / w of a binder; d. at least 1% w / w of a disintegrant; and e. at least 0.5% w / w of a lubricant, and these weights are relative to the total weight of the plurality of granules. 【0121】 Suitably, the pharmaceutical composition comprises a plurality of granules, and the plurality of granules: a. less than 0.05% w / w of N-(2-(tert-butyl)-1-((4,4-difluorocyclohexyl)methyl)-1H-benzimidazol-5-yl)ethanesulfonamide or a pharmaceutically acceptable salt thereof; b. at least 90% w / w of a diluent; c. at least 1% w / w of a binder; d. at least 1% w / w of a disintegrant; and e. Containing at least 0.5% w / w of a lubricant, these weights being relative to the total weight of a large number of granules. 【0122】 Suitably, the pharmaceutical composition comprises a large number of granules, and this large number of granules: a. About 0.01% w / w to about 0.15% w / w of N-(2-(tert-butyl)-1-((4,4-difluorocyclohexyl)methyl)-1H-benzimidazol-5-yl)ethanesulfonamide or a pharmaceutically acceptable salt thereof; b. About 85% w / w to about 98% w / w of a diluent; c. About 2% w / w to about 3% of a binder; d. About 2% w / w to about 6% w / w of a disintegrant; and e. Containing about 0.5% w / w to about 1.5% w / w of a lubricant, these weights being relative to the total weight of a large number of granules. 【0123】 Suitably, the pharmaceutical composition comprises a large number of granules, and this large number of granules: a. About 0.04% w / w of N-(2-(tert-butyl)-1-((4,4-difluorocyclohexyl)methyl)-1H-benzimidazol-5-yl)ethanesulfonamide or a pharmaceutically acceptable salt thereof; b. About 93% w / w of a diluent; c. About 2.5% w / w of a binder; d. About 4% w / w of a disintegrant; and e. Containing about 1% w / w of a lubricant, these weights being relative to the total weight of a large number of granules. 【0124】 Suitably, the pharmaceutical composition comprises a large number of granules, and this large number of granules: a. About 0.1% w / w of N-(2-(tert-butyl)-1-((4,4-difluorocyclohexyl)methyl)-1H-benzimidazol-5-yl)ethanesulfonamide or a pharmaceutically acceptable salt thereof; b. About 92% w / w of a diluent; c. About 2.5% w / w of a binder; d. About 4% w / w of a disintegrant; and e. About 1% w / w of a lubricant, these weights being relative to the total weight of a large number of granules. 【0125】 Suitably, the pharmaceutical composition comprises a large number of granules, and this large number of granules: a. N-(2-(tert-Butyl)-1-((4,4-difluorocyclohexyl)methyl)-1H-benzimidazol-5-yl)ethanesulfonamide or a pharmaceutically acceptable salt thereof; b. Mannitol; c. Hydroxypropylmethylcellulose; and d. Low-substituted hydroxypropylcellulose. 【0126】 Suitably, the pharmaceutical composition comprises a large number of granules, and this large number of granules: a. N-(2-(tert-Butyl)-1-((4,4-difluorocyclohexyl)methyl)-1H-benzimidazol-5-yl)ethanesulfonamide or a pharmaceutically acceptable salt thereof; b. Mannitol; c. Hydroxypropylmethylcellulose; d. Low-substituted hydroxypropylcellulose; and e. Sodium stearyl fumarate. 【0127】 Suitably, the pharmaceutical composition comprises a large number of granules, and this large number of granules: a. About 0.01% w / w to about 0.15% w / w of N-(2-(tert-Butyl)-1-((4,4-difluorocyclohexyl)methyl)-1H-benzimidazol-5-yl)ethanesulfonamide or a pharmaceutically acceptable salt thereof; b. About 85% w / w to about 98% w / w of mannitol; c. About 2% w / w to about 3% of hydroxypropylmethylcellulose; d. About 2% w / w to about 6% w / w of low-substituted hydroxypropylcellulose; and e. containing about 0.5% w / w to about 1.5% w / w of sodium stearyl fumarate, these weights being relative to the total weight of a number of granules. 【0128】 Diluent The diluent expands the size of the granules / composition, making the manufacturing practical and user-friendly for consumers. 【0129】 Suitable diluents include, but are not limited to, calcium carbonate, calcium phosphate, dicalcium phosphate, tribasic calcium sulfate, calcium carboxymethylcellulose, dextrin derivatives, dextrin, dextrose, fructose, lactitol, lactose (e.g., anhydrous lactose, spray-dried lactose, α-lactose, β-lactose, Tablettose®, various grades of Pharmatose®, Microtose® or Fast-Floc®), lactose monohydrate mannitol, methylcellulose polymers such as Methocel A®, Methocel A4C®, Methocel A 15C®, Metocel A4M®, etc., hydroxyethylcellulose, hydroxypropylcellulose, L-hydroxypropylcellulose (low substitution), hydroxypropylmethylcellulose (HPMC) (e.g., Methocel E®, F and K, Shin-Etsu's Metolose SH®, several grades of Methocel F® and Metolose 65 SH®, 4,000, 15,000, and 100,000 cps grades of Methocel K®; and 4,000, 15,000, 39,000, and 100,000 grades of Metolose 90 SH®), sodium carboxymethylcellulose, carboxymethylene, carboxymethylhydroxyethylcellulose and other cellulose derivatives, starch or modified starch (including potato starch, wheat starch, corn starch, rice starch, pregelatinized corn starch), magnesium carbonate, magnesium oxide, maltitol, maltodextrin, maltose, mannitol, kaolin, sorbitol, starch, sucrose, sugar, xylitol, erythritol, isomalt, and mixtures thereof. 【0130】 Preferably, the diluent is mannitol. 【0131】 In one embodiment, the diluent is not microcrystalline cellulose. 【0132】 Binder The binder is used to impart cohesiveness and thus facilitate the formation of granules during the granulation process and their subsequent maintenance intact. 【0133】 Examples of binders include, but are not limited to, hydroxymethylcellulose, hydroxypropylcellulose, starches (including corn starch and pregelatinized starch), gelatin, saccharides (including sucrose, glucose, dextrose, lactose, and sorbitol), waxes, polyethylene glycol, natural and synthetic gums (such as acacia, tragacanth, sodium alginate, cellulose, and Veegum), and synthetic polymers such as polymethacrylate and polyvinylpyrrolidone (povidone), ethylcellulose, hydroxyethylcellulose, polyethylene oxide, carboxymethylcellulose, mannitol, methylcellulose, isomalt, polyvinyl alcohol, and mixtures thereof. 【0134】 Preferably, the binder is hydroxypropylmethylcellulose or povidone. More preferably, the binder is hydroxypropylmethylcellulose. 【0135】 Suitably, the hydroxypropylmethylcellulose is a 6 cps grade of hydroxypropylmethylcellulose. 【0136】 Disintegrant The disintegrant is a substance that aids in the decomposition of the composition when ingested. 【0137】 Disintegrants include, but are not limited to, cross-linked polyvinylpyrrolidone (crospovidone, polyplyplasdone XL (registered trademark), kollidon CL (registered trademark)); starches such as corn starch and sodium starch glycolate; gums such as corn starch and sodium starch glycolate; gums such as alginic acid, sodium alginate, and guar gum; croscarmellose sodium; microcrystalline cellulose, low-substituted hydroxypropyl cellulose, carboxymethyl cellulose, sodium bicarbonate, soy polysaccharides, and mixtures thereof. 【0138】 Preferably, the disintegrant is selected from low-substituted hydroxypropyl cellulose, sodium starch glycolate, and croscarmellose sodium. More preferably, the disintegrant is low-substituted hydroxypropyl cellulose. 【0139】 Low-substituted hydroxypropyl cellulose is as defined in the U.S. monograph. For example, when dried at 105°C for 1 hour, low-substituted hydroxypropyl cellulose contains 5.0% or more and 16.0% or less hydroxypropoxy groups (-OCH2CHOHCH3). 【0140】 Lubricant The lubricant prevents the components of the composition from aggregating and adhering to the tablet punches or capsule filling machines, and improves the fluidity of the mixture of the composition. 【0141】 Lubricants include, but are not limited to, sodium oleate, sodium stearate, sodium benzoate, sodium stearate, sodium chloride, stearic acid, sodium stearyl fumarate, calcium stearate, magnesium lauryl sulfate, sodium stearyl fumarate, sucrose esters or fatty acids, zinc, polyethylene glycol, talc, glyceryl behenate, and mixtures thereof. 【0142】 Preferably, the lubricant is sodium stearyl fumarate. 【0143】 In one embodiment, the lubricant is not magnesium stearate. 【0144】 Additional excipients in the pharmaceutical composition Optionally, the additional excipients may be included in a number of granules or pharmaceutical compositions according to the present disclosure. 【0145】 Suitably, the number of granules and / or pharmaceutical compositions further comprises preservatives such as colorants, sweeteners, flavors, and / or antioxidants. 【0146】 Suitably, the antioxidants include butylated hydroxyanisole, butylated hydroxytoluene, ascorbic acid, or α-tocopherol. 【0147】 Content uniformity of the active substance in the pharmaceutical composition Advantageously, the pharmaceutical composition has a low acceptance value for content uniformity. Thereby, the required amount of the active substance is guaranteed to be present in each unit of the pharmaceutical composition, and thereby, when the pharmaceutical composition is administered to a patient, the intended dose is guaranteed to be administered. This is important from the viewpoints of patient safety and efficacy. 【0148】 Suitably, when the pharmaceutical composition as defined herein is subjected to a content uniformity test as described in the European Pharmacopoeia, the acceptance value is less than 15. 【0149】 Suitably, the content uniformity test includes a chromatographic assay of the pharmaceutical composition. Suitably, the chromatographic assay includes HPLC. HPLC in this context includes UPLC. 【0150】 Advantageously, the active substance in the pharmaceutical composition is uniformly distributed and meets the regulatory requirements. Thereby, it is ensured that the intended amount of the active substance is present in each dosage unit of the pharmaceutical composition. This is important from the viewpoints of patient safety and efficacy. 【0151】 Suitably, the content uniformity test of the European Pharmacopoeia is 2.9.40. 【0152】 Properly, the content uniformity test involves determining the amount of the active substance in the pharmaceutical composition. Properly, the amount of the active substance in the pharmaceutical composition is determined using a chromatography method. Properly, the chromatography method is the HPLC method. Properly, the HPLC method includes a UV detector. Properly, the UV detector measures the assay of the active substance at about 217 nm. 【0153】 Properly, the HPLC method is a reverse-phase HPLC method. Properly, the reverse-phase HPLC method includes two eluents, and the ratio of the two eluents changes during the HPLC analysis. Properly, the first eluent contains water, and the second eluent contains acetonitrile. Properly, the first eluent contains water and phosphoric acid, and the second eluent contains acetonitrile. Properly, the first eluent contains water and 0.1% phosphoric acid, and the second eluent contains acetonitrile. 【0154】 Properly, the reverse-phase HPLC method includes an HPLC column. Properly, the HPLC column contains a C18 stationary phase. Properly, the HPLC column is at about 40 °C. Properly, the eluent flows through the HPLC column at about 0.5 mL / min. 【0155】 Properly, the chromatography method is a reverse-phase HPLC method, and the reverse-phase HPLC method is: a. A UV detector; b. An HPLC column; and c. It includes two eluents, and the ratio of the two eluents changes during the HPLC analysis. 【0156】 Properly, the pharmaceutical composition is added to a diluent, and the active substance is dissolved in the diluent. Properly, the diluent is 90:10 v / v 0.1 M HCl:acetonitrile. 【0157】 Properly, the acceptance value is determined using the following formula: AV = |M - X| + ks Where: X = the average of the individual contents (x1, x2....x3) expressed as a percentage of the quantity; k = acceptance constant. When n = 10, k = 2.4; when n = 30, 2.0 (n = sample size); s = sample standard deviation; M = reference value, where: In Example 1, when T ≤ 101.5: When 98.5% ≤ X ≤ 101.5%, M = X (therefore AV = ks) When X < 98.5%, M = 98.5% (therefore AV = 98.5 - X + ks) When X > 101.5%, M = 101.5% (therefore AV = X - 101.5 + ks) In Example 2, when T > 101.5: When 98.5% ≤ X ≤ T, M = X (therefore AV = ks) When X < 98.5%, M = 98.5% (therefore AV = 98.5 - X + ks) When X > T, M = T% (therefore AV = X - T + ks); and T = the target test sample amount during production. 【0158】 Release rate of the active substance from the pharmaceutical composition Suitably, the pharmaceutical composition is an immediate release pharmaceutical composition. 【0159】 Suitably, 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, at least about 75% of the total amount of the active substance contained in the pharmaceutical composition is released within the first about 45 minutes, and the dissolution profile is determined at about 37°C using a rotation speed of about 50 rpm. Suitably, 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, at least 75% of the total amount of the active substance contained in the pharmaceutical composition is released within the first 45 minutes, and the dissolution profile is determined at 37°C using a rotation speed of 50 rpm. 【0160】 Advantageously, such a release profile provides optimal absorption of the active substance when administered to a patient. 【0161】 Suitably, when the pharmaceutical composition is subjected to an in vitro dissolution test using 0.1M HCl or pH 6.8 phosphate buffer as the dissolution medium, at least about 75% of the total amount of the active substance contained in the pharmaceutical composition is released within the first about 30 minutes, and the dissolution profile is determined at about 37 °C using a rotation speed of about 50 rpm. Suitably, when the pharmaceutical composition is subjected to an in vitro dissolution test using 0.1M HCl or pH 6.8 phosphate buffer as the dissolution medium, at least about 75% of the total amount of the active substance contained in the pharmaceutical composition is released within the first 30 minutes, and the dissolution profile is determined at 37 °C using a rotation speed of 50 rpm. 【0162】 Suitably, when the pharmaceutical composition is subjected to an in vitro dissolution test using 0.1M HCl or pH 6.8 phosphate buffer as the dissolution medium, at least about 85% of the total amount of the active substance contained in the pharmaceutical composition is released within the first about 15 minutes, and the dissolution profile is determined at about 37 °C using a rotation speed of about 50 rpm. Suitably, when the pharmaceutical composition is subjected to an in vitro dissolution test using 0.1M HCl or pH 6.8 phosphate buffer as the dissolution medium, at least 85% of the total amount of the active substance contained in the pharmaceutical composition is released within the first 15 minutes, and the dissolution profile is determined at 37 °C using a rotation speed of 50 rpm. 【0163】 Suitably, the in vitro dissolution test comprises a container filled with about 500 mL of the dissolution medium, which is 0.1M HCl or pH 6.8 phosphate buffer. 【0164】 Suitably, the in vitro dissolution test is determined as described in the United States Pharmacopeia. 【0165】 Suitably, the in vitro dissolution test comprises a container filled with about 500 mL of the dissolution medium, which is 0.1M HCl or pH 6.8 phosphate buffer, and the dissolution profile is determined at about 37 °C using a rotation speed of about 50 rpm for the first about 45 minutes of the test and a rotation speed of about 200 rpm after about 45 minutes. 【0166】 Preferably, the in vitro dissolution test further comprises a sinker for the pharmaceutical composition. Preferably, the sinker is an O-ring sinker. 【0167】 Preferably, the in vitro dissolution test includes a detector. Preferably, the detector includes a UV detector. 【0168】 Preferably, 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 chromatography or UV spectroscopy. Preferably, the chromatography method is HPLC. Preferably, the HPLC method includes a UV detector. Preferably, the UV detector measures the assay of the active substance at about 217 nm. 【0169】 Preferably, the HPLC method is a reverse-phase HPLC method. Preferably, the reverse-phase HPLC method includes two eluents, and the ratio of the two eluents changes during the HPLC analysis. Preferably, the first eluent contains water, and the second eluent contains acetonitrile. Preferably, the first eluent contains water and phosphoric acid, and the second eluent contains acetonitrile. Preferably, the first eluent contains water and 0.1% phosphoric acid, and the second eluent contains acetonitrile. 【0170】 Preferably, the reverse-phase HPLC method includes an HPLC column. Preferably, the HPLC column includes a C18 stationary phase. Preferably, the temperature of the HPLC column is about 40 °C. Preferably, the eluent flows through the HPLC column at about 0.5 mL / min. 【0171】 Preferably, the chromatography method is a reverse-phase HPLC method, and the reverse-phase HPLC method is: a. A UV detector; b. An HPLC column; and c. Includes two eluents, and the ratio of the two eluents changes during the HPLC analysis. 【0172】 Stability of a plurality of granules and a pharmaceutical composition Suitably, the active substance is stable in the plurality of granules and / or the pharmaceutical composition. 【0173】 Preferably, the active substance is stable in the plurality of granules and / or during the shelf life of the pharmaceutical composition, for example, during the manufacture of the plurality of granules and / or the pharmaceutical composition, preferably until at least the pharmaceutical composition is administered to a patient. Stability is an important safety aspect of the pharmaceutical (the input substance, i.e., the plurality of granules and the pharmaceutical composition). Having stability throughout the manufacturing process for forming the product (granules and composition) means that the intended dose of the active substance is present in the manufactured product and the degradation products of the active substance are minimized. Further, a stable product results in a consistent assay of the active substance over a long period and minimal levels of degradation products. These factors enable consistent administration of the active substance to the patient, and as a result, the desired dose is administered to the patient. Further, the end user, e.g., the patient, is not administered the degradation products of the active substance. The stability of the active substance in the pharmaceutical composition is important from the viewpoints of patient safety and efficacy. 【0174】 Suitably, the active substance is stable during the process of preparing the plurality of granules and / or the pharmaceutical composition. <J 【0175】 Suitably, the assay of the active substance in the plurality of granules after manufacture is about 90% to about 110% of the nominal value, for example, about 95% to about 105% or about 98% to about 102% as determined by a chromatographic method. Suitably, the assay of the active substance in the pharmaceutical composition after manufacture is about 90% to about 110% of the nominal value, for example, about 95% to about 105% or about 98% to about 102% as determined by a chromatographic method. 【0176】 Suitably, the total amount of the degradation products of the active substance in the plurality of granules after manufacture is about 4 area% or less, for example, 3, 2, or 1 area% or less as determined by a chromatographic method. Suitably, the total amount of the degradation products of the active substance in the pharmaceutical composition after manufacture is about 4 area% or less, for example, 3, 2, or 1 area% or less as determined by a chromatographic method. 【0177】 Preferably, the active substance is stable in a plurality of granules and / or in a 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. Preferably, the active substance is stable in a plurality of granules and / or in a pharmaceutical composition for at least 2 weeks, 1, 2, 3, 6, 12, or 24 months. 【0178】 Preferably, the active substance is chemically stable in a plurality of granules and / or in a 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. Preferably, the active substance is chemically stable in a plurality of granules and / or in a pharmaceutical composition for at least 2 weeks, 1, 2, 3, 6, 12, or 24 months. 【0179】 Preferably, the active substance is stable in a plurality of granules 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 plurality of granules are stored at 25°C / 60%RH and / or 40°C / 75%RH. Preferably, the active substance is stable in a plurality of granules for at least 2 weeks, 1, 2, 3, 6, 12, or 24 months when the plurality of granules are stored at 25°C / 60%RH and / or 40°C / 75%RH. 【0180】 Preferably, the active substance is stable in a 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 stored at 25°C / 60%RH and / or 40°C / 75%RH. Preferably, the active substance is stable in a pharmaceutical composition for at least 2 weeks, 1, 2, 3, 6, 12, or 24 months when the pharmaceutical composition is stored at 25°C / 60%RH and / or 40°C / 75%RH. 【0181】 Suitably, the total amount of the degradation products of the active substance is about 4 area % or less, for example, 3, 2, or 1 area % or less as determined by chromatography when a large number of granules are 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. Suitably, the total amount of the degradation products of the active substance is 4 area % or less, for example, 3, 2, or 1 area % or less as determined by chromatography when a large number of granules are stored at 25°C / 60% RH and / or 40°C / 75% RH for 2 weeks, 1, 2, 3, 6, 12, or 24 months. 【0182】 Suitably, the total amount of the degradation products of the active substance is about 4 area % or less, for example, 3, 2, or 1 area % or less 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. Suitably, the total amount of the degradation products of the active substance is 4 area % or less, for example, 3, 2, or 1 area % or less 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. 【0183】 The degradation products of the active substance are impurities formed during storage of the active substance (or during manufacture of the pharmaceutical composition). The degradation products can be formed by exposure of the active substance to water, oxygen, peroxide, or ultraviolet light. 【0184】 Preferably, when a large number of granules are 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, the assay of the active substance is about 90% to about 110% of the nominal value, for example, about 95% to about 105% or about 98% to about 102% as determined by chromatography. Preferably, when a large number of granules are stored at 25°C / 60%RH and / or 40°C / 75%RH for 2 weeks, 1, 2, 3, 6 months, 12 months, or 24 months, the assay of the active substance is 90% to 110% of the nominal value, for example, about 95% to about 105% or about 98% to about 102% as determined by chromatography. 【0185】 Preferably, 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, the assay of the active substance is about 90% to about 110% of the nominal value, for example, about 95% to about 105% or about 98% to about 102% as determined by chromatography. Preferably, 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 months, or 24 months, the assay of the active substance is 90% to 110% of the nominal value, for example, about 95% to about 105% or about 98% to about 102% as determined by chromatography. 【0186】 Preferably, the total amount of the decomposition products of the active substance is about 4 area% or less as determined by chromatography, and the assay of the active substance is about 90% to about 110% of the nominal value as determined by chromatography when a large number of granules are 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 ...... months, or about 24 months. Preferably, the total amount of the decomposition products of the active substance is 4 area% or less, and the assay of the active substance is 90% to 110% of the nominal value as determined by chromatography when a large number of granules are stored at 25°C / 60%RH and / or 40°C / 75%RH for 2 weeks, 1, 2, 3, 6, 12, or 24 months. 【0187】 Preferably, the total amount of the degradation products of the active substance is about 4 area % or less as determined by chromatography, and the assay of the active substance is about 90 to about 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. Preferably, the total amount of the degradation products of the active substance is 4 area % or less, and the assay of the active substance is from 90 to 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 2 weeks, 1, 2, 3, 6, 12, or 24 months. 【0188】 Preferably, the active substance is stable in a large number of granules 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 a large number of granules are protected from light, preferably ultraviolet light. Preferably, the active substance is stable in a large number of granules for at least 2 weeks, 1, 2, 3, 6, 12, or 24 months when a large number of granules are protected from light, preferably ultraviolet light. 【0189】 Preferably, 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, preferably ultraviolet light. Preferably, 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, preferably ultraviolet light. 【0190】 Preferably, the chromatography method is the HPLC method. HPLC in this context includes UPLC. 【0191】 Preferably, the HPLC method includes a UV detector. Preferably, the UV detector measures the assay of the active substance and / or the degradation products at about 256 nm. 【0192】 Preferably, the HPLC method is a reverse-phase HPLC method. Preferably, the reverse-phase HPLC method includes two eluents, and the ratio of the two eluents changes during the HPLC analysis. Preferably, the first eluent contains water, and the second eluent contains acetonitrile. Preferably, the first eluent contains water and ammonium acetate, and the second eluent contains acetonitrile. Preferably, the first eluent contains water and 10 mM ammonium acetate, and the second eluent contains acetonitrile. 【0193】 Preferably, the reverse-phase HPLC method includes an HPLC column. Preferably, the HPLC column contains a C18 stationary phase. Preferably, the temperature of the HPLC column is about 40 °C. 【0194】 Preferably, the eluent flows through the HPLC column at about 0.3 mL / min. 【0195】 Preferably, the chromatography method is a reverse-phase HPLC method, and the reverse-phase HPLC method is: a. A UV detector; b. An HPLC column; and c. Two eluents, and the ratio of the two eluents changes during the HPLC analysis. 【0196】 Manufacturing process Preferably, a number of granules are prepared using a wet granulation method. The use of the wet granulation method for the preparation of a number of granules helps to ensure that the active substance is evenly distributed throughout the granules, so that the correct dose of the active substance is guaranteed to be present in the pharmaceutical composition. 【0197】 In a further aspect, a process for a number of granules is provided, and this process is: a. Mixing a binder and a diluent together; b. Injecting a primary granulation liquid into the mixture of step a and mixing until granules are formed; and c. A step of drying the mixture of step b is included, and N-(2-(tert-butyl)-1-((4,4-difluorocyclohexyl)methyl)-1H-benzimidazol-5-yl)ethanesulfonamide or a pharmaceutically acceptable salt thereof is mixed with a binder and a diluent in step a, or dissolved in a primary granulation liquid. 【0198】 Preferably, N-(2-(tert-butyl)-1-((4,4-difluorocyclohexyl)methyl)-1H-benzimidazol-5-yl)ethanesulfonamide or a pharmaceutically acceptable salt thereof is mixed with a binder and a diluent in step a. 【0199】 Preferably, N-(2-(tert-butyl)-1-((4,4-difluorocyclohexyl)methyl)-1H-benzimidazol-5-yl)ethanesulfonamide or a pharmaceutically acceptable salt thereof is dissolved in a primary granulation liquid. 【0200】 Preferably, step a further includes a step of mixing a disintegrant with a binder and a diluent. 【0201】 Preferably, N-(2-(tert-butyl)-1-((4,4-difluorocyclohexyl)methyl)-1H-benzimidazol-5-yl)ethanesulfonamide or a pharmaceutically acceptable salt thereof has a solubility of at least 0.6 mg / mL, for example, at least 7 mg / mL, in a primary granulation liquid at room temperature. 【0202】 Preferably, the primary granulation liquid is selected from ethanol, 0.1 M HCl, pH 3 citrate buffer, and 5% SLS aqueous solution. Advantageously, the active substance is stable in these primary granulation liquids and the solubility is >0.6 mg / mL. 【0203】 Preferably, the primary granulation liquid is 0.1 M HCl. 【0204】 Preferably, the primary granulation liquid is added at a rate of about 2 to about 10 mL / min, preferably about 4 to about 7 mL / min, more preferably about 5 to about 6 mL / min, in step b. 【0205】 Suitably, the mixture is mixed at high speed in step b. 【0206】 Suitably, the granules are dried at a high temperature in step c. Suitably, the high temperature is above 30°C, for example above 40°C, above 50°C. 【0207】 Suitably, this process further comprises adding a secondary granulation liquid to step b. Suitably, the secondary granulation liquid is selected from ethanol, 0.1M HCl, pH 3 citrate buffer, and 5% aqueous SLS solution. Preferably, the secondary granulation liquid is 0.1M HCl. 【0208】 Suitably, the secondary granulation liquid is added over at least 1 minute, for example at least 2 minutes, at least 5 minutes, or at least 8 minutes. 【0209】 Therapeutic uses and applications The present disclosure provides a pharmaceutical composition as defined herein for use as a medicament. 【0210】 The present disclosure provides a pharmaceutical composition as defined herein for use in therapy. 【0211】 The present disclosure provides the use of a pharmaceutical composition as defined herein for use in the manufacture of a medicament. 【0212】 The present disclosure provides a pharmaceutical composition as defined herein for use in a disease state or disorder in which there is a dysfunction of the CB1 and / or CB2 receptor or which exhibits such a dysfunction. 【0213】 The present disclosure provides a method of treating a disease state or disorder in which there is a dysfunction of the CB1 and / or CB2 receptor or which exhibits such a dysfunction, said method comprising administering to said patient a therapeutically effective amount of a pharmaceutical composition as defined herein. 【0214】 The present disclosure provides the use of a pharmaceutical composition as defined herein for use in the manufacture of a medicament for use in a disease state or disorder in which there is a deficiency in the function of the CB1 and / or CB2 receptor or which exhibits such a deficiency. 【0215】 The present disclosure provides a pharmaceutical composition for use in the treatment of an appetite-related condition; a cachexia-related condition; or anorexia nervosa. 【0216】 The present disclosure provides a method of treating an appetite-related condition, a cachexia-related condition, or anorexia nervosa, the method comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition as defined herein. 【0217】 The present disclosure provides the use of a pharmaceutical composition as defined herein for use in the manufacture of a medicament for the treatment of an appetite-related condition; a cachexia-related condition; or anorexia nervosa. 【0218】 Suitably, the appetite-related condition is appetite loss associated with cancer, appetite loss associated with HIV (human immunodeficiency virus), appetite loss associated with chronic kidney disease, appetite loss associated with dementia, or appetite loss associated with chronic congestive heart failure. 【0219】 Suitably, the appetite-related condition is appetite loss associated with cancer. 【0220】 Suitably, the cachexia-related condition is cachexia associated with cancer, cachexia associated with HIV, cachexia associated with chronic kidney disease, cachexia associated with dementia, or cachexia associated with chronic congestive heart failure. 【0221】 The present disclosure provides a pharmaceutical composition as defined herein for use in the treatment of a pain condition. 【0222】 The present disclosure provides a method of treating a pain condition in a patient in need of such treatment, the method comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition as defined herein. 【0223】 The present disclosure provides the use of a pharmaceutical composition as defined herein for use in the manufacture of a medicament for the treatment of a pain condition. 【0224】 Suitably, the pain condition is a pain condition in cancer, acute pain, chronic pain, neuropathic pain, low back pain, cancer pain, visceral pain, pain due to rheumatoid arthritis, migraine. Suitably, the pain condition in cancer is a pain condition in cancer associated with a reduction in opioid use and / or a reduction in nausea and / or vomiting in cancer patients. 【0225】 The present disclosure provides a pharmaceutical composition as defined herein for use in the treatment of an anxiety disorder, cancer, multiple sclerosis, Parkinson's disease, Huntington's disease, Alzheimer's disease, AIDS (acquired immunodeficiency syndrome), amyotrophic lateral sclerosis, gastrointestinal disorder, cardiovascular disorder, or insomnia. 【0226】 The present disclosure provides a method of treating an anxiety disorder, cancer, multiple sclerosis, Parkinson's disease, Huntington's disease, Alzheimer's disease, AIDS, amyotrophic lateral sclerosis, gastrointestinal disorder, cardiovascular disorder, or insomnia, the method comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition as defined herein. 【0227】 The present disclosure provides the use of a pharmaceutical composition as defined herein for use in the manufacture of a medicament for the treatment of an anxiety disorder, cancer, multiple sclerosis, Parkinson's disease, Huntington's disease, Alzheimer's disease, AIDS, amyotrophic lateral sclerosis, gastrointestinal disorder, cardiovascular disorder, or insomnia. 【0228】 The present disclosure provides a pharmaceutical composition as defined herein for use as an immunomodulatory agent. Suitably, the pharmaceutical composition as defined herein is for use in the treatment of autoimmune diseases such as arthritis, collagen diseases, or allergies. Suitably, the pharmaceutical composition as defined herein is for use in skin graft therapy, organ transplant therapy, and other surgical needs. Suitably, the pharmaceutical composition as defined herein is for use as an anti-tumor agent or an antiviral agent. 【0229】 The present disclosure provides a method for treating an autoimmune disease such as arthritis, collagen disease, or allergy, said method comprising administering to said patient a therapeutically effective amount of a pharmaceutical composition. The present disclosure provides a method of treatment in skin graft therapy, organ transplant therapy, and other surgical needs, said method comprising administering to said patient a therapeutically effective amount of a pharmaceutical composition as defined herein. 【0230】 The present disclosure provides the use of a pharmaceutical composition as defined herein for use in the manufacture of a medicament for use as an immunomodulatory agent. The present disclosure provides the use of a pharmaceutical composition as defined herein for use in the manufacture of a medicament for the treatment of autoimmune diseases such as arthritis, collagen diseases, or allergies. The present disclosure provides the use of a pharmaceutical composition as defined herein for use in the manufacture of a medicament for use in skin graft therapy, organ transplant therapy, and other surgical needs. The present disclosure provides the use of a pharmaceutical composition as defined herein for use in the manufacture of a medicament for use as an anti-tumor agent or an antiviral agent. 【0231】 The present disclosure provides a pharmaceutical composition as defined herein for use in the treatment of diarrhea; depression; anxiety and stress-related disorders; urinary incontinence; premature ejaculation; various mental disorders; cough; pulmonary edema; various gastrointestinal disorders; Parkinson's disease and other movement disorders; traumatic brain injury; stroke; cardioprotection after myocardial infarction; spinal cord injury and drug poisoning including the treatment of alcohol, nicotine, opioid, and other drug abuse; and disorders of the sympathetic nervous system such as hypertension. 【0232】 The present disclosure provides a method for treating diarrhea; depression; anxiety and stress-related disorders; urinary incontinence; premature ejaculation; various mental disorders; cough; pulmonary edema; various gastrointestinal disorders; Parkinson's disease and other movement disorders; traumatic brain injury; stroke; cardiac protection after myocardial infarction; spinal cord injury and drug poisoning including the treatment of alcohol, nicotine, opioid, and other drug abuse; and disorders of the sympathetic nervous system such as hypertension, the method comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition as defined herein. 【0233】 The present disclosure provides the use of a pharmaceutical composition as defined herein for the manufacture of a medicament for use in the treatment of diarrhea; depression; anxiety and stress-related disorders; urinary incontinence; premature ejaculation; various mental disorders; cough; pulmonary edema; various gastrointestinal disorders; Parkinson's disease and other movement disorders; traumatic brain injury; stroke; cardiac protection after myocardial infarction; spinal cord injury and drug poisoning including the treatment of alcohol, nicotine, opioid, and other drug abuse; and disorders of the sympathetic nervous system such as hypertension. 【0234】 Suitably, the anxiety and stress disorders are selected from post-traumatic stress disorder, panic disorder, generalized anxiety disorder, social phobia, and obsessive-compulsive disorder. 【0235】 Suitably, the gastrointestinal disorders are selected from constipation and functional gastrointestinal disorders such as irritable bowel syndrome and functional dyspepsia. 【0236】 The present disclosure provides a pharmaceutical composition as defined herein for use as an analgesic, for example, for use during general anesthesia and monitored anesthesia care. 【0237】 The present disclosure provides a method for providing an analgesic effect, for example, for use during general anesthesia and monitored anesthesia care, the method comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition as defined herein. 【0238】 The present disclosure provides the use of a pharmaceutical composition as defined herein for use in the manufacture of a medicament for use as an analgesic, for example, for use during general anesthesia and monitored anesthesia care. 【0239】 Combinations of agents with different properties are often used to achieve a balance of effects necessary to maintain an anesthetic state (e.g., amnesia, analgesia, muscle relaxation, and sedation). Such combinations include inhaled anesthetics, hypnotics, anxiolytics, neuromuscular blocking agents, and opioids. 【0240】 Accordingly, the present disclosure provides a method for activating CB1 and / or CB2 receptors in vitro or in vivo, the method comprising contacting a cell with an effective amount of a pharmaceutical composition as defined herein. 【0241】 The present disclosure also provides a method for treating a disease or disorder characterized by CB1 and / or CB2 receptor dysfunction in a patient in need of such treatment, the method comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition as defined herein. 【0242】 The therapeutically effective amount of a pharmaceutical composition comprising an active substance of the present disclosure for use in therapy is an amount that achieves certain biological or therapeutic results such as, but not limited to, those disclosed, described, or exemplified herein. For example, treating or preventing a disease or condition referred to herein delays its progression and / or reduces the symptoms associated with the condition and / or disease. 【0243】 The amount of the active substance combined with one or more excipients to produce a pharmaceutical composition will necessarily vary depending on the individual being treated and the particular route of administration. Immediate release compositions intended for oral administration to humans generally contain from about 10 μg to about 1000 μg (e.g., from about 10 μg to about 650 μg) of the active substance, formulated with a suitable convenient amount of excipient, which can vary from about 0.01 to about 99.99 weight percent of the total pharmaceutical composition. 【0244】 The size of the dose of the active substance for therapeutic or prophylactic purposes will vary naturally according to the nature and severity of the condition, the age and sex of the animal or patient, and the route of administration, in accordance with well-known medical principles. 【0245】 In one embodiment, Compound I at about 25 to about 700 μg / dose / day, such as about 50 to about 650 μg / dose / day, is administered to the patient. Suitably, Compound I at about 50, 150, 250, 400 or 650 μg / dose / day is administered to the patient. 【0246】 Route of administration The pharmaceutical composition as defined herein can be administered to the subject by any convenient oral route of administration (e.g., by oral ingestion). 【0247】 Combination therapy The pharmaceutical compositions of the present disclosure are useful for the treatment of conditions in which treatment with an agonist of CB1 and / or CB2 is beneficial. Examples of such conditions are outlined in the above Therapeutic Use section of the present disclosure. 【0248】 The pharmaceutical compositions of the present disclosure can be used in combination with one or more additional therapeutic agents for the treatment of the condition in question. 【0249】 The additional therapeutic agent can be included in a pharmaceutical composition comprising Compound I or a pharmaceutically acceptable salt thereof as defined herein, or alternatively, can be administered separately, simultaneously with, or before or after a pharmaceutical composition as defined herein. 【0250】 Accordingly, according to a further aspect of the present disclosure, there is provided a combination product comprising a pharmaceutical composition as defined herein and a pharmaceutical composition comprising an additional therapeutic agent useful in the treatment or prevention of any one of the therapeutic conditions referred to herein, wherein the pharmaceutical composition as defined herein and the pharmaceutical composition comprising the additional therapeutic agent are administered simultaneously, sequentially or separately. 【0251】 According to this aspect of the present disclosure, there is provided a combination for use in the treatment of a disease or condition (e.g., cancer anorexia) in which treatment with a CB1 and / or CB2 agonist is beneficial, the combination comprising a pharmaceutical composition of the present disclosure as previously defined herein, and one or more additional therapeutic agents. 【0252】 The present disclosure also provides a pharmaceutical composition as defined herein and one or more additional therapeutic agents for use in the treatment of anorexia, particularly cancer anorexia, the pharmaceutical composition and the additional therapeutic agent being administered simultaneously, sequentially or separately as defined herein. 【0253】 In certain embodiments, a pharmaceutical composition as defined herein can be used in the treatment of cancer anorexia in a patient undergoing cancer treatment. The cancer treatment can be in the form of radiotherapy, surgery, chemotherapy, immunotherapy or a combination thereof. 【0254】 As used herein, it should be understood that the term "combination" refers to simultaneous, separate or sequential administration. In one aspect of the invention, "combination" refers to simultaneous administration. In another aspect of the invention, "combination" refers to separate administration. According to a further aspect of the invention, "combination" refers to sequential administration. Where administration is sequential or separate, the delay in administration of the second component must not be such as to impair the beneficial effect of the combination. 【0255】 As noted above, the 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 a pharmaceutical composition as defined herein within the dosage ranges previously described herein and one or more additional pharmaceutically active agents, each of the additional agents being used within its approved dosage range. 【0256】 Specific aspects and embodiments of the present disclosure The following numbered paragraphs further define specific aspects and embodiments of the present disclosure. (1) A plurality of granules comprising: a. N-(2-(tert-Butyl)-1-((4,4-difluorocyclohexyl)methyl)-1H-benzimidazol-5-yl)ethanesulfonamide or a pharmaceutically acceptable salt thereof; and b. At least one pharmaceutically acceptable excipient, said plurality of granules. 【0257】 (2) The plurality of granules according to item 1, wherein the pharmaceutically acceptable excipient is selected from diluents, disintegrants, and binders. 【0258】 (3) The plurality of granules according to any one of the preceding items, comprising a diluent and a binder. 【0259】 (4) The plurality of granules according to any one of the preceding items, wherein N-(2-(tert-Butyl)-1-((4,4-difluorocyclohexyl)methyl)-1H-benzimidazol-5-yl)ethanesulfonamide or a pharmaceutically acceptable salt thereof is present in the plurality of granules in an amount of less than 0.5% w / w, for example, less than 0.4, 0.3, 0.2, 0.15, 0.14, 0.13, 0.12, 0.11, 0.10, 0.08, 0.06, or 0.05% w / w of the total weight of the plurality of granules. 【0260】 (5) The plurality of granules according to any one of the preceding items, wherein N-(2-(tert-Butyl)-1-((4,4-difluorocyclohexyl)methyl)-1H-benzimidazol-5-yl)ethanesulfonamide or a pharmaceutically acceptable salt thereof is present in the plurality of granules in an amount of about 0.01% w / w to about 0.5% w / w, for example, about 0.01% w / w to about 0.4% w / w, about 0.01% w / w to about 0.3% w / w, about 0.01% w / w to about 0.2% w / w, about 0.01% w / w to about 0.15% w / w, about 0.01% w / w to about 0.12% w / w, about 0.02% w / w to about 0.12% w / w, or about 0.03% w / w to about 0.10% w / w of the total weight of the plurality of granules. 【0261】 (6) N-(2-(tert-Butyl)-1-((4,4-difluorocyclohexyl)methyl)-1H-benzimidazol-5-yl)ethanesulfonamide or a pharmaceutically acceptable salt thereof is present in a number of granules in an amount of about 0.04, about 0.10, or about 0.12% w / w of the total weight of the number of granules, the number of granules according to any one of the preceding items. 【0262】 (7) The diluent is present in a number of granules in an amount of at least 70% w / w of the total weight of the number of granules, for example, at least 75, 80, 85, or 90% w / w, the number of granules according to items (2) to (6). 【0263】 (8) The diluent is present in a number of granules in an amount of about 75% w / w to about 98% w / w of the total weight of the number of granules, for example, about 85% w / w to about 98% w / w or about 90% w / w to about 95% w / w, the number of granules according to items (2) to (7). 【0264】 (9) The diluent is present in a number of granules in an amount of about 93% w / w of the total weight of the number of granules, the number of granules according to items (2) to (8). 【0265】 (10) The binder is present in a number of granules in an amount of at least 0.5% w / w of the total weight of the number of granules, for example, at least 1 or 2% w / w, the number of granules according to items (2) to (9). 【0266】 (11) The binder is present in a number of granules in an amount of about 0.5% w / w to about 5% w / w of the total weight of the number of granules, for example, about 1% w / w to about 4% w / w or about 2% w / w to about 3% w / w, the number of granules according to items (2) to (10). 【0267】 (12) The binder is present in a number of granules in an amount of about 2.5% w / w of the total weight of the number of granules, the number of granules according to items (2) to (11). 【0268】 (13) The plurality of granules according to any one of the preceding items, comprising a diluent, a disintegrant, and a binder. 【0269】 (14) The plurality of granules according to items (2) to (13), wherein the disintegrant is present in the plurality of granules in an amount of at least 0.5% w / w, for example, at least 1, 2, or 3% w / w of the total weight of the plurality of granules. 【0270】 (15) The plurality of granules according to items (2) to (14), wherein the disintegrant is present in the plurality of granules in an amount of about 1% w / w to about 10% w / w, for example, about 2% w / w to about 6% w / w or about 3% w / w to about 5% w / w of the total weight of the plurality of granules. 【0271】 (16) The plurality of granules according to items (2) to (14), wherein the disintegrant is present in the plurality of granules in an amount of about 4% w / w of the total weight of the plurality of granules. 【0272】 (17) The diluent is selected from calcium carbonate, calcium phosphate, dicalcium phosphate, tribasic calcium sulfate, calcium carboxymethylcellulose, dextrin derivatives, dextrin, dextrose, fructose, lactitol, lactose (e.g., anhydrous lactose, spray-dried lactose, α-lactose, β-lactose, Tablettose (registered trademark), various grades of Pharmatose (registered trademark), Microtose (registered trademark) or Fast-Floc (registered trademark)), lactose monohydrate mannitol, methylcellulose polymers such as Methocel A (registered trademark), Methocel A4C (registered trademark), Methocel A 15C (registered trademark), Metocel A4M (registered trademark), etc., hydroxyethylcellulose, hydroxypropylcellulose, L-hydroxypropylcellulose (low substitution), hydroxypropylmethylcellulose (HPMC) (e.g., Methocel E (registered trademark), F and K, Shin-Etsu's Metolose SH (registered trademark), several grades of Methocel F (registered trademark) and Metolose 65 SH (registered trademark), 4,000, 15,000, and 100,000 cps grades of Methocel K (registered trademark); and 4,000, 15,000, 39,000, and 100,000 grades of Metolose 90 SH (registered trademark)), sodium carboxymethylcellulose, carboxymethylene, carboxymethylhydroxyethylcellulose and other cellulose derivatives, starch or modified starch (including potato starch, wheat starch, corn starch, rice starch, pregelatinized corn starch), magnesium carbonate, magnesium oxide, maltitol, maltodextrin, maltose, mannitol, kaolin, sorbitol, starch, sucrose, sugar, xylitol, erythritol, isomalt, and mixtures thereof, and a number of granules according to items (2) to (16). 【0273】 (18) The number of granules according to item (17), wherein the diluent is mannitol. 【0274】 (19) The binder is selected from hydroxymethylcellulose, hydroxypropylcellulose, starch (including corn starch and pregelatinized starch), gelatin, saccharides (including sucrose, glucose, dextrose, lactose, and sorbitol), wax, polyethylene glycol, natural and synthetic gums (such as acacia, tragacanth sodium alginate, cellulose, and Veegum), and synthetic polymers such as polymethacrylate and polyvinylpyrrolidone (povidone), ethylcellulose, hydroxyethylcellulose, polyethylene oxide, carboxymethylcellulose, mannitol, methylcellulose, isomalt, polyvinyl alcohol, and mixtures thereof, the numerous granules according to items (2) to (18). 【0275】 (20) The binder is hydroxypropylmethylcellulose or povidone, the numerous granules according to item (19). 【0276】 (21) The binder is hydroxypropylmethylcellulose, the numerous granules according to item (20). 【0277】 (22) The binder is 6 cps grade hydroxypropylmethylcellulose, the numerous granules according to item (21). 【0278】 (23) The disintegrant is selected from crosslinked polyvinylpyrrolidone (crospovidone, polyplyplasdone XL (registered trademark), kollidon CL (registered trademark)); starch such as corn starch and sodium starch glycolate; gums such as corn starch and sodium starch glycolate; gums such as alginic acid, sodium alginate, and guar gum; croscarmellose sodium; microcrystalline cellulose, low-substituted hydroxypropylcellulose, carboxymethylcellulose, sodium bicarbonate, soy polysaccharides, and mixtures thereof, the numerous granules according to items (2) to (22). 【0279】 (24) The plurality of granules according to item (23), wherein the disintegrant is selected from low-substituted hydroxypropyl cellulose, sodium starch glycolate, and croscarmellose sodium. 【0280】 (25) The plurality of granules according to item (24), wherein the disintegrant is low-substituted hydroxypropyl cellulose. 【0281】 (26) The plurality of granules according to any one of the preceding paragraphs, wherein the bulk density of the granules is about 0.1 to about 0.7 g / mL, for example, about 0.2 to about 0.6 g / mL or about 0.3 to about 0.5 g / mL. 【0282】 (27) The plurality of granules of any one of the preceding paragraphs, further comprising a lubricant. 【0283】 (28) A large number of granules according to item (27), wherein the lubricant is selected from sodium oleate, sodium stearate, sodium benzoate, sodium stearate, sodium chloride, stearic acid, sodium stearyl fumarate, calcium stearate, magnesium lauryl sulfate, sodium stearyl fumarate, sucrose esters or fatty acids, zinc, polyethylene glycol, talc, glyceryl behenate, and mixtures thereof. 【0284】 (29) The plurality of granules according to item (28), wherein the lubricant is sodium stearyl fumarate. 【0285】 (30) The plurality of granules of any one of the preceding paragraphs, wherein the size of the granules is less than 1200 μm. 【0286】 (31) The plurality of granules of any one of the preceding paragraphs, wherein the active substance is stable in the plurality of granules. 【0287】 (32) The plurality of granules of any one of the preceding paragraphs, wherein the active substance is stable during the process of preparing the plurality of granules. 【0288】 (33) The assay of the active substance in a large number of granules after production is about 90 to about 110% of the nominal value, for example, about 95 to about 105% or about 98 to about 102% as determined by chromatography, for the large number of granules according to item (32). 【0289】 (34) The total amount of the decomposition products of the active substance in a large number of granules after production is about 4 area% or less, for example, 3, 2, or 1 area% or less as determined by chromatography, for the large number of granules according to item (32) or (33). 【0290】 (35) The active substance is chemically stable in a large number of granules 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, for the large number of granules according to items (31) to (34). 【0291】 (36) The total amount of the decomposition products of the active substance is about 4 area% or less, for example, 3, 2, or 1 area% or less as determined by chromatography when a large number of granules are 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, for the large number of granules according to item (35). [[ID=!13]] 【0292】 (37) The assay of the active substance is about 90 to about 110% of the nominal value, for example, about 95 to about 105% or about 98 to about 102% as determined by chromatography when a large number of granules are 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, for the large number of granules according to item (35) or (36). 【0293】 (38) An oral pharmaceutical composition containing the large number of granules according to items (1) to (37). 【0294】 (39) The pharmaceutical composition according to item (38), wherein the pharmaceutical composition consists essentially of the large number of granules according to items (1) to (37). 【0295】 It should be noted that there seems to be a misspelling in the original text where "!13" is present. It should likely be "13" for proper formatting. The translation has been done as accurately as possible based on the given text.(40) The pharmaceutical composition according to item (38), wherein the pharmaceutical composition consists of a large number of granules according to items (1) to (37). 【0296】 (41) The pharmaceutical composition according to item (38), wherein the pharmaceutical composition is a capsule or a tablet. 【0297】 (42) The pharmaceutical composition according to item (41), wherein the pharmaceutical composition is a capsule. 【0298】 (43) The pharmaceutical composition according to item (42), wherein the pharmaceutical composition contains a capsule shell. 【0299】 (44) The pharmaceutical composition according to item (43), wherein the capsule shell contains hydroxypropyl methylcellulose or gelatin. 【0300】 (45) The pharmaceutical composition according to item (44), wherein the capsule shell contains gelatin such as hard gelatin. 【0301】 (46) The pharmaceutical composition according to items (43) to (45), wherein the capsule shell is a size 4 capsule shell. 【0302】 (47) The pharmaceutical composition according to items (38) to (46), wherein the large number of granules contain from about 0.001 to about 0.8% w / w, for example, from about 0.01 to about 0.8% w / w, from about 0.02 to about 0.2% w / w, or from about 0.03 to about 0.15% w / w of the active substance based on their total weight. 【0303】 (48) The pharmaceutical composition according to items (38) to (47), wherein the large number of granules contain about 0.1% w / w of the active substance based on their total weight. 【0304】 (49) The pharmaceutical composition according to items (38) to (47), wherein the large number of granules contain about 0.4% w / w of the active substance based on their total weight. 【0305】 (50) The pharmaceutical composition according to items (38) to (49), wherein the pharmaceutical composition contains an active substance in an amount of about 10 μg to about 1000 μg, 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. 【0306】 (51) The pharmaceutical composition according to items (38) to (50), wherein the pharmaceutical composition contains an active substance in an amount of about 50 μg. 【0307】 (52) The pharmaceutical composition according to items (38) to (50), wherein the pharmaceutical composition contains an active substance in an amount of about 200 μg. 【0308】 (53) The pharmaceutical composition according to items (38) to (52), wherein a large number of granules contain a diluent. 【0309】 (54) The pharmaceutical composition according to item (53), wherein the diluent is present in a large number of granules in an amount of at least 70% w / w, for example, at least 75, 80, 85, or 90% w / w of the total weight of the large number of granules. 【0310】 (55) The pharmaceutical composition according to item (53), wherein the diluent is present in a large number of granules in an amount of about 75% w / w to about 98% w / w, for example, about 85% w / w to about 98% w / w or about 90% w / w to about 95% w / w of the total weight of the large number of granules. 【0311】 (56) The pharmaceutical composition according to items (52) to (55), wherein the diluent is present in a large number of granules in an amount of about 93% w / w of the total weight of the large number of granules. 【0312】 (57) The pharmaceutical composition according to items (38) to (56), wherein a large number of granules contain a binder. 【0313】 (58) The pharmaceutical composition according to item (57), wherein the binder is present in a large number of granules in an amount of at least 0.5% w / w, for example, at least 1 or 2% w / w of the total weight of the large number of granules. 【0314】 (59) The pharmaceutical composition according to item (57), wherein the binder is present in a number of granules in an amount of about 0.5% w / w to about 5% w / w, for example, about 1% w / w to about 4% w / w or about 2% w / w to about 3% w / w of the total weight of the number of granules. 【0315】 (60) The pharmaceutical composition according to items (57) to (59), wherein the binder is present in a number of granules in an amount of about 2.5% w / w of the total weight of the number of granules. 【0316】 (61) The pharmaceutical composition according to items (38) to (60), wherein a number of granules contain a disintegrant. 【0317】 (62) The pharmaceutical composition according to item (61), wherein the disintegrant is present in a number of granules in an amount of at least 0.5% w / w, for example, at least 1, 2, or 3% w / w of the total weight of the number of granules. 【0318】 (63) The pharmaceutical composition according to item (61), wherein the disintegrant is present in a number of granules in an amount of about 1% w / w to about 10% w / w, for example, about 2% w / w to about 6% w / w or about 3% w / w to about 5% w / w of the total weight of the number of granules. 【0319】 (64) The pharmaceutical composition according to items (61) to (63), wherein the disintegrant is present in a number of granules in an amount of about 4% w / w of the total weight of the number of granules. 【0320】 (65) The pharmaceutical composition according to items (38) to (64), wherein a number of granules contain a lubricant. 【0321】 (66) The pharmaceutical composition according to item (65), wherein the lubricant is present in a number of granules in an amount of at least 0.1% w / w, for example, at least 0.5 or 0.8% w / w of the total weight of the number of granules. 【0322】 (67) The pharmaceutical composition according to item (65), wherein the lubricant is present in a number of granules in an amount of about 0.1% w / w to about 2% w / w, for example, about 0.5% w / w to about 1.5% w / w of the total weight of the number of granules. 【0323】 (68) The pharmaceutical composition according to items (65) to (67), wherein the lubricant is present in a number of granules in an amount of about 1% w / w of the total weight of the number of granules. 【0324】 (69) The pharmaceutical composition according to items (53) to (68), wherein the diluent is selected from calcium carbonate, calcium phosphate, dicalcium phosphate, tribasic calcium sulfate, calcium carboxymethylcellulose, dextrin derivatives, dextrin, dextrose, fructose, lactitol, lactose (for example, anhydrous lactose, spray-dried lactose, α-lactose, β-lactose, Tablettose (registered trademark), various grades of Pharmatose (registered trademark), Microtose (registered trademark) or Fast-Floc (registered trademark)), lactose monohydrate mannitol, methylcellulose polymers such as Methocel A (registered trademark), Methocel A4C (registered trademark), Methocel A 15C (registered trademark), Metocel A4M (registered trademark), etc., hydroxyethylcellulose, hydroxypropylcellulose, L-hydroxypropylcellulose (low substitution), hydroxypropylmethylcellulose (HPMC) (for example, Methocel E (registered trademark), F and K, Shin-Etsu's Metolose SH (registered trademark), several grades of Methocel F (registered trademark) and Metolose 65 SH (registered trademark), 4,000, 15,000, and 100,000 cps grades of Methocel K (registered trademark); and 4,000, 15,000, 39,000, and 100,000 grades of Metolose 90 SH (registered trademark)), sodium carboxymethylcellulose, carboxymethylene, carboxymethylhydroxyethylcellulose and other cellulose derivatives, starch or modified starch (including potato starch, wheat starch, corn starch, rice starch, pregelatinized corn starch), magnesium carbonate, magnesium oxide, maltitol, maltodextrin, maltose, mannitol, kaolin, sorbitol, starch, sucrose, sugar, xylitol, erythritol, isomalt, and mixtures thereof. 【0325】 (70) The pharmaceutical composition according to item (69), wherein the diluent is mannitol. 【0326】 (71) The pharmaceutical composition according to any one of items (57) to (70), wherein the binder is selected from hydroxymethylcellulose, hydroxypropylcellulose, starch (including corn starch and pregelatinized starch), gelatin, sugars (including sucrose, glucose, dextrose, lactose, and sorbitol), waxes, polyethylene glycol, natural and synthetic gums (e.g., acacia, tragacanth sodium alginate, cellulose, and Veegum), and synthetic polymers such as polymethacrylates and polyvinylpyrrolidone (povidone), ethylcellulose, hydroxyethylcellulose, polyethylene oxide, carboxymethylcellulose, mannitol, methylcellulose, isomalt, polyvinyl alcohol, and mixtures thereof. 【0327】 (72) The pharmaceutical composition according to item (71), wherein the binder is hydroxypropylmethylcellulose or povidone. 【0328】 (73) The pharmaceutical composition according to item (72), wherein the binder is hydroxypropylmethylcellulose. 【0329】 (74) The pharmaceutical composition according to item (73), wherein the binder is 6 cps grade hydroxypropyl methylcellulose. 【0330】 (75) The pharmaceutical composition according to any one of items (61) to (74), wherein the disintegrant is selected from the group consisting of cross-linked polyvinylpyrrolidone (crospovidone, polyplyplasdone XL®, kollidon CL®); starches such as corn starch and dry sodium starch glycolate; gums such as corn starch and dry sodium starch glycolate; gums such as alginic acid, sodium alginate, and guar gum; croscarmellose sodium; microparticulate cellulose, low-substituted hydroxypropyl cellulose, carboxymethylcellulose, sodium bicarbonate, soybean polysaccharides, and mixtures thereof. 【0331】 (76) The pharmaceutical composition according to item (75), wherein the disintegrant is selected from low-substituted hydroxypropyl cellulose, sodium starch glycolate, and croscarmellose sodium. 【0332】 (77) The pharmaceutical composition according to item (76), wherein the disintegrant is low-substituted hydroxypropyl cellulose. 【0333】 (78) The pharmaceutical composition according to items (65) to (77), wherein the lubricant is selected from sodium oleate, sodium stearate, sodium benzoate, sodium stearate, sodium chloride, stearic acid, sodium stearyl fumarate, calcium stearate, magnesium lauryl sulfate, sodium stearyl fumarate, sucrose ester or fatty acid, zinc, polyethylene glycol, talc, glyceryl behenate, and mixtures thereof. 【0334】 (79) The pharmaceutical composition according to item (78), wherein the lubricant is sodium stearyl fumarate. 【0335】 (80) The pharmaceutical composition according to items (38) to (79), wherein the pharmaceutical composition is an immediate-release pharmaceutical composition. 【0336】 (81) When the pharmaceutical composition is subjected to an in vitro dissolution test using 0.1M HCl or pH 6.8 phosphate buffer as the dissolution medium, at least 75% of the total amount of N-(2-(tert-butyl)-1-((4,4-difluorocyclohexyl)methyl)-1H-benzimidazol-5-yl)ethanesulfonamide contained in the pharmaceutical composition is released within the first 45 minutes, and the dissolution profile is determined at 37°C using a rotation speed of 50 rpm as described in the United States Pharmacopeia. The pharmaceutical composition according to item (80). 【0337】 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, at least 75% of the total amount of N-(2-(tert-butyl)-1-((4,4-difluorocyclohexyl)methyl)-1H-benzimidazol-5-yl)ethanesulfonamide contained in the pharmaceutical composition is released within the first 30 minutes, and the dissolution profile is determined at 37 °C using a rotation speed of 50 rpm as described in the United States Pharmacopeia, the pharmaceutical composition according to item (80) or (81). 【0338】 (83) 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, at least 75% of the total amount of N-(2-(tert-butyl)-1-((4,4-difluorocyclohexyl)methyl)-1H-benzimidazol-5-yl)ethanesulfonamide contained in the pharmaceutical composition is released within the first 15 minutes, and the dissolution profile is determined at 37 °C using a rotation speed of 50 rpm as described in the United States Pharmacopeia, the pharmaceutical composition according to items (80) to (82). 【0339】 (84) When the pharmaceutical composition is subjected to a content uniformity test as described in the European Pharmacopeia, the acceptance value is less than 15, the pharmaceutical composition according to items (38) to (83). 【0340】 (85) N-(2-(tert-butyl)-1-((4,4-difluorocyclohexyl)methyl)-1H-benzimidazol-5-yl)ethanesulfonamide or a pharmaceutically acceptable salt thereof is stable in the pharmaceutical composition, the pharmaceutical composition according to items (38) to (84). 【0341】 (86) The active substance is stable during the process of preparing the pharmaceutical composition, the pharmaceutical composition according to item (85). 【0342】 The pharmaceutical composition according to item (86), wherein the assay of the active substance in the pharmaceutical composition after manufacture is about 90% to about 110% of the nominal value, for example, about 95% to about 105% or about 98% to about 102% as determined by chromatography. 【0343】 (88) The pharmaceutical composition according to item (86) or (87), wherein the total amount of the decomposition products of the active substance in the pharmaceutical composition after manufacture is about 4 area% or less, for example, 3, 2, or 1 area% or less as determined by chromatography. 【0344】 (89) The pharmaceutical composition according to items (85) to (88), wherein the active substance is chemically 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. 【0345】 (90) The pharmaceutical composition according to item (89), wherein 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, the total amount of the decomposition products of the active substance is about 4 area% or less, for example, 3, 2, or 1 area% or less as determined by chromatography. 【0346】 (91) The pharmaceutical composition according to item (89) or (90), wherein 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, the assay of the active substance is about 90% to about 110% of the nominal value, for example, about 95% to about 105% or about 98% to about 102% as determined by chromatography. 【0347】 (92) A process for preparing a plurality of granules according to items (1) to (37), comprising: a. A step of mixing a binder and a diluent together; b. A step of injecting a primary granulation liquid into the mixture of step a and mixing until granules are formed; and c. A process comprising the step of drying the mixture of step b, wherein N-(2-(tert-butyl)-1-((4,4-difluorocyclohexyl)methyl)-1H-benzimidazol-5-yl)ethanesulfonamide or a pharmaceutically acceptable salt thereof is mixed with a binder and a diluent in step a or dissolved in a primary granulation liquid. 【0348】 (93) The process according to item (92), wherein N-(2-(tert-butyl)-1-((4,4-difluorocyclohexyl)methyl)-1H-benzimidazol-5-yl)ethanesulfonamide or a pharmaceutically acceptable salt thereof is mixed with a binder and a diluent in step a. 【0349】 (94) The process according to item (92) or (93), wherein step a further comprises mixing a disintegrant with the binder and the diluent. 【0350】 (95) The process according to items (92) to (94), wherein N-(2-(tert-butyl)-1-((4,4-difluorocyclohexyl)methyl)-1H-benzimidazol-5-yl)ethanesulfonamide or a pharmaceutically acceptable salt thereof has a solubility of at least 0.6 mg / mL in the primary granulation liquid at room temperature. 【0351】 (96) The process according to items (92) to (95), wherein the primary granulation liquid is selected from ethanol, 0.1 M HCl, pH 3 citrate buffer, and 5% aqueous SLS solution. 【0352】 (97) The process according to item (96), wherein the primary granulation liquid is 0.1 M HCl. 【0353】 (98) The process according to items (92) to (97), wherein in step b, the primary granulation liquid is added at a rate of about 2 to about 10 mL / min, preferably about 4 to about 7 mL / min, more preferably about 5 to about 6 mL / min. 【0354】 (99) The process according to items (92) to (98), wherein in step b, the mixture is mixed at a high speed. 【0355】 (100) In process c, the process according to items (92) to (99), wherein the granules are dried at a high temperature. 【0356】 (101) The process according to items (92) to (100), wherein the high temperature is above 30°C, for example, above 40°C, above 50°C. 【0357】 (102) The process according to items (92) to (101), wherein the process further comprises adding a secondary granulation liquid in process b. 【0358】 (103) The process according to item (102), wherein the secondary granulation liquid is selected from ethanol, 0.1 M HCl, pH 3 citrate buffer, and 5% SLS aqueous solution. 【0359】 (104) The process according to item (103), wherein the secondary granulation liquid is 0.1 M HCl. 【0360】 (105) The process according to items (102) to (104), wherein the secondary liquid is added over at least 1 minute, for example, at least 2 minutes, at least 5 minutes, or at least 8 minutes. 【0361】 (106) N-(2-(tert-butyl)-1-((4,4-difluorocyclohexyl)methyl)-1H-benzimidazol-5-yl)ethanesulfonamide or a pharmaceutically acceptable salt thereof is present in a plurality of granules in an amount less than 0.5% w / w of the total weight of the plurality of granules, for example, less than 0.4, 0.3, 0.2, 0.15, 0.14, 0.13, 0.12, 0.11, 0.10, 0.08, 0.06, or 0.05% w / w, in the process according to items (92) to (105). 【0362】 (107) The process according to items (92) to (106), wherein N-(2-(tert-butyl)-1-((4,4-difluorocyclohexyl)methyl)-1H-benzimidazol-5-yl)ethanesulfonamide or a pharmaceutically acceptable salt thereof is present in a number of granules in an amount of about 0.01% w / w to about 0.5% w / w, for example, about 0.01% w / w to about 0.4% w / w, about 0.01% w / w to about 0.3% w / w, about 0.01% w / w to about 0.2% w / w, about 0.01% w / w to about 0.15% w / w, about 0.01% w / w to about 0.12% w / w, about 0.02% w / w to about 0.12% w / w, or about 0.03% w / w to about 0.10% w / w of the total weight of the number of granules. 【0363】 (108) The process according to items (92) to (107), wherein N-(2-(tert-butyl)-1-((4,4-difluorocyclohexyl)methyl)-1H-benzimidazol-5-yl)ethanesulfonamide or a pharmaceutically acceptable salt thereof is present in a number of granules in an amount of about 0.04, 0.10, or 0.12% w / w of the total weight of the number of granules. 【0364】 (109) The process according to items (92) to (108), wherein the diluent is present in a number of granules in an amount of at least 70% w / w, for example, at least 75, 80, 85, or 90% w / w of the total weight of the number of granules. 【0365】 (110) The process according to items (92) to (109), wherein the diluent is present in a number of granules in an amount of about 75% w / w to about 98% w / w, for example, about 85% w / w to about 98% w / w or about 90% w / w to about 95% w / w of the total weight of the number of granules. 【0366】 (111) The process according to items (92) to (110), wherein the diluent is present in a number of granules in an amount of about 93% w / w of the total weight of the number of granules. 【0367】 (112) The process according to items (92) to (111), wherein the binder is present in a number of granules in an amount of at least 0.5% w / w, for example at least 1 or 2% w / w, of the total weight of the number of granules. 【0368】 (113) The process according to items (92) to (112), wherein the binder is present in a number of granules in an amount of about 0.5% w / w to about 5% w / w, for example about 1% w / w to about 4% w / w or about 2% w / w to about 3% w / w, of the total weight of the number of granules. 【0369】 (114) The process according to items (92) to (113), wherein the binder is present in a number of granules in an amount of about 2.5% w / w of the total weight of the number of granules. 【0370】 (115) The process according to items (94) to (114), wherein the disintegrant is present in a number of granules in an amount of at least 0.5% w / w, for example at least 1, 2, or 3% w / w, of the total weight of the number of granules. 【0371】 (116) The process according to items (94) to (115), wherein the disintegrant is present in a number of granules in an amount of about 1% w / w to about 10% w / w, for example about 2% w / w to about 6% w / w or about 3% w / w to about 5% w / w, of the total weight of the number of granules. 【0372】 (117) The process according to items (94) to (116), wherein the disintegrant is present in a number of granules in an amount of about 4% w / w of the total weight of the number of granules. 【0373】 (118) The diluent is selected from calcium carbonate, calcium phosphate, dibasic calcium phosphate, tribasic calcium sulfate, calcium carboxymethyl cellulose, dextrin derivatives, dextrin, dextrose, fructose, lactitol, lactose (for example, anhydrous lactose, spray-dried lactose, α-lactose, β-lactose, Tablettose®, various grades of Pharmatose®, Microtose® or Fast-Floc®), lactose monohydrate mannitol, methyl cellulose polymers such as Methocel A®, Methocel A4C®, Methocel A 15C®, Metocel A4M®, etc., hydroxyethyl cellulose, hydroxypropyl cellulose, L-hydroxypropylcellulose (low substitution), hydroxypropyl methylcellulose (HPMC) (for example, Methocel E®, F and K, Shin-Etsu's Metolose SH®, several grades of Methocel F® and Metolose 65 SH®, 4,000, 15,000, and 100,000 cps grades of Methocel K®; and 4,000, 15,000, 39,000, and 100,000 grades of Metolose 90 SH®), sodium carboxymethyl cellulose, carboxymethylene, carboxymethyl hydroxyethyl cellulose and other cellulose derivatives, starch or modified starch (including potato starch, wheat starch, corn starch, rice starch, pregelatinized corn starch), magnesium carbonate, magnesium oxide, maltitol, maltodextrin, maltose, mannitol, kaolin, sorbitol, starch, sucrose, sugar, xylitol, erythritol, isomalt, and mixtures thereof, the process according to items (92) to (117). 【0374】 (119) The process according to item (118), wherein the diluent is mannitol. 【0375】 (120) The process according to any one of items (92) to (119), wherein the binder is selected from hydroxymethylcellulose, hydroxypropylcellulose, starch (including corn starch and pregelatinized starch), gelatin, sugars (including sucrose, glucose, dextrose, lactose, and sorbitol), waxes, polyethylene glycol, natural and synthetic gums (e.g., acacia, tragacanth sodium alginate, cellulose, and Veegum), and synthetic polymers such as polymethacrylates and polyvinylpyrrolidone (povidone), ethylcellulose, hydroxyethylcellulose, polyethylene oxide, carboxymethylcellulose, mannitol, methylcellulose, isomalt, polyvinyl alcohol, and mixtures thereof. 【0376】 (121) The process according to item (120), wherein the binder is hydroxypropyl methylcellulose or povidone. 【0377】 (122) The process according to item (121), wherein the binder is hydroxypropyl methylcellulose. 【0378】 (123) The process according to item (122), wherein the binder is 6 cps grade hydroxypropyl methylcellulose. 【0379】 (124) The process according to items (94) to (123), wherein the disintegrant is selected from cross-linked polyvinylpyrrolidone (crospovidone, polyplyplasdone XL®, kollidon CL®); starches such as corn starch and dry sodium starch glycolate; gums such as corn starch and dry sodium starch glycolate; gums such as alginic acid, sodium alginate, guar gum; croscarmellose sodium; microparticulate cellulose, low-substituted hydroxypropyl cellulose, carboxymethylcellulose, sodium bicarbonate, soybean polysaccharides, and mixtures thereof. 【0380】 (125) The process according to item (124), wherein the disintegrant is selected from low-substituted hydroxypropyl cellulose, sodium starch glycolate, and croscarmellose sodium. 【0381】 (126) The process according to item (125), wherein the disintegrant is low-substituted hydroxypropyl cellulose. 【0382】 (127) The process according to items (92) to (126), wherein the bulk density of the prepared multiple granules is about 0.1 to about 0.7 g / mL, for example, about 0.2 to about 0.6 g / mL or about 0.3 to about 0.5 g / mL. 【0383】 (128) The process according to items (92) to (127), further comprising adding a lubricant in step b. 【0384】 (129) The process according to item (128), wherein the lubricant is selected from sodium oleate, sodium stearate, sodium benzoate, sodium stearate, sodium chloride, stearic acid, sodium stearyl fumarate, calcium stearate, magnesium lauryl sulfate, sodium stearyl fumarate, sucrose ester or fatty acid, zinc, polyethylene glycol, talc, glyceryl behenate, and mixtures thereof. 【0385】 (130) The process according to item (130), wherein the lubricant is sodium stearyl fumarate. 【0386】 (131) The pharmaceutical composition according to items (38) to (91) for use as a medicament. 【0387】 (132) The pharmaceutical composition according to items (38) to (91) for use in a disease state or disorder in which there is a dysfunction of CB1 and / or CB2 receptors or which exhibits such a dysfunction. 【0388】 (133) A pharmaceutical composition according to items (38) to (91) for use in the treatment of anorexia-related conditions; cachexia-related conditions; or anorexia nervosa. 【Example】 【0389】 In the examples, the following abbreviations were used: API Active pharmaceutical ingredient, which in this example is N-(2-(tert-butyl)-1-((4,4-difluorocyclohexyl)methyl)-1H-benzimidazol-5-yl)ethanesulfonamide (Compound I) AV Acceptable value HPMC Hydroxypropyl methylcellulose NMT Below 【0390】 Example 1 - Forced Degradation Study of N-(2-(tert-butyl)-1-((4,4-difluorocyclohexyl)methyl)-1H-benzimidazol-5-yl)ethanesulfonamide The forced degradation of N-(2-(tert-butyl)-1-((4,4-difluorocyclohexyl)methyl)-1H-benzimidazol-5-yl)ethanesulfonamide (active substance) was carried out for up to 13 days under a number of stress conditions. The active substance was shown to be stable to 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 photostability 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 showed decomposition as a solution when heated to 80 °C. Major decomposition of the active substance as a solution occurred under photostability conditions. 【0391】 Materials Active substance N-(2-(tert-butyl)-1-((4,4-difluorocyclohexyl)methyl)-1H-benzimidazol-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 【0392】 Analysis HPLC conditions Instrument: Agilent 1100 / 1200 Column: YMC Triart Phenyl, 4.6x150mm. Particle size 3μm (ex-YMC P.N.TPH12S03-1546PTH) Mobile phase: A - 10mM Ammonium acetate pH6.0 B - Acetonitrile Flow rate: 1.0ml / min Injection volume: 5μl Detection: UV@220nm Column temperature: 30℃ Post run: 4 minutes 【Table 1】 Diluent: Acetonitrile: Deionized water (1:1) Standard solution: Prepare a 0.2mg / ml solution. This should be freshly prepared before use at T = 3 and T = 7 days. 【0393】 Stock solution preparation Accurately weigh 80mg of the active substance into a 100mL volumetric flask and dissolve it in 50mL of the diluent. Dilute the resulting solution to a specific volume with the diluent and mix well. 【0394】 Procedure Table 1 below details the various research tests conducted. All solution samples were prepared, stored in sealed vials, and heated samples were cooled to room temperature before sampling to prevent evaporation. Analyses were performed on the 3rd and 7th days after the start of stress application for the solutions described in Tests 1 - 6, and after the exposure was completed for the samples described in Tests 7 - 10. Due to the low level of decomposition observed on the 7th day, Tests 3, 4, and 5 were further heated at 80°C for 4 days and analyzed, and Test 6 was analyzed 6 days later. 【0395】 A total of 1.92 million lux - hours of light stability samples were exposed to a total near - ultraviolet energy of 374.6 Wh / m². -2 【0396】 [Table 2] [Table 3] 1[Table 4] 【0397】 Results Observations [Table 5] 【0398】 Analysis [Table 6] 【0399】 [Table 7] 【0400】 Example 2 - Pre - preparation study - Compatibility of active ingredient with capsule shell and wet - granulation excipients ​Preformulation studies were conducted to select excipients for the development of immediate-release capsules containing low-dose granular N-(2-(tert-butyl)-1-((4,4-difluorocyclohexyl)methyl)-1H-benzimidazol-5-yl)ethanesulfonamide. The chemical stability of granular N-(2-(tert-butyl)-1-((4,4-difluorocyclohexyl)methyl)-1H-benzimidazol-5-yl)ethanesulfonamide was evaluated at 40 °C and 50 °C for up to 28 days. Both types of capsule shells evaluated (HPMC and PEG softened hard gelatin shells) were compatible with the active ingredient. Four out of the six granulation liquids tested showed sufficient solubility to solution-dope the active ingredient into granules for potential high-dose capsules of 200 μg. None of these granulation systems showed any signs of degradation towards potential overnight drying under ambient conditions. However, only two of these granulation liquids (0.1 M HCl and ethanol) showed sufficient solubility to fill size 2-4 capsules. 【0401】 The 28-day stability of three prototype wet granulation formulations showed no evidence of active ingredient degradation. In the remaining formulations, the peak area of one compound-related substance was unacceptably high after 28 days at 50 °C. From this, two excipients can be excluded from further consideration due to chemical incompatibility with the active ingredient (magnesium stearate and microcrystalline cellulose). However, for each type of function, there are several candidate excipients (binders, disintegrants, diluents, and lubricants) that appear to be compatible with the active ingredient. 【0402】 Materials [Table 8] [Table 9] 【0403】 Analytical methods UPLC conditions Column: Waters Acquity BEH Shield 100x2.1mm, 1.7μm Column temperature 40°C Sample manager cleaning solution (UPLC) Acetonitrile Sample manager purge (UPLC) HPLC water:ACN 50:50% v / v Mobile phase A (for volatile solvents) 0.18 mM ammonia solution Mobile phase A (for capsule shell) 25% ammonia solution Mobile phase A (for prototype granules) 10 mM ammonium acetate pH 7.0 Mobile phase B Acetonitrile Flow rate 0.3 mL / min Injection volume 10 μL (for nominal concentration of 0.01 mg / mL) 5 μL (for nominal concentration of 0.02 mg / mL) Wavelength 215 nm Gradient program 【Table 10】 【0404】 Diluent All analytical solutions were prepared at a nominal concentration of 0.01 mg / mL in 50:50 acetonitrile:aqueous solution. 【0405】 Stability test Note that all stability test incubations were performed in the same manner: · All were placed in 4 mL amber glass vials. · Instead of analyzing the initial samples immediately after sampling, the samples were frozen at -20°C until the time of analysis of the incubated samples (e.g., after 28 days at 25°C, 40°C, or 50°C) to avoid decomposition of the active ingredient. 【0406】 Part 1 - Solubility and compatibility of the active ingredient in volatile solvents The active ingredient was dissolved in various solvents, and the stability of the solution was evaluated after holding at ambient temperature overnight. Solvents of ethanol, 50:50 EtOH:water, 0.1M HCl, pH3 citrate buffer, 5% SLS aqueous solution, 5% Tween80 aqueous solution were tested. 【0407】 Method For each of the above solvents: · 15.5 - 16.5 mg of the active ingredient was dispensed into a vial. · As shown in Table 6 (Addition of solvent aliquots requiring Volatile solvent Table 6), solvent aliquots were added to the vial and mixed at 250 RPM for 30 - 180 minutes using a magnetic stirrer to confirm that no more active compound dissolved. · Solvent aliquots (total solvent up to 30 mL) were added only if the active ingredient did not dissolve completely after the previous aliquot. · The stability of the active ingredient was evaluated after incubating in the solvent at 20 - 25 °C for 20 - 28 hours: HPLC data (assay and related substances) were compared with samples taken initially (frozen at -20 °C to prevent decomposition). 【Table 11】 【0408】 Results: In this study, the solubility and chemical stability of the active ingredient in various volatile solvents for use in wet granulation were evaluated. Solubility was measured visually (by disappearance of undissolved solid) after mixing. As described above, the amount of each solvent was increased and added. The results are summarized in Table 7: · The solubility of the active ingredient was found to be highest in both ethanol and 0.1M HCl: 7 mg / ml, and it was estimated to be sufficient to achieve the potential maximum dose (200 μg) with the smallest capsule size (size 4). · The next highest solubility was achieved in 5% SLS aqueous solution and pH3 citrate buffer. These solvents had a low solubility of >0.6 mg / mL and were estimated to be sufficient to achieve the potential maximum dose (200 μg) with the largest capsule size (size 00). · The active ingredient did not dissolve in 50:50 EtOH:water or 5% Tween80 at the maximum dilution (<0.6 mg / mL). That is, at any capsule size, it was insufficient for a 200 μg dose. Therefore, both 50:50 EtOH:water and 5% Tween80 were excluded from further studies. 【0409】 【Table 12】 【0410】 Chemical stability was determined by assay (results in Table 8) and quantification of potential active ingredient related substances (shown in Table 9). These were identified by overlay of chromatograms of the active ingredient solutions and compared after holding for 20 - 28 hours at initial and ambient temperatures (and control samples without active ingredient). The purpose was to confirm whether any active ingredient related substances might have increased as a result of holding at room temperature. Overall, there was no evidence of decomposition of the active ingredient. · Total impurities in all cases did not exceed 1.17% of the total peak area. Most of these peaks were also shown by the active ingredient standard (as indicated by asterisks in Table 9), so there might have been contaminants or existing impurities in the incorporated active ingredient. · There was no peak increase between the initial sample (frozen at collection) and the sample held at ambient temperature for 20 - 28 hours. 【0411】 All impurity peaks are listed in Table 9. Peaks that are present in the placebo / diluent and large in the sample are highlighted in bold. Values related to the active ingredient standard are * marked. However, since multiple mobile phase related peaks are seen with inconsistent elution times, it cannot be said for certain that all other peaks are truly related to the active ingredient. In particular, peaks between RRT 0.38 and 0.86 are not consistent between replicates. 【0412】 【Table 13】 【0413】 【Table 14】 【Table 15】 【0414】 Part 2 - Compatibility of Active Ingredient with HPMC and Gelatin Capsule Shells · A binary mixture of the active ingredient and the capsule shell was formed as follows: · An active ingredient doping solution (active ingredient dissolved in ethanol) was formed (3 mg / ml). Using 100 μL aliquots of this doping, 10 vials of each capsule shell type were "spiked" as described in Table 5. Thus, the nominal amount of active ingredient per vial was 50 μg. · The doping solution was not added to three control vials of the excipient. · The active vials were left open overnight, all ethanol was evaporated, and then the vials were closed. · Both the active vials and the placebo control vials were stabilized at 25 °C and 50 °C for up to 28 days. 【0415】 Results: Table 10 shows the results of the assay of the active ingredient in HPMC and gelatin capsules. 【Table 16】 【0416】 Overall, the % assay of both sample sets appears to be consistent at all conditions and time points, indicating no degradation of the active ingredient in either HPMC capsules or gelatin capsules. 【0417】 The peak areas of potential active ingredient-related substances are shown in Table 11. Since all impurities remained below 1% and there was no increase in any impurity due to incubation time or temperature, there was no evidence of active ingredient degradation in either capsule type. 【Table 17】 【0418】 Part 3 - Stability of the Active Ingredient in Prototypes Produced by Wet Granulation In this part, the focus is on the study of the stability of various blends granulated using different aqueous solutions of the active ingredient. Each granule was formed as follows: · 6.7 mg was dissolved in 10 mL of ethanol to prepare a solution of the active ingredient (0.67 mg / mL). · While stirring 1.25 mL of the active ingredient solution with a pestle, it was gradually added to a 5 g bed of dry excipients (excluding magnesium stearate or Pruv lubricant) in a mortar to form granules. · An equal amount of solvent was added without dissolving the active ingredient to form equivalent placebo granules. · The granules were left overnight in the mortar on a warm hot plate to dry. Measuring a sample of water filled in the same mortar on a hot plate with the same settings reached a temperature of 37.6 °C. · After drying, the required amount of magnesium stearate was added to the entire mass of granules in the mortar and, using a pestle, a homogeneous mixture was obtained without grinding. · The blend was then dispensed into vials (10 active vials and 3 placebo vials) using a 5-dp balance and stabilized. The assay value of the active ingredient determined by HPLC analysis was calculated using the mass of the granules in each vial. 【0419】 Table 12 shows in detail the composition of the four granules produced. 【0420】 【Table 18】 【Table 19】 【0421】 Results The assay values of each incubated sample of the wet granular prototype formulation are summarized in Table 13. The areas of the impurity peaks of the corresponding samples of the four formulations are shown in Table 14, Table 15, Table 16, and Table 17, respectively. Note that since the LOQ (limit of quantification) is only about 0.20% of the peak area in these analyses, values below this will have low accuracy. From these data, the following can be seen: · The replicate agreement is generally low among samples, i.e., there are large differences in the active ingredient assay between replicate pairs at each time point / condition. These values are corrected for the weight of the samples tested. Therefore, this variability suggests insufficient homogeneity of the active ingredient in these samples, probably due to low doses of the active ingredient and small batch sizes being prepared (making it difficult to achieve homogeneity). However, there is no tendency for the active ingredient assay to decrease with incubation time or temperature, i.e., there is no evidence of overall degradation. · In most cases, there is no change in the relative peak area of impurities with increasing incubation time or temperature, i.e., there is no evidence of chemical degradation of the active ingredient. In fact, most of the peaks are also seen at the same area as the active ingredient standard, so they are not true degradation products. o One notable exception is the RRT 1.84 impurity, whose area increased significantly with incubation time and temperature. After 28 days under accelerated stability conditions (50 °C), the peak area will be higher than the acceptance limit for unknown impurities according to the ICH Q3B guideline (< 1% of the peak area). Therefore, formulation 0.1M HCl Avicel is excluded from further consideration. o Two other peaks (RRT 0.78 and 0.92) that are not seen in the API standard were also shown in formulation 0.1M HCl Avicel, but these peak areas are hardly detectable. ·In the citrate buffer with a formulation pH of 3, there is an abnormal increasing trend in the LS sequence order, that is, the assays using sample numbers 1 to 10. Therefore, the assay clearly increases with the increase in incubation time and temperature. The area of impurities increases correspondingly (that is, there is no trend in the peak area of impurities relative to the active ingredient in samples 1 to 10). The area of the active ingredient in the standard solution also increases throughout this column, the peak symmetry deteriorates, the column pressure rises, and it is considered that particulate matter increasingly interferes with chromatography. Therefore, in this case, the absolute peak area is not considered reliable. 【0422】 【Table 20】 【0423】 【Table 21】 【0424】 【Table 22】 【0425】 【Table 23】 【0426】 【Table 24】 [[ID=�9]] 【0427】 Conclusion Formulation prototype The physical solubility of the active ingredient was measured through the observation of undissolved active ingredient in six potential granulation liquids. It was found that the active ingredient was sufficiently soluble to be wet granulated at 200 μg per capsule with the achievable minimum capsule size shown for each liquid: o0.1M HCl and ethanol: [Active ingredient] > 7 mg / mL, i.e., suitable for 200 g with a shell of capsule size 4 or above. o5% SLS aqueous solution and pH 3 citrate buffer: 3 mg / mL > [Active ingredient] > 0.6 mg / mL, i.e., suitable for 200 μg with a capsule size of 00 (but not below). 【0428】 The stability of the active ingredient was evaluated for each of these four options during a potential drying time of 20 - 28 hours at ambient temperature. Since no active ingredient-related impurities were observed, all four liquids can be considered as options for wet granulation formulations. The solubility of the active ingredient in the remaining two liquids (50:50 EtOH: water or 5% Tween 80 aqueous solution) was less than 0.6 mg / ml, and a high dose of 200 μg could not be administered with capsules of any size. Therefore, these two options were excluded. 【0429】 Among the four acceptable candidates, 0.1M HCl was selected as the primary granulation liquid because it can deliver both 50 μg and 200 μg doses with preferred capsule sizes (sizes 2 - 4) without using a non-aqueous solvent. 【0430】 The stability of four prototype wet granulation formulations was evaluated over 28 days. The components of these formulations are listed in Table 12. Of these formulations, only the 0.1M HCl Avicel prototype showed evidence of increased degradation of the active ingredient with time and temperature. This formulation has one peak (RRT 1.84) that exceeds the ICH Q3B criteria for unknown impurities (i.e., > 1% of the total area) and thus may not need to be considered. The components of this formulation that are not present in the other three formulations are Avicel and magnesium stearate. Therefore, these components can be excluded from future consideration in the wet granulation of the active ingredient due to potential chemical incompatibility, and the other excipients in this formulation (0.1M HCl, HPC-LS, and HPMC Methocel E5) have been shown to be chemically compatible with the active ingredient in the other three formulations. This, even considering only the results of the other three formulations, suggests that all of the following are chemically compatible with the active ingredient in such formulations: · Granulation aqueous solution: 0.1M HCl, pH 3 citrate buffer, and 5% SLS · Diluent: Mannitol · Disintegrant: Sodium starch glycolate, HPC-LS, and croscarmellose sodium · Binder: Both HPMC and povidone · Lubricant: Sodium stearyl fumarate. 【0431】 Capsule shell The stability of the active ingredient in HPMC and gelatin capsule shells was evaluated over 28 days. There was no evidence of degradation of the active ingredient in either HPMC or gelatin capsules. The % assay of the shell remained close to the nominal value over 28 days of incubation, and there were no impurity peaks that increased with incubation temperature or time. Therefore, both capsules showed compatibility with the active ingredient. 【0432】 Example 3 - Evaluation of Binders for Granule-Containing Capsule Formulations Two binders, PVP and HPMC, were studied at high and low granulation sizes. At low granulation size, the blend was granulated using a primary granulation fluid (PGF) and a small amount of 0.1 M HCl in which the active ingredient was not dissolved (secondary granulation fluid (SGF)). At high granulation size, the same amount of PGF was used, but more SGF was added to achieve a higher granulation size. Both binders showed good stability and compatibility with the active ingredient as reported in Example 2. However, the granules produced using HPMC showed excellent active ingredient uniformity and less active ingredient loss. Therefore, HPMC was selected for the manufacture of the ICH stability batch. 【0433】 When studied at a 50 μg dose (size 4 capsule), it was found that the dissolution rate was similar at high and low granulation sizes. However, high granulation size showed better content uniformity than low granulation size. Therefore, this was selected for the ICH stability batch. The low dose of 50 μg was filled into size 4 capsules, and the high dose of 200 μg was put into size 00 capsules for the ICH batch, and both used Quali-G PEG (hard gelatin). 【0434】 All of the appearance, assay, content uniformity, dissolution, and microbiological analysis of the stability batch met the specifications at T = 0, and no detectable degradation occurred by LC during manufacture. 【0435】 Materials Used Active ingredient Onyx (lot: JCM1019B) Mannitol (Pearlitol 100 SD) Roquette L-HPC LS-B1 Chemlink Harke PVP (Kollidon K25) BASF HPMC (Methocel E5 Premium) Colorcon Pruv (sodium stearyl fumarate) JRS Pharma Red size 4 Quali V (HPMC) capsules Qualicaps Green / grey size 4 Quali-G PEG (hard gelatin) capsules Qualicaps White Size 2 Quali-V (HPMC) Capsules Qualicaps White Size 2 Quali-G PEG (Hard Gelatin) Capsules Qualicaps 【0436】 Analytical Tests Dissolution Test Dissolution test in USP II container at 37 °C, paddle speed 50 RPM (and 200 RPM infinity spin after 45 minutes of sampling) in 500 mL of 0.1 M HCl QC medium (or 500 mL of pH 6.8 phosphate buffer). Use a 0.2 μm PVDF cannula filter and an O-ring sinker (4 - 5 mm for size 4 capsules, 6 - 7 mm for size 2 capsules). 【0437】 Content Uniformity 10 μL of 1.0 μg / mL and 25 μL of 0.25 μg / mL diluent (90:10 v / v 0.1 M HCl: acetonitrile) solutions for high and low doses respectively. 【0438】 HPLC / UPLC Conditions for Dissolution and Content Uniformity 【Table 25】 【0439】 HPLC / UPLC Method Conditions for Assay / Related Substances Both the assay (1) and the related substances (2) tests were performed using acetonitrile as the analytical diluent; the nominal concentration of (1) was 0.01 g / mL and that of (2) was 0.025 mg / mL. The HPLC / UPLC conditions are shown in Table 19. 【0440】 【Table 26】 【0441】 Part 1 - Influence of Binder Type and Granulation Size on Blend Uniformity Four granule batches were prepared. Briefly, the preparation method was as follows: i. PGF (primary granulation fluid) was prepared by stirring for 10 minutes to dissolve the active ingredient in 500 mL of 0.1 M HCl. ii. The required amounts of binder (HPMC / PVP), mannitol, and L-HPC were added to a Multipro high-shear mixer and mixed at high speed for 5 minutes. iii. While mixing at high speed, a certain amount of PGF and SGF (secondary granulation fluid = 0.1 M HCl) were added as summarized in Table 20 until the required granulation endpoint was reached. o The PGF dispensing container was rinsed with SGF to confirm no loss of API. o Note that the amount of SGF added was intentionally different between pairs of HPMC batches and PVP batches to evaluate high and low granulation degrees. iv. The batches were dried in a warmed tray. v. Sampling of the batches was performed for blend uniformity testing to create two sets of samples. o For "without sieving", the granule batch was divided into 3 g using a sampling and splitting box, and then approximately 200 mg of the sample was weighed and placed in a vial for analysis. o For "fine powder", the material was passed through a 125 μm mesh to obtain approximately 200 mg of the sample (a sieve shaker was used at an amplitude of 1 mm for 5 minutes). 【0442】 Table 20 shows the amount of active ingredient used in the preparation of the composition.Table 21 summarizes the composition of granules formed at low and high granulation degrees using HPMC and PVP. 【0443】 【Table 27】 【0444】 【Table 28】 【0445】 Result: Granules were successfully manufactured. The granulation process is summarized in Table 22. Visually, all granules (high and low granulation) appear to be uniform and have low fines. Increasing the granulation visually decreased the amount of fines for both binders as expected. The LOD was consistent across all four batches. 【0446】 [Table 29] 【0447】 From this study and Table 23, the following can be seen: · All granule batches except those manufactured at high granulation (PH) using PVP showed good blend uniformity, i.e., AV ≤ 15.0. o The magnitude of AV is mainly governed here by the difference in the active ingredient content in terms of RSD. The RSD was unacceptably high at high granulation for both binders but acceptably low at low granulation. o Note on PH: The high value of AV (20.3) is brought about by one capsule with an active ingredient content of 117.3% which causes a very high RSD. · The average active ingredient content was lower than the nominal value throughout and o For both binders, it is closer to the nominal value at high granulation compared to low granulation. o For both granulation levels, HPMC is closer to the nominal value than PVP. 【0448】 [Table 30] 【0449】 Not only was the uniformity of the active ingredient in the granules evaluated, but also the uniformity of the % active ingredient and fines (defined as particles < 125 μm) was evaluated. From the results in Table 24, the following can be seen: · The amount of fine powder is generally uniform among all granules, and this amount corresponds to the amount in the granules. This indicates that the active ingredient was well distributed in all size fractions in the granules, with one exception: o At high granulation degrees, HPMC has the highest proportion of fine powder: 110.5%, i.e., significantly higher than the average result (without sieving) in Table 23. This demonstrates that. 【0450】 Therefore, the active ingredient is uniformly distributed in the blend, ensuring the uniformity of the acceptable dosage. 【0451】 Overall, regarding blend uniformity, HPMC showed better results than PVP, at least at low granulation degrees. HPMC was designated as the binder used in subsequent studies. The results at this stage suggest that low - degree granulation may lead to excellent blend uniformity, but blend uniformity alone is not the target response. The degree of granulation with HPMC was further studied to obtain more knowledge about the performance of the capsules regarding dissolution, and to evaluate the content uniformity of the active ingredient in the capsules at high and low granulation degrees (see Part 2). 【0452】 【Table 31】 【0453】 Part 2 - Study on the Degree of Granulation with Respect to Capsule Dissolution and Content Uniformity In this study, a total of 4 granule batches of 2 active agents and 2 placebos, each weighing 350 g, were prepared. One active batch and the corresponding placebo batch were granulated for each granulation degree. In the ICH study, a total of 4 active agent sub - lots were prepared, and for the placebo, 8 sub - lots were prepared. 【0454】 The difference between low and high is the addition of further SGF to make larger granules without making the resulting material finer. The active batches were granulated in a humidity-controlled environment (15 - 25% RH), and the placebo (diluent) batches were granulated and dried at ambient humidity. The PGF (i.e., primary granulation fluid) was prepared by dissolving the active ingredient in 0.1 M HCl at 0.49% w / w. Each granule sublot was prepared as shown in Tables 25 and 27 as follows: i. Dispense all excipients / active ingredients (except lubricant) into a high-shear Multipro and blend dry for approximately 5 minutes. ii. Add the required amount of PGF (primary granulation fluid) at a constant rate (approx. 5 - 6 mL / min) while continuing mixing at high speed over 15 minutes as shown in Table 27. iii. Add further SGF (secondary granulation fluid, i.e., 0.1 M HCl) as shown in Table 27. For each of the active and placebo batches, two different levels of granulation fluid were added to investigate the effect of granulation degree on the properties of the final pharmaceutical product. o Low level (10 mL) - l = low granulation degree was added over 2 minutes to the high granulation degree batch and over 3 minutes to the low granulation degree batch. o High level (15 mL) - high granulation degree was added over 8 minutes. iv. Dry the granules as a thin layer on a 60 °C tray on a hot plate. 【0455】 At this point in Part 2, the two blends of Table 26 were prepared from the sublots of Table 27 using the following method: i. Determine the mass of the required active granules based on the dosage of the active ingredient and the mass of the diluent based on the density of the granules. ii. Using an Erweka AR401, blend the active and diluent granules at 15 rpm for 15 minutes, add the lubricant, and then blend at the same speed for 5 minutes. iii. Set up a Profiller 1100 with size 4 capsules. iv. Dispense the mass of the active granules and add them to the profiller. The amount per plate was determined by calculating the mass of the active granules necessary to deliver the desired dose per capsule (50 μg in this case), and thus scaled up to 100 capsules. Based on the density of the granules and the volume of the capsules, the diluent necessary to fill the capsules was calculated. v. The granules were evenly spread into the capsules using a spreader until the capsules were filled horizontally. vi. The blend was tempered as necessary until all of the blend was filled into the capsules. vii. The capsules were dissolved and the type of granules was selected based on the dissolution profile. 【0456】 【Table 32】 【0457】 【Table 33】 【0458】 【Table 34】 【0459】 Results: Encapsulation: All granules (high and low granulation) were successfully manufactured. The properties are summarized in Tables 28 and 29. The granules appear as white granular powders with different proportions of fines (as expected, more fines in low granulation). Granule A had a higher density (bulk density and tapped density) than Granule B. However, all other quantifiable properties were essentially the same between the two batches: · The Carr index, Hausner ratio, and flow rate of Granule A were consistent with those of Granule B. · The PSD of Option A was consistent with that of Option B. 【0460】 【Table 35】 【0461】 【Table 36】 【0462】 The corresponding active granule batches and diluent granule batches were blended as shown in Tables 26 and 27. Each blend was successfully encapsulated into size 4 capsules using the masses necessary to achieve a theoretical dose of 50 μg, i.e., to obtain a set of highly granulated -4A capsules and a set of lowly granulated -4B capsules. 【0463】 The density of each granule was considered when determining the fill weight. As shown in Table 30, the -4A capsules showed an RSD of capsule weight equivalent to that of -4B. Both the -4A capsules and the -4B capsules were close to the target weight. However, the average weight of the -4A capsules was slightly closer to the target weight than that of -4B. Slight underfilling was observed during the encapsulation of the -4A capsules, but the fill weight was appropriate to achieve the target dose of the 50 μg ICH stability batch. 【0464】 【Table 37】 【0465】 Dissolution The dissolution rates of both granule A and B capsules in 0.1 M HCl were the same (Figure 1). Therefore, the degree of granulation did not affect the dissolution rate in the 0.1 M HCl medium. The dissolution rate of Option A was initially faster than that of Option B in pH 6.8 phosphate buffer (Figure 2), but this difference does not need to be considered for the following reasons: · Regardless of the degree of granulation, the dissolution rate was very slow at 45 RPM for the first 45 minutes and insufficient at 200 RPM after the last 15 minutes. · The slow and insufficient dissolution rate is due to the slow dissolution of HPMC capsules caused by the presence of potassium ions in the medium. For this reason (and for the reduction of LC interference), hard gelatin capsules were used instead of HPMC in the ICH stability batches. Their degradation is not retarded by potassium ions. 【0466】 Content uniformity Capsules containing granule options A and B consistently impart acceptable content uniformity, i.e., AV < 15 (Table 31). As expected (due to the influence of the blending process and the encapsulation process), the AV values were slightly higher than the values of the blend uniformity in Part 1 (Table 23). The trend of AV is explained by the following two factors: · RSD of the active ingredient content: An important advantage of Option A (high granulation size) was that it provided excellent uniformity (in contrast to the opposite trend in the blend uniformity data of Part 1 (Table 23), the RSD was as low as 2.5). · Active ingredient content close to the target: For both Option A and B, the values of the average active ingredient content were far from the target (100%) and lower than in Part 1. However, the average active ingredient rate of Option B was slightly higher than that of A, i.e., closer to the target. However, its advantage for B is not so much of a problem: o The low capsule filling weight of Option A contributes to the low average content value. o The average active ingredient content of Option A may improve with scale-up (less loss of the active ingredient). · Even if its advantage for B decreases, Option A is more preferable to B in terms of its excellent uniformity (as described above). 【0467】 The above theoretical basis regarding content uniformity was a determining factor in selecting Option A (high granulation size) for preparing the ICH stability batches. 【0468】 【Table 38】 【0469】 Part 3: Preparation of ICH Stability Batches Based on the results of the study of high and low granulation sizes (Table 32), as described in Part 2, granulation size options were selected. A reminder of the granule sublots was made, and all sublots were mixed and lubricated before encapsulating them into Size 2 and Size 4 Quali - G PEG capsules to form dose capsules of 200 μg and 50 μg, respectively (Table 33). Corresponding placebos were also formed (Table 34). 【0470】 [Table 39] 【0471】 [Table 40] 【0472】 [Table 41] 【0473】 Results The active batches and the matching placebo granules (Option A) were successfully manufactured in 350 g sublots (4 active sublots and 8 placebo sublots). No problems were reported during granulation. The granulation process is summarized in Table 27. The LODs of the different granules are recorded in Table 35. It was found that the LODs were consistently between 0.3% and 0.7%. [Table 42] 【0474】 The active granules and diluent granules were filled into Size 2 capsules to achieve a theoretical dose of 200 μg and into Size 4 capsules to achieve a theoretical dose of 50 μg (Table 33). Corresponding placebo capsules for the active capsules were also formed (Table 34). From the individual capsule fill weights measured during capsule filling, the capsules showed good weight uniformity, as shown in Table 36: · The average weight of all batches is close to the target. · Note that the minimum fill weight of size 4 placebo capsules and the maximum fill weight of size 2 placebo are outside the target range. However, this is a very small number of capsules, and the RSD of the fill weight is low (about 2%) for all batches, indicating excellent weight uniformity, so it is not a problem. 【Table 43】 【0475】 Karl Fischer results of the ICH stability batches at T = 0 The KF results at T = 0 of the ICH stability batches are summarized in Table 37. Similar results were obtained for all batches. 【Table 44】 【0476】 Content uniformity of the ICH stability batches The system suitability met the criteria set in this method. The results of the content uniformity of the active ingredient in both 50 μg and 200 μg capsules (Table 38) meet the specifications (acceptance value, AV < 15). Note that the RSD of the active ingredient content was higher at the 50 μg dose than the following: · The 200 μg dose, as expected · The 50 μg dose in Part 2 (Table 31). 【Table 45】 【0477】 Appearance of the ICH stability batches at T = 0 All capsules appear as expected, as summarized in Table 39: intact and without defects. 【Table 46】 【0478】 Assay and Related Substances of the ICH Stability Batch at T = 0 Assay The results of the T = 0 assay are shown in Table 40. The average assay was found to be 97.1% at 50 μg and 98.3% at 200 μg, i.e., slightly lower than the target and similar to that observed in the content uniformity results (Table 38). 【0479】 Related Substances (RS) The final results of the related substances are shown in Table 41. Overall, there were no individual related substances exceeding 0.23% at both 50 μg and 200 μg, i.e., well within the target specification (<1%). 【0480】 【Table 47】 【0481】 【Table 48】 【0482】 Dissolution at T = 0 TRI002 / 89G50 - 4H: Dose of 50 μg (Figures 3 - 5) In both 0.1 M HCl and pH 6.8 phosphate buffer, essentially all of the active ingredient was released within 10 minutes after dissolution, i.e., meeting the specification (>80% in HCl within 45 minutes). In the pH 6.8 phosphate buffer, acceptable release of the active ingredient was achieved. Different from Part 22 (Figures 1 and 2), there was no delay in the release of the active ingredient. The improvement in dissolution here is due to the replacement of Quali - V (HPMC) capsules with Quali - G (gelatin). As expected, the dissolution of hard gelatin capsules was not reduced by the introduction of potassium ions into the medium. 【0483】 TRI002 / 89G200 - 2H: 200 μg (Figures 6 - 8) In both HCl and pH 6.8 phosphate buffer, the active ingredient was released essentially completely within the first 10 minutes. Drug release was consistent in all vessels, and almost the same release profiles were seen in both HCl and pH 6.8 phosphate buffer. 【0484】 Microbiological analysis Two active batches (low dose and high dose) and the corresponding placebo meet the specifications of the microbiological results as summarized in Table 42. 【Table 49】 【0485】 Conclusions of Parts 1 - 3 Both HPMC and PVP were shown to be suitable as binders. However, the granules manufactured using PVP with high particle size did not meet the blend uniformity specification (<15 AV). On the other hand, the HPMC binder passed the blend uniformity (<15 AV) for both high and low degrees of granulation. Based on the excellent average value and RSD of the active ingredient content of Option A (the high degree of granulation batch in Part 2), this degree was selected for the ICH stability batches over Option B. This degree of granulation did not affect the dissolution rate. 【0486】 Formulation process Both granulation and encapsulation were successfully carried out. The high degree of granulation batch seems to have a higher density than the low degree of granulation batch (as expected, 0.43 g / mL for high degree of granulation and 0.39 g / mL for low degree of granulation). Furthermore, the high degree of granulation batch was shown to have a lower RSD of the active ingredient content and excellent content uniformity compared to the low degree of granulation batch. However, dissolution was the same for both degrees of granulation, i.e., within the target (active ingredient dissolved >80% in 45 minutes). Based on these findings, the high degree of granulation was selected for the manufacture of ICH capsules. 【0487】 Assay and related substances / content uniformity The area of individual related substances (NMT 0.23%) was well within the specification (<1.0%) at T = 0, so process-related API degradation is not a concern. The average assay results for both active batches are within ±2.5% of the nominal value. Content uniformity is within the acceptable range (AV < 15, i.e., 10.1 at 50 μg and 8.4 at 200 μg). 【0488】 Dissolution / Microbiological analysis The results of QC dissolution in 0.1 M HCl medium and pH 6.8 phosphate buffer dissolution medium showed essentially complete release in 10 - 20 minutes. All four capsule batches met the specifications for microbiological analysis.

Claims

[Claim 1] a. N-(2-(tert-butyl)-1-((4,4-difluorocyclohexyl)methyl)-1H-benzimidazole-5-yl)ethanesulfonamide or a pharmaceutically acceptable salt thereof; and b. A number of granules containing at least one pharmaceutically acceptable excipient. [Claim 2] The plurality of granules according to claim 1, wherein the pharmaceutically acceptable excipient is selected from diluents, disintegrants, and binders. [Claim 3] A plurality of granules according to claim 1, comprising a diluent and a binder. [Claim 4] A number of granules according to claim 1, comprising a diluent, a disintegrant, and a binder. [Claim 5] The plurality of granules according to claim 1, wherein N-(2-(tert-butyl)-1-((4,4-difluorocyclohexyl)methyl)-1H-benzimidazole-5-yl)ethanesulfonamide or a pharmaceutically acceptable salt thereof is present in the plurality of granules in an amount less than 0.5% w / w of the total weight of the plurality of granules, for example, less than 0.4, 0.3, 0.2, 0.15, 0.14, 0.13, 0.12, 0.11, 0.10, 0.08, 0.06, or 0.05% w / w of the plurality of granules. [Claim 6] The plurality of granules according to claim 2, wherein the diluent is present in the plurality of granules in an amount of at least 70% by weight w / w of the total weight of the plurality of granules, for example, at least 75, 80, 85, or 90% w / w. [Claim 7] The plurality of granules according to claim 2, wherein the disintegrant is present in the plurality of granules in an amount of at least 0.5% w / w of the total weight of the plurality of granules, for example, at least 1, 2, or 3% w / w. [Claim 8] The plurality of granules according to claim 2, wherein the binder is present in the plurality of granules in an amount of at least 0.5% w / w of the total weight of the plurality of granules, for example, at least 1 or 2% w / w. [Claim 9] The plurality of granules according to claim 2, wherein the diluent is mannitol. [Claim 10] The plurality of granules according to claim 2, wherein the disintegrant is selected from low-substituted hydroxypropyl cellulose, sodium starch glycolate, and sodium croscarmellose. [Claim 11] The plurality of granules according to claim 10, wherein the disintegrant is low-substituted hydroxypropyl cellulose. [Claim 12] The plurality of granules according to claim 2, wherein the binder is selected from hydroxypropyl methylcellulose and povidone. [Claim 13] The plurality of granules according to claim 12, wherein the binder is hydroxypropyl methylcellulose. [Claim 14] The plurality of granules according to claim 13, wherein the hydroxypropyl methylcellulose is 6cps grade hydroxypropyl methylcellulose. [Claim 15] The plurality of granules according to claim 1, wherein the average size of the granules is less than 1200 μm. [Claim 16] The plurality of granules according to claim 1, wherein the bulk density of the granules is about 0.1 to about 0.7 g / mL, for example, about 0.2 to about 0.6 g / mL or about 0.3 to about 0.5 g / mL. [Claim 17] A plurality of granules according to claim 1, further comprising a lubricant. [Claim 18] The plurality of granules according to claim 17, wherein the lubricant is sodium stearyl fumarate. [Claim 19] An oral pharmaceutical composition comprising a number of granules as described in any one of claims 1 to 18. [Claim 20] The pharmaceutical composition according to claim 19, which is a capsule or a tablet. [Claim 21] The pharmaceutical composition according to claim 19, which is a capsule. [Claim 22] The pharmaceutical composition according to claim 21, wherein the capsule comprises hydroxypropyl methylcellulose or a gelatin capsule shell. [Claim 23] The pharmaceutical composition according to claim 19, which is an immediate-release pharmaceutical composition. [Claim 24] The pharmaceutical composition according to claim 23, wherein at least 75% of the total amount of N-(2-(tert-butyl)-1-((4,4-difluorocyclohexyl)methyl)-1H-benzimidazole-5-yl)ethanesulfonamide 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. [Claim 25] The pharmaceutical composition according to claim 19, wherein when subjected to a content uniformity test as described in the European Pharmacopoeia, the acceptable value is less than 15. [Claim 26] The pharmaceutical composition according to claim 19, wherein N-(2-(tert-butyl)-1-((4,4-difluorocyclohexyl)methyl)-1H-benzimidazole-5-yl)ethanesulfonamide or a pharmaceutically acceptable salt thereof is stable in the pharmaceutical composition for at least two weeks, one, two, three, six, twelve, or twenty-four months. [Claim 27] A process for preparing a large number of granules: a. The process of mixing the binder and diluent together; b. The step of injecting the primary granulation liquid into the mixture of step a and mixing until granules are formed; and c. The process includes drying the mixture from step b, A process comprising mixing N-(2-(tert-butyl)-1-((4,4-difluorocyclohexyl)methyl)-1H-benzimidazole-5-yl)ethanesulfonamide or a pharmaceutically acceptable salt thereof with the binder and the diluent in step a, or dissolving it in the primary granulation solution. [Claim 28] The process according to claim 27, wherein N-(2-(tert-butyl)-1-((4,4-difluorocyclohexyl)methyl)-1H-benzimidazole-5-yl)ethanesulfonamide or a pharmaceutically acceptable salt thereof is mixed with the binder and the diluent in step a. [Claim 29] The process according to claim 27, further comprising step a mixing the disintegrant with the binder and the diluent. [Claim 30] The process according to claim 27, wherein N-(2-(tert-butyl)-1-((4,4-difluorocyclohexyl)methyl)-1H-benzimidazole-5-yl)ethanesulfonamide or a pharmaceutically acceptable salt thereof has a solubility of at least 0.6 mg / mL in the primary granulation solution at room temperature. [Claim 31] The process according to claim 27, wherein the primary granulation solution is selected from ethanol, 0.1 M HCl, pH 3 citrate buffer, and a 5% SLS aqueous solution. [Claim 32] The process according to claim 31, wherein the primary granulation solution is 0.1 M HCl. [Claim 33] The process according to claim 27, wherein in step b, the primary granulation liquid is added at a rate of about 2 to about 10 mL / min, preferably about 4 to about 7 mL / min, and more preferably about 5 to about 6 mL / min. [Claim 34] The process according to claim 27, wherein in step b, the mixture is mixed at high speed. [Claim 35] The process according to claim 27, wherein in step c, the granules are dried at a high temperature. [Claim 36] The process according to claim 27, wherein the high temperature is greater than 30°C, for example, greater than 40°C or greater than 50°C. [Claim 37] The process according to claim 27, further comprising adding a secondary granulation solution in step b. [Claim 38] The process according to claim 37, wherein the secondary granulation solution is selected from ethanol, 0.1 M HCl, pH 3 citrate buffer, and a 5% SLS aqueous solution. [Claim 39] The process according to claim 38, wherein the secondary granulation solution is 0.1 M HCl. [Claim 40] The process according to claim 37, wherein the secondary liquid is added for at least one minute, for example, at least two minutes, at least five minutes, or at least eight minutes. [Claim 41] A pharmaceutical composition according to claim 19 for use as a pharmaceutical. [Claim 42] CB １ and / or CB ２ The pharmaceutical composition according to claim 19, for use in a disease state or disorder in which receptor dysfunction is present or exhibits such dysfunction. [Claim 43] The pharmaceutical composition according to claim 19, for use in the treatment of anorexia-related conditions; cachexia-related conditions; or anorexia nervosa.

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