PHARMACEUTICAL COMPOSITIONS WITH CANNABINOID AGONGISTS

Description

FIELD OF THE DISCLOSURE

[0001] The present disclosure relates to pharmaceutical compositions comprising N-(2-(tert-butyl)-1-((4,4-difluorocyclohexyl)methyl)-1H-benzimidazol-5-yl)ethanesulfonamide, or a pharmaceutically acceptable salt thereof, as an active substance. The pharmaceutical compositions are suitable for use in immediate release pharmaceutical formulations. The pharmaceutical formulations are suitable for use in the treatment of medical conditions in which treatment with agonists of CB 1 / CB 2 receptors are beneficial.BACKGROUND OF THE DISCLOSURE

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

[0003] Compound I and a synthetic route to prepare it were first disclosed in WO2006 / 033631 A1. Compound I has been evaluated in a number of phase 1 clinical trials as a potential treatment for pain.

[0004] Cannabinoid agonists have potential uses in a number of clinical settings, which include pain relief and cancer therapy (Cancer Prev Res (Phila). 2011 January; 4(1): 65-75).

[0005] Furthermore, multiple cannabinoid agonists have been approved in the US and other major markets for the treatment of nausea and vomiting related to cancer, and clinical studies have been conducted which evaluate the potential for cannabinoids to be used for anorexia and cachexia associated with cancer.

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

[0007] Due to the high potency of Compound I, very low therapeutic doses of the active substance (in the microgram range) are required. Pharmaceutical formulations requiring very low amounts of an active substance are difficult to manufacture as it can be difficult to achieve an acceptable level of content uniformity. It is imperative that pharmaceutical formulations have an acceptable content uniformity as it ensures that the patient receiving the pharmaceutical formulation receives the intended dose. This is critical from a safety and an efficacy perspective. In the present case it is anticipated the lowest dose could be as low as 50 µg.

[0008] Because of the very low amounts of active substance needed, problems can arise during mixing and formulation of the active substance, for example due to segregation, content uniformity and physical stability. The small quantity of the active substance required must be evenly distributed throughout a powder blend. This is especially difficult if the active substance is poor flowing and / or cohesive.

[0009] Furthermore, Compound I is prone to degradation when present in a solution and on exposure to light, see Example 1 herein. This is problematic when considering viable formulations for this active substance. The active substance needs to be stable during manufacturing process of the pharmaceutical formulation and the resultant formulation must also be stable over an extended period of time.

[0010] The combination of requiring a low dose of Compound I and its instability in solution present difficulties when it comes to developing a suitable pharmaceutical formulation.

[0011] In the present case, an immediate release pharmaceutical formulation comprising Compound I is also required to provide optimal absorption. Thus, there is a need for an immediate release oral dosage form of Compound I with good uniformity of content and good physical and chemical stability over prolonged period of times.

[0012] The present disclosure was devised with the foregoing in mind.SUMMARY OF THE DISCLOSURE

[0013] Disclosed herein are pharmaceutical compositions for oral use according to the claims comprising as an active substance Compound I, or a pharmaceutically acceptable salt thereof, and immediate release pharmaceutical formulations comprising the pharmaceutical composition.

[0014] According to a first aspect of the disclosure, there is provided a pharmaceutical composition for oral use comprising as an active substance Compound I, or a pharmaceutically acceptable salt thereof, and a non-aqueous solvent for the active substance, wherein (i) the pharmaceutical composition comprises 0.001% (+ / - 10%) to 0.8% (+ / - 10%) w / w of the active substance by weight of the total pharmaceutical composition; (ii) the pharmaceutical composition comprises at least 20% w / w of the non-aqueous solvent by weight of the total pharmaceutical composition and the non-aqueous solvent comprises polyethylene glycol having an average molecular weight of between 400 and 10000 g / mol.

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

[0016] According to a further aspect of the disclosure, there is provided a pharmaceutical composition for oral use according to the claims comprising as an active substance Compound I, or a pharmaceutically acceptable salt thereof, wherein the active substance is stable in the pharmaceutical composition for at least about 2 weeks, about 1 month, about 2 months, about 3 months, about 6 months, about 12 months, or about 24 months.

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

[0018] According to a further aspect of the disclosure, there is provided a pharmaceutical composition for oral use according to the claims comprising as an active substance Compound I, or a pharmaceutically acceptable salt thereof, and a non-aqueous solvent for the active substance wherein the active substance is homogenously distributed throughout the non-aqueous solvent.

[0019] Also disclosed but not claimed is a method of manufacturing the pharmaceutical composition described herein comprising the step of mixing as an active substance Compound I, or a pharmaceutically acceptable salt thereof, into a non-aqueous solvent.

[0020] In a further aspect, there is provided an immediate release pharmaceutical formulation for oral use comprising the pharmaceutical composition according to the claims.

[0021] In a further aspect, there is provided a pharmaceutical composition according to the claims or an immediate release pharmaceutical formulation according to the claims for use as a medicament.BRIEF DESCRIPTION OF THE DRAWINGS

[0022] For a better understanding of the disclosure, and to show how embodiments of the same are put into effect, reference is now made, by way of example, to the following figures, in which: Figure 1: Dissolution profiles in 0.1M HCl for 50 µg active substance capsules (50 mg fill) manufactured with D-α-Tocopherol polyethylene glycol 1000 succinate (Vitamin E TPGS). Figure 2: Dissolution profiles in 0.1M HCl for 50 µg active substance capsules (50 mg fill) manufactured with polyethylene glycol (PEG) 1500. Figure 3: Dissolution profiles in 0.1M HCl for 200 µg active substance capsules (50 mg fill) manufactured with Vitamin E TPGS. Figure 4: Dissolution profiles in 0.1M HCl for 200 µg active substance capsules (50 mg fill) manufactured with PEG 1500. Figure 5: Dissolution profiles in 0.1M HCl for 200 µg active substance capsules (200 mg fill) manufactured with Vitamin E TPGS. Figure 6: Dissolution profiles in 0.1M HCl for 200 µg active substance capsules (200 mg fill) manufactured with PEG 1500. Figure 7: Dissolution profiles in pH 6.8 phosphate buffer for 50 µg active substance capsules (50 mg fill) manufactured with Vitamin E TPGS. Figure 8: Dissolution profiles in pH 6.8 phosphate buffer for 50 µg active substance capsules (50 mg fill) manufactured with PEG 1500. Figure 9: Dissolution profiles in pH 6.8 phosphate buffer for 200 µg active substance immediate release (IR) capsules (50 mg fill) manufactured with Vitamin E TPGS. Figure 10: Dissolution profiles in pH 6.8 phosphate buffer for 200 µg active substance capsules (50 mg fill) manufactured with PEG 1500. Figure 11: Dissolution profiles in pH 6.8 phosphate buffer for 200 µg active substance capsules (200 mg fill) manufactured with Vitamin E TPGS Figure 12: Dissolution profiles in pH 6.8 phosphate buffer for 200 µg active substance capsules (200 mg fill) manufactured with PEG 1500 Figure 13: % Area of RRT 1.35 peak in vial aliquots of the 50 µg filling fluid as a function of incubation time at 60 °C. Figure 14: Mean release of active substance (%label claim) from 50 µg capsules versus time in 0.1M HCl and pH 6.8 media. Figure 15: Mean release of active substance (%label claim) from 200 µg capsules versus time in 0.1M HCl and pH 6.8 media. Figure 16: Mean release of active substance (% of nominal dose) for 0.4% w / w API and solvent capsules (solvent = Vitamin E TPGS, PEG1500, PEG6000, PEG1500: TPGS (1:1), PEG1500: TPGS (9:1), and PEG1500: TPGS (1:9)) Figure 17: Mean release of active substance (normalised data) for 0.4% w / w API and solvent capsules (solvent = Vitamin E TPGS, PEG1500, PEG6000, PEG1500: TPGS (1:1), PEG1500: TPGS (9:1), and PEG1500: TPGS (1:9)) Figure 18: Mean release of active substance (% of nominal dose) for single solvent and API capsules Figure 19: Mean release of active substance (normalised data) for single solvent and API capsules Figure 20: Mean release of active substance (% of nominal dose) for binary solvent and API capsules Figure 21: Mean release of active substance (normalised data) for binary solvent and API capsules Figure 22: Mean release of active substance (%dissolved) from 50 µg capsules stored at 25°C / 60%RH in 0.1M HCl Figure 23: Mean release of active substance (%dissolved) from 50 µg capsules stored at 40°C / 75%RH in 0.1M HCl Figure 24: Mean release of active substance (%dissolved) from 50 µg capsules stored at 25°C / 60%RH in pH 6.8 phosphate buffer Figure 25: Mean release of active substance (%dissolved) from 50 µg capsules stored at 40°C / 75%RH in pH 6.8 phosphate buffer Figure 26: Mean release of active substance (%dissolved) from 200 µg capsules stored at 25°C / 60%RH in 0.1M HCl Figure 27: Mean release of active substance (%dissolved) from 200 µg capsules stored at 40°C / 75%RH in 0.1M HCl Figure 28: Mean release of active substance (%dissolved) from 200 µg capsules stored at 25°C / 60%RH in pH 6.8 phosphate buffer Figure 29: Mean release of active substance (%dissolved) from 200 µg capsules stored at 40°C / 75%RH in pH 6.8 phosphate buffer DETAILED DESCRIPTION OF THE DISCLOSURE

[0023] Unless otherwise stated, the following terms used in the specification and claims have the following meanings set out below.

[0024] The disclosed compositions, formulations, processes of manufacture and methods may be understood more readily by reference to the following detailed description taken in connection with the accompanying figures, which form a part of this disclosure. It is to be understood that the disclosed compositions, formulations, processes of manufacture and methods are not limited to the specific compositions, formulations, processes of manufacture and methods described and / or shown herein, and that the terminology used herein is for the purpose of describing particular embodiments by way of example only and is not intended to be limiting of the claimed compositions, formulations, processes of manufacture and methods.

[0025] Reference to a particular numerical value includes at least that particular value, unless the context clearly dictates otherwise. When a range of values is expressed, another embodiment includes from the one particular value and / or to the other particular value. Further, reference to values stated in ranges include each and every value within that range. All ranges are inclusive and combinable.

[0026] When values are expressed as approximations, by use of the antecedent "about," it will be understood that the particular value forms another embodiment.

[0027] The term "about" when used in reference to numerical ranges, cut-offs, or specific values is used to indicate that the recited values may vary by up to as much as 10% from the listed value. As many of the numerical values used herein are experimentally determined, it should be understood by those skilled in the art that such determinations can, and often times will, vary among different experiments. The values used herein should not be considered unduly limiting by virtue of this inherent variation. Thus, the term "about" is used to encompass variations of ± 10% or less, variations of ± 5% or less, variations of ± 1% or less, variations of ± 0.5% or less, or variations of ± 0.1% or less from the specified value.

[0028] It is to be appreciated that certain features of the disclosed compositions, formulations, processes of manufacture and methods which are, for clarity, described herein in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the disclosed compositions, formulations processes of manufacture and methods that are, for brevity, described in the context of a single embodiment, may also be provided separately or in any sub-combination.

[0029] As used herein, the singular forms "a," "an," and "the" include the plural.

[0030] Where a composition is said to comprise a stipulated ingredient, it is to include the composition comprising one type of the stipulated ingredient, or a mixture of types of the stipulated ingredients. For example, said composition may comprise at least one type of the stipulated ingredient, such as at least two types, at least three types, or at least four types. Suitably, the composition comprises one type of the stipulated ingredient, two types of the stipulated ingredients, three types of the stipulated ingredients or four types of the stipulated ingredients.

[0031] Where a composition is said to comprise a stipulated ingredient (optionally in a stipulated amount or concentration), said composition may optionally include additional ingredients other than that stipulated. However, in certain embodiments, a composition said to comprise a stipulated ingredient may in fact consist essentially of or consist of all the stipulated ingredient.

[0032] Herein, where a composition is said to "consists essentially of" a particular component, said composition suitably comprises at least 70 wt% of said component, suitably at least 80 wt% thereof, suitably at least 90 wt% thereof, suitably at least 95 wt% thereof, most suitably at least 99 wt% thereof. Suitably, a composition said to "consist essentially of" a particular component consists of said component save for one or more trace impurities.

[0033] Herein, the term semi-solid is used to indicate a material which is a solid at room temperature and is a liquid at a temperature above room temperature, for example, the material has a melting point of at least about 30°C, such as at least about 35°C, at least about 40°C. Suitably, the material has a melting point between about 35°C and about 80°C, such as between about 35°C and about 70°C, about 35°C and about 60°C, about 35°C and about 50°C, or about 40°C and about 50°C. Suitably, the material has a melting point of at least 30°C, such as at least 35°C, at least 40°C. Suitably, the material has a melting point between 35°C and 80°C, such as between 35°C and 70°C, 35°C and 60°C, 35°C and 50°C, or 40°C and 50°C.

[0034] Room temperature is herein defined as a temperature of about 15°C to about 25°C, such as about 20°C to about 25°C. Suitably, room temperature is about 20°C. Suitably, room temperature is 15°C to 25°C, such as 20°C to 25°C. Suitably, room temperature is 20°C.

[0035] It is to be appreciated that references to "treating" or "treatment" include prophylaxis as well as the alleviation of established symptoms of a condition. "Treating" or "treatment" of a state, disorder or condition therefore includes: (1) preventing or delaying the appearance of clinical symptoms of the state, disorder or condition developing in a human that may be afflicted with or predisposed to the state, disorder or condition but does not yet experience or display clinical or subclinical symptoms of the state, disorder or condition, (2) inhibiting the state, disorder or condition, i.e., arresting, reducing or delaying the development of the disease or a relapse thereof (in case of maintenance treatment) or at least one clinical or subclinical symptom thereof, or (3) relieving or attenuating the disease, i.e., causing regression of the state, disorder or condition or at least one of its clinical or subclinical symptoms.

[0036] As used herein, the phrase "therapeutically effective dose" refers to an amount of the pharmaceutical composition or immediate release pharmaceutical formulation comprising the active substance, as described herein, effective to achieve a particular biological or therapeutic result such as, but not limited to, biological or therapeutic results disclosed, described, or exemplified herein. The therapeutically effective dose may vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of the composition to cause a desired response in a subject. Such results include, but are not limited to, the reduction, remission, and / or regression of the benign or malignant disease or prevention of the development of the benign or malignant disease, as determined by any means suitable in the art.

[0037] As used herein, "subject" includes a vertebrate; mammal, such as primates, humans, dogs, cattle, and horses; or a domestic animal.PHARMACEUTICAL COMPOSITIONS

[0038] According to a first aspect of the disclosure, there is provided a pharmaceutical composition for oral use according to the claims comprising as an active substance Compound I, or a pharmaceutically acceptable salt thereof, and a non-aqueous solvent for the active substance.

[0039] Suitably, there is provided a pharmaceutical composition for oral use consisting of: a. as an active substance Compound I, or a pharmaceutically acceptable salt thereof; and b. a non-aqueous solvent for the active substance.

[0040] Suitably, there is provided a pharmaceutical composition for oral use comprising as an active substance Compound I, or a pharmaceutically acceptable salt thereof, and a non-aqueous solvent for the active substance, wherein the pharmaceutical composition is a semi-solid at room temperature.

[0041] Suitably, there is provided a pharmaceutical composition for oral use comprising as an active substance Compound I, or a pharmaceutically acceptable salt thereof, and a non-aqueous solvent for the active substance, and wherein the non-aqueous solvent is a semi-solid at room temperature.

[0042] Suitably, there is provided a pharmaceutical composition for oral use comprising as an active substance Compound I, or a pharmaceutically acceptable salt thereof, and a non-aqueous solvent for the active substance, wherein the active substance has a solubility in the non-aqueous solvent of at least about 0.1% w / w at room temperature.

[0043] Suitably, the non-aqueous solvent comprises polyethylene glycol, ethanol, stearoyl polyoxylglyceride, polyoxyethylene stearate, medium chain fatty acid, long chain monoglyceride, long chain diglyceride, medium chain monoglyceride, medium chain diglyceride, polyoxyethylene castor oil derivative, polyoxyethylene sorbitan fatty acid ester, polyoxyethylated 12-hydroxystearic acid, caprylocaproyl polyoxylglyceride, oleoyl polyoxylglyceride, propylene glycol mono fatty ester, propylene glycol di fatty acid ester, diethylene glycol monoethyl ether, poloxamer, or vitamin E TPGS or combinations thereof. According to the claims, the non-aqueous solvent comprises polyethylene glycol.

[0044] Suitably, the non-aqueous solvent comprises polyethylene glycol, stearoyl polyoxylglyceride, polyoxyethylene stearate, long chain fatty acid, medium chain fatty acid, long chain monoglyceride, long chain diglyceride, medium chain monoglyceride, medium chain diglyceride, polyoxyethylene castor oil derivative, polyoxyethylene sorbitan fatty acid ester, polyoxyethylated 12-hydroxystearic acid, caprylocaproyl polyoxylglyceride, propylene glycol mono fatty ester, propylene glycol di fatty acid ester, diethylene glycol monoethyl ether, or poloxamer or combinations thereof. According to the claims, the non-aqueous solvent comprises polyethylene glycol.

[0045] Suitably, there is provided a pharmaceutical composition for oral use comprising as an active substance Compound I, or a pharmaceutically acceptable salt thereof, and a non-aqueous solvent for the active substance, wherein the active substance has a solubility in the non-aqueous solvent of at least about 0.1% w / w at room temperature, and the pharmaceutical composition is a semi-solid at room temperature.

[0046] Suitably, there is provided a pharmaceutical composition for oral use comprising as an active substance Compound I, or a pharmaceutically acceptable salt thereof, and a non-aqueous solvent for the active substance, wherein the active substance is dissolved in the non-aqueous solvent.

[0047] Suitably, there is provided a pharmaceutical composition for oral use comprising as an active substance Compound I, or a pharmaceutically acceptable salt thereof, and a non-aqueous solvent for the active substance, wherein the non-aqueous solvent is water soluble.

[0048] According to the claims, there is provided a pharmaceutical composition for oral use comprising as an active substance Compound I, or a pharmaceutically acceptable salt thereof, and a non-aqueous solvent for the active substance, wherein the pharmaceutical composition comprises at least 20% w / w of the non-aqueous solvent by weight of the total pharmaceutical composition, such as at least about 30% w / w, at least about 40% w / w, at least about 50% w / w, at least about 60% w / w, at least about 70% w / w, at least about 80% w / w, at least about 90% w / w, at least about 95% w / w, at least about 96% w / w, at least about 97% w / w, at least about 98% w / w, at least about 99% w / w, at least about 99.2% w / w, or at least about 99.5% w / w.

[0049] Suitably, there is provided a pharmaceutical composition for oral use comprising as an active substance Compound I, or a pharmaceutically acceptable salt thereof, and a non-aqueous solvent for the active substance, wherein the pharmaceutical composition comprises between 20 and about 99.99% w / w of the non-aqueous solvent by weight of the total pharmaceutical composition, such as between about 30 and about 99.99% w / w, about 40 and about 99.99% w / w, about 50 and about 99.99% w / w, about 60 and about 99.99% w / w, about 70 and about 99.99% w / w, about 80 and about 99.99% w / w, about 90 and about 99.99% w / w, about 95 and about 99.99% w / w, about 96 and about 99.99% w / w, about 97 and about 99.99% w / w, about 98 and about 99.99% w / w, about 99 and about 99.99% w / w, about 99.2 and about 99.99% w / w, or about 99.5 and about 99.99% w / w.

[0050] According to the claims, there is provided a pharmaceutical composition for oral use comprising as an active substance Compound I, or a pharmaceutically acceptable salt thereof, and a non-aqueous solvent for the active substance, wherein the pharmaceutical composition comprises at least 20% w / w of the non-aqueous solvent by weight of the total pharmaceutical composition, and between about 0.001 and about 0.8% w / w of the active substance by weight of the total pharmaceutical composition.

[0051] Suitably, there is provided a pharmaceutical composition for oral use comprising as an active substance Compound I, or a pharmaceutically acceptable salt thereof, and a non-aqueous solvent for the active substance, wherein the pharmaceutical composition comprises between 20 and about 99.99% w / w of the non-aqueous solvent by weight of the total pharmaceutical composition, and between about 0.001 and about 0.8% w / w of the active substance by weight of the total pharmaceutical composition.

[0052] According to the claims, there is provided a pharmaceutical composition for oral use comprising as an active substance Compound I, or a pharmaceutically acceptable salt thereof, and a non-aqueous solvent for the active substance, wherein the non-aqueous solvent comprises polyethylene glycol.

[0053] Suitably, there is provided a pharmaceutical composition for oral use comprising as an active substance Compound I, or a pharmaceutically acceptable salt thereof, and a non-aqueous solvent for the active substance, wherein the non-aqueous solvent comprises polyethylene glycol wherein the polyethylene glycol has an average molecular weight between 400 and about 6000 g / mol, such as between about 1000 and about 6000 g / mol, such as between about 1200 and about 1800 g / mol, such as between about 1400 and about 1600 g / mol. Suitably, the polyethylene glycol has an average molecular weight of 400 g / mol, about 1500 g / mol, about 4000 g / mol, or about 6000 g / mol.

[0054] Suitably, there is provided a pharmaceutical composition for oral use comprising as an active substance Compound I, or a pharmaceutically acceptable salt thereof, and a non-aqueous solvent for the active substance, wherein: a. the non-aqueous solvent is polyethylene glycol; b. the pharmaceutical composition comprises between 20 and about 99.99% w / w of the non-aqueous solvent by weight of the total pharmaceutical composition; and c. the pharmaceutical composition comprises between about 0.001 and about 0.8% w / w of the active substance by weight of the total pharmaceutical composition.

[0055] Also disclosed but not claimed is a pharmaceutical composition for oral use comprising as an active substance Compound I, or a pharmaceutically acceptable salt thereof, and a non-aqueous solvent for the active substance, wherein: a. the non-aqueous solvent is polyethylene glycol wherein the polyethylene glycol has an average molecular weight between about 200 and about 25000 g / mol; b. the pharmaceutical composition comprises between about 50 and about 99.99% w / w of the non-aqueous solvent by weight of the total pharmaceutical composition; and c. the pharmaceutical composition comprises between about 0.01 and about 0.8% w / w of the active substance by weight of the total pharmaceutical composition.

[0056] Suitably, there is provided a pharmaceutical composition for oral use comprising as an active substance Compound I, or a pharmaceutically acceptable salt thereof, and a non-aqueous solvent for the active substance, wherein: a. the non-aqueous solvent is polyethylene glycol wherein the polyethylene glycol has an average molecular weight between about 1000 and about 6000 g / mol; b. the pharmaceutical composition comprises between about 50 and about 99.99% w / w of the non-aqueous solvent by weight of the total pharmaceutical composition; and c. the pharmaceutical composition comprises between about 0.01 and about 0.8% w / w of the active substance by weight of the total pharmaceutical composition.

[0057] Suitably, there is provided a pharmaceutical composition for oral use comprising as an active substance Compound I, or a pharmaceutically acceptable salt thereof, a non-aqueous solvent for the active substance and vitamin E TPGS; wherein the non-aqueous solvent comprises polyethylene glycol.

[0058] Suitably, there is provided a pharmaceutical composition for oral use comprising as an active substance Compound I, or a pharmaceutically acceptable salt thereof, and a non-aqueous solvent for the active substance, wherein the active substance is stable in the pharmaceutical composition for at least about 2 weeks, about 1 month, about 2 months, about 3 months, about 6 months, about 12 months, or about 24 months.

[0059] Suitably, there is provided a pharmaceutical composition for oral use comprising as an active substance Compound I, or a pharmaceutically acceptable salt thereof, and a non-aqueous solvent for the active substance, wherein: a. the total amount of degradation products of the active substance is less than or equal to about 4 area% as determined by a chromatographic method when the pharmaceutical composition is stored at 25°C / 60%RH and / or 40°C / 75%RH for at least about 2 weeks, about 1 month, about 2 months, about 3 months, about 6 months, about 12 months, or about 24 months; and / or b. the assay of the active substance is about 90 to about 110% of nominal as determined by a chromatographic method 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.

[0060] Suitably, there is provided a pharmaceutical composition for oral use comprising as an active substance Compound I, or a pharmaceutically acceptable salt thereof, and a non-aqueous solvent for the active substance, wherein at least about 75% of the total amount of the active substance contained in the pharmaceutical composition is released within about the first 45 minutes when the pharmaceutical composition is subjected to an in vitro dissolution test employing 0.1 M HCl or pH 6.8 phosphate buffer as the dissolution medium and the dissolution profile is determined as described in the United States Pharmacopeia at 37°C using a rotation speed of 50 rpm.

[0061] Suitably, there is provided a pharmaceutical composition for oral use comprising as an active substance Compound I, or a pharmaceutically acceptable salt thereof, and a non-aqueous solvent for the active substance, wherein the active substance is homogeneously distributed throughout the non-aqueous solvent.

[0062] According to a second aspect of the disclosure, there is provided a pharmaceutical composition for oral use according to the claims comprising as an active substance Compound I, or a pharmaceutically acceptable salt thereof, wherein the pharmaceutical composition is a semi-solid at room temperature.

[0063] A semi-solid is any material which at room temperature is a solid and at a temperature above room temperature is a liquid. Suitably, room temperature is about 15°C to about 25°C, such as about 20°C to about 25°C. Suitably, room temperature is about 20°C. Suitably, room temperature is 15°C to 25°C, such as 20°C to 25°C. Suitably, room temperature is 20°C.

[0064] Advantageously, the semi-solid nature of the pharmaceutical composition facilitates the continued uniform distribution of the active substance within the non-aqueous solvent upon storage, and / or an acceptable stability profile of the pharmaceutical composition as the active substance is dispersed / dissolved in a semi-solid within the pharmaceutical composition at typical storage conditions, i.e., room temperature. Furthermore, during manufacture the pharmaceutical composition is a liquid which facilitates the uniform distribution of the active substance throughout the pharmaceutical composition.

[0065] Suitably, there is provided a pharmaceutical composition for oral use comprising as an active substance Compound I, or a pharmaceutically acceptable salt thereof, wherein the pharmaceutical composition is a semi-solid at room temperature and has a melting point of at least about 30°C, such as at least about 35°C, or at least about 40°C.

[0066] Suitably, there is provided a pharmaceutical composition for oral use comprising as an active substance Compound I, or a pharmaceutically acceptable salt thereof, wherein the pharmaceutical composition is a semi-solid at room temperature and has a melting point between about 35°C and about 80°C, such as between about 35°C and about 70°C, about 35°C and about 60°C, about 35°C and about 50°C, or about 40°C and about 50°C.

[0067] Suitably, there is provided a pharmaceutical composition for oral use comprising as an active substance Compound I, or a pharmaceutically acceptable salt thereof, wherein the pharmaceutical composition is a semi-solid at room temperature and the pharmaceutical composition comprises a non-aqueous solvent for the active substance.

[0068] Suitably, there is provided a pharmaceutical composition for oral use comprising as an active substance Compound I, or a pharmaceutically acceptable salt thereof, wherein the pharmaceutical composition is a semi-solid at room temperature and wherein the active substance is stable in the pharmaceutical for at least about 2 weeks, about 1 month, about 2 months, about 3 months, about 6 months, about 12 months, or about 24 months.

[0069] Suitably, there is provided a pharmaceutical composition for oral use comprising as an active substance Compound I, or a pharmaceutically acceptable salt thereof, wherein the pharmaceutical composition is a semi-solid at room temperature and wherein: a. the total amount of degradation products of the active substance is less than or equal to about 4 area% as determined by a chromatographic method when the pharmaceutical composition is stored at 25°C / 60%RH and / or 40°C / 75%RH for at least about 2 weeks, about 1 month, about 2 months, about 3 months, about 6 months, about 12 months, or about 24 months; and / or b. the assay of the active substance is about 90 to about 110% of nominal as determined by a chromatographic method 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.

[0070] Suitably, there is provided a pharmaceutical composition for oral use comprising as an active substance Compound I, or a pharmaceutically acceptable salt thereof, wherein the pharmaceutical composition is a semi-solid at room temperature and wherein at least about 75% of the total amount of the active substance contained in the pharmaceutical composition is released within about the first 45 minutes when the pharmaceutical composition is subjected to an in vitro dissolution test employing 0.1 M HCl or pH 6.8 phosphate buffer as the dissolution medium and the dissolution profile is determined as described in the United States Pharmacopeia at 37°C using a rotation speed of 50 rpm.

[0071] Suitably, there is provided a pharmaceutical composition for oral use comprising as an active substance Compound I, or a pharmaceutically acceptable salt thereof, and a non-aqueous solvent for the active substance wherein the pharmaceutical composition is a semi-solid at room temperature and the active substance is homogeneously distributed throughout the non-aqueous solvent.

[0072] According to a further aspect of the disclosure, there is provided a pharmaceutical composition for oral use according to the claims comprising as an active substance Compound I, or a pharmaceutically acceptable salt thereof, wherein the active substance is stable in the pharmaceutical composition for at least about 2 weeks, about 1 month, about 2 months, about 3 months, about 6 months, about 12 months, or about 24 months.

[0073] Advantageously, the active substance is stable in the pharmaceutical composition. Stability of a pharmaceutical composition is required to ensure the end user, i.e., the patient, receives the intended dose of the active substance and is not exposed to degradants of the active substance. This is critical from a patient safety and efficacy perspective. Furthermore, a stable pharmaceutical composition which does not require special storage conditions, for example, refrigerated storage, is advantageous as means supply chains are simpler and / or cheaper.

[0074] Suitably, there is provided a pharmaceutical composition for oral use comprising as an active substance Compound I, or a pharmaceutically acceptable salt thereof, wherein the active substance is stable in the pharmaceutical composition for at least 2 weeks, 1, 2, 3, 6, 12, or 24 months.

[0075] Suitably, there is provided a pharmaceutical composition for oral use comprising as an active substance Compound I, or a pharmaceutically acceptable salt thereof, wherein the active substance is stable in the pharmaceutical composition when the pharmaceutical composition is stored at 25°C / 60%RH and / or 40°C / 75%RH for at least about 2 weeks, about 1 month, about 2 months, about 3 months, about 6 months, about 12 months, or about 24 months.

[0076] Suitably, there is provided a pharmaceutical composition for oral use comprising as an active substance Compound I, or a pharmaceutically acceptable salt thereof, wherein the active substance is stable in the pharmaceutical composition when the pharmaceutical composition is stored at 25°C / 60%RH and / or 40°C / 75%RH for 2 weeks, 1, 2, 3, 6, 12, or 24 months.

[0077] Suitably, there is provided a pharmaceutical composition for oral use comprising as an active substance Compound I, or a pharmaceutically acceptable salt thereof, wherein: a. the total amount of degradation products of the active substance is less than or equal to about 4 area% as determined by a chromatographic method when the pharmaceutical composition is stored at 25°C / 60%RH and / or 40°C / 75%RH for at least about 2 weeks, about 1 month, about 2 months, about 3 months, about 6 months, about 12 months, or about 24 months; and / or b. the assay of the active substance is about 90 to about 110% of nominal as determined by a chromatographic method 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.

[0078] Suitably, there is provided a pharmaceutical composition for oral use comprising as an active substance Compound I, or a pharmaceutically acceptable salt thereof, wherein: a. the total amount of degradation products of the active substance is less than or equal to about 3 area% as determined by a chromatographic method when the pharmaceutical composition is stored at 25°C / 60%RH and / or 40°C / 75%RH for at least about 2 weeks, about 1 month, about 2 months, about 3 months, about 6 months, about 12 months, or about 24 months; and / or b. the assay of the active substance is about 95 to about 105% of nominal as determined by a chromatographic method 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.

[0079] Suitably, there is provided a pharmaceutical composition for oral use comprising as an active substance Compound I, or a pharmaceutically acceptable salt thereof, wherein: a. the total amount of degradation products of the active substance is less than or equal to about 2 area% as determined by a chromatographic method when the pharmaceutical composition is stored at 25°C / 60%RH and / or 40°C / 75%RH for at least about 2 weeks, about 1 month, about 2 months, about 3 months, about 6 months, about 12 months, or about 24 months; and / or b. the assay of the active substance is about 95 to about 105% of nominal as determined by a chromatographic method when the pharmaceutical composition is stored at 25°C / 60%RH and / or 40°C / 75%RH for at least about 2 weeks, about 1 month, about 2 months, about 3 months, about 6 months, about 12 months, or about 24 months.

[0080] There is provided a pharmaceutical composition for oral use according to the claims comprising as an active substance Compound I, or a pharmaceutically acceptable salt thereof, wherein the active substance is stable in the pharmaceutical composition for at least about 2 weeks, about 1 month, about 2 months, about 3 months, about 6 months, about 12 months, or about 24 months, and wherein the pharmaceutical composition is a semi-solid at room temperature.

[0081] Suitably, the non-aqueous solvent comprises polyethylene glycol, stearoyl polyoxylglyceride, medium chain fatty acid, medium chain monoglyceride, medium chain diglyceride, polyoxyethylene castor oil derivative, polyoxyethylene sorbitan fatty acid ester, polyoxyethylated 12-hydroxystearic acid, propylene glycol di fatty acid ester, diethylene glycol monoethyl ether, or poloxamer or combinations thereof. Suitably, the polyoxyethylene castor oil derivative comprises polyoxyl 40 hydrogenated castor oil. Suitably, the polyoxyethylene castor oil derivative is polyoxyl 40 hydrogenated castor oil. According to the claims, the non-aqueous solvent comprises polyethylene glycol.

[0082] Suitably, the non-aqueous solvent comprises polyethylene glycol, stearoyl polyoxylglyceride, polyoxyethylene stearate, medium chain monoglyceride, medium chain diglyceride, polyoxyethylene sorbitan fatty acid ester, propylene glycol di fatty acid ester, or combinations thereof. According to the claims, the non-aqueous solvent comprises polyethylene glycol.

[0083] Suitably, there is provided a pharmaceutical composition for oral use comprising as an active substance Compound I, or a pharmaceutically acceptable salt thereof, wherein the active substance is stable in the pharmaceutical composition for at least about 2 weeks, about 1 month, about 2 months, about 3 months, about 6 months, about 12 months, or about 24 months, and wherein at least about 75% of the total amount of the active substance contained in the pharmaceutical composition is released within about the first 45 minutes when the pharmaceutical composition is subjected to an in vitro dissolution test employing 0.1 M HCl or pH 6.8 phosphate buffer as the dissolution medium and the dissolution profile is determined as described in the United States Pharmacopeia at 37°C using a rotation speed of 50 rpm.

[0084] There is provided a pharmaceutical composition for oral use according to the claims comprising as an active substance Compound I, or a pharmaceutically acceptable salt thereof, and a non-aqueous solvent for the active substance wherein the active substance is stable in the pharmaceutical composition for at least about 2 weeks, about 1 month, about 2 months, about 3 months, about 6 months, about 12 months, or about 24 months.

[0085] There is provided a pharmaceutical composition for oral use according to the claims comprising as an active substance Compound I, or a pharmaceutically acceptable salt thereof, and a non-aqueous solvent for the active substance wherein the active substance is stable in the pharmaceutical composition for at least about 2 weeks, about 1 month, about 2 months, about 3 months, about 6 months, about 12 months, or about 24 months, and wherein active substance is homogeneously dispersed throughout the non-aqueous solvent.

[0086] According to a further aspect of the disclosure, there is provided a pharmaceutical composition for oral use according to the claims comprising as an active substance Compound I, or a pharmaceutically acceptable salt thereof, wherein: a. at least about 75% of the total amount of the active substance contained in the pharmaceutical composition is released within about the first 45 minutes when the pharmaceutical composition is subjected to an in vitro dissolution test employing 0.1 M HCl or pH 6.8 phosphate buffer as the dissolution medium and the dissolution profile is determined as described in the United States Pharmacopeia at 37°C using a rotation speed of 50 rpm; and b. the pharmaceutical composition is a semi-solid at room temperature.

[0087] Advantageously, the release rate of the active substance from the pharmaceutical composition provides optimal absorption of the pharmaceutical composition upon oral administration to a patient.

[0088] Suitably, there is provided a pharmaceutical composition for oral use comprising as an active substance Compound I, or a pharmaceutically acceptable salt thereof, wherein: a. at least about 75% of the total amount of the active substance contained in the pharmaceutical composition is released within about the first 45 minutes when the pharmaceutical composition is subjected to an in vitro dissolution test employing 0.1 M HCl or pH 6.8 phosphate buffer as the dissolution medium and the dissolution profile is determined as described in the United States Pharmacopeia at 37°C using a rotation speed of 50 rpm; b. the pharmaceutical composition is a semi-solid at room temperature; and c. the pharmaceutical composition comprises a non-aqueous solvent.

[0089] Suitably, the non-aqueous solvent comprises polyethylene glycol, stearoyl polyoxylglyceride, polyoxyethylene stearate, medium chain fatty acid, long chain monoglyceride, long chain diglyceride, medium chain monoglyceride, medium chain diglyceride, polyoxyethylene castor oil derivative, polyoxyethylene sorbitan fatty acid ester, polyoxyethylated 12-hydroxystearic acid, caprylocaproyl polyoxylglyceride, propylene glycol mono fatty ester, propylene glycol di fatty acid ester, diethylene glycol monoethyl ether, poloxamer, vitamin E TPGS or combinations thereof. According to the claims, the non-aqueous solvent comprises polyethylene glycol.

[0090] Suitably, the non-aqueous solvent comprises polyethylene glycol, polyoxyethylene stearate, polyoxyethylene castor oil derivative, polyoxyethylated 12-hydroxystearic acid, diethylene glycol monoethyl ether, or poloxamer, vitamin E TPGS, or combinations thereof. According to the claims, the non-aqueous solvent comprises polyethylene glycol.

[0091] Suitably, there is provided a pharmaceutical composition for oral use comprising as an active substance Compound I, or a pharmaceutically acceptable salt thereof, wherein: a. at least about 75% of the total amount of the active substance contained in the pharmaceutical composition is released within about the first 30 minutes when the pharmaceutical composition is subjected to an in vitro dissolution test employing 0.1 M HCl or pH 6.8 phosphate buffer as the dissolution medium and the dissolution profile is determined as described in the United States Pharmacopeia at 37°C using a rotation speed of 50 rpm; and b. the pharmaceutical composition is a semi-solid at room temperature.

[0092] Suitably, there is provided a pharmaceutical composition for oral use comprising as an active substance Compound I, or a pharmaceutically acceptable salt thereof, wherein: a. at least about 85% of the total amount of the active substance contained in the pharmaceutical composition is released within about the first 15 minutes when the pharmaceutical composition is subjected to an in vitro dissolution test employing 0.1 M HCl or pH 6.8 phosphate buffer as the dissolution medium and the dissolution profile is determined as described in the United States Pharmacopeia at 37°C using a rotation speed of 50 rpm; and b. the pharmaceutical composition is a semi-solid at room temperature.

[0093] Suitably, there is provided a pharmaceutical composition for oral use comprising as an active substance Compound I, or a pharmaceutically acceptable salt thereof, wherein: a. at least about 85% of the total amount of the active substance contained in the pharmaceutical composition is released within about the first 15 minutes when the pharmaceutical composition is subjected to an in vitro dissolution test employing 0.1 M HCl or pH 6.8 phosphate buffer as the dissolution medium and the dissolution profile is determined as described in the United States Pharmacopeia at 37°C using a rotation speed of 50 rpm; b. the pharmaceutical composition is a semi-solid at room temperature; and c. the pharmaceutical comprises a non-aqueous solvent.

[0094] Suitably, the non-aqueous solvent comprises polyethylene glycol, stearoyl polyoxylglyceride, medium chain fatty acid, long chain monoglyceride, long chain diglyceride, medium chain monoglyceride, medium chain diglyceride, polyoxyethylene sorbitan fatty acid ester, caprylocaproyl polyoxylglyceride, propylene glycol mono fatty ester, propylene glycol di fatty acid ester, diethylene glycol monoethyl ether, poloxamer,or combinations thereof. According to the claims, the non-aqueous solvent comprises polyethylene glycol.

[0095] Suitably, the non-aqueous solvent comprises polyethylene glycol, polyoxyethylene castor oil derivative, polyoxyethylated 12-hydroxystearic acid, diethylene glycol monoethyl ether, or poloxamer, or combinations thereof. According to the claims, the non-aqueous solvent comprises polyethylene glycol.

[0096] Suitably, there is provided a pharmaceutical composition for oral use comprising as an active substance Compound I, or a pharmaceutically acceptable salt thereof, wherein: a. at least about 75% of the total amount of the active substance contained in the pharmaceutical composition is released within about the first 45 minutes when the pharmaceutical composition is subjected to an in vitro dissolution test employing 0.1 M HCl or pH 6.8 phosphate buffer as the dissolution medium and the dissolution profile is determined as described in the United States Pharmacopeia at 37°C using a rotation speed of 50 rpm; b. the pharmaceutical composition is a semi-solid at room temperature; and c. the active substance is stable in the pharmaceutical composition for at least about 2 weeks, about 1 month, about 2 months, about 3 months, about 6 months, about 12 months, or about 24 months.

[0097] Suitably, there is provided a pharmaceutical composition for oral use comprising as an active substance Compound I, or a pharmaceutically acceptable salt thereof, wherein: a. at least about 75% of the total amount of the active substance contained in the pharmaceutical composition is released within about the first 45 minutes when the pharmaceutical composition is subjected to an in vitro dissolution test employing 0.1 M HCl or pH 6.8 phosphate buffer as the dissolution medium and the dissolution profile is determined as described in the United States Pharmacopeia at 37°C using a rotation speed of 50 rpm; b. the pharmaceutical composition is a semi-solid at room temperature; and c. the pharmaceutical composition has a melting point between about 35°C and about 80°C.

[0098] Suitably, there is provided a pharmaceutical composition for oral use comprising as an active substance Compound I, or a pharmaceutically acceptable salt thereof, and a non-aqueous solvent for the active substance wherein: a. at least about 75% of the total amount of the active substance contained in the pharmaceutical composition is released within about the first 45 minutes when the pharmaceutical composition is subjected to an in vitro dissolution test employing 0.1 M HCl or pH 6.8 phosphate buffer as the dissolution medium and the dissolution profile is determined as described in the United States Pharmacopeia at 37°C using a rotation speed of 50 rpm; and b. the pharmaceutical composition is a semi-solid at room temperature.

[0099] Suitably, there is provided a pharmaceutical composition for oral use comprising as an active substance Compound I, or a pharmaceutically acceptable salt thereof, and a non-aqueous solvent for the active substance wherein: a. at least about 75% of the total amount of the active substance contained in the pharmaceutical composition is released within about the first 45 minutes when the pharmaceutical composition is subjected to an in vitro dissolution test employing 0.1 M HCl or pH 6.8 phosphate buffer as the dissolution medium and the dissolution profile is determined as described in the United States Pharmacopeia at 37°C using a rotation speed of 50 rpm; b. the pharmaceutical composition is a semi-solid at room temperature; and c. the active substance is homogenously distributed throughout the non-aqueous solvent.

[0100] According to a further aspect of the disclosure, there is provided a pharmaceutical composition for oral use according to the claims comprising as an active substance Compound I, or a pharmaceutically acceptable salt thereof, and a non-aqueous solvent for the active substance wherein the active substance is homogenously distributed throughout the non-aqueous solvent.

[0101] Advantageously, the active substance is uniformly dispersed within the pharmaceutical composition. This ensures the required amount of the active substance is present in the portion of the pharmaceutical composition, for example, upon dosing of the pharmaceutical composition to a patient, or the use of the pharmaceutical composition in the preparation of an immediate release pharmaceutical formulation. This is important from a patient safety and efficacy perspective.

[0102] Suitably, there is provided a pharmaceutical composition for oral use comprising as an active substance Compound I, or a pharmaceutically acceptable salt thereof, and a non-aqueous solvent for the active substance wherein the active substance is homogenously distributed throughout the non-aqueous solvent for at least about 2 weeks, about 1 month, about 2 months, about 3 months, about 6 months, about 12 months, or about 24 months.

[0103] Suitably, there is provided a pharmaceutical composition for oral use comprising as an active substance Compound I, or a pharmaceutically acceptable salt thereof, and a non-aqueous solvent for the active substance wherein the active substance is homogenously distributed throughout the non-aqueous solvent for at least about 2 weeks, about 1 month, about 2 months, about 3 months, about 6 months, about 12 months, or about 24 months upon storage of the pharmaceutical composition at room temperature.

[0104] Suitably, there is provided a pharmaceutical composition for oral use comprising as an active substance Compound I, or a pharmaceutically acceptable salt thereof, and a non-aqueous solvent for the active substance wherein: a. the active substance is homogenously distributed throughout the non-aqueous solvent; and b. the homogeneous distribution of the active substance in the non-aqueous solvent is determined by determining the weight percentage of the active substance within a portion of the pharmaceutical composition and wherein the weight percentage of the active substance within the portion of the pharmaceutical composition is ±5% of the expected value based on the total amount of the active substance added to the total amount of the pharmaceutical composition.

[0105] Suitably, there is provided a pharmaceutical composition for oral use comprising as an active substance Compound I, or a pharmaceutically acceptable salt thereof, and a non-aqueous solvent for the active substance wherein the active substance is homogenously distributed throughout the non-aqueous solvent and the pharmaceutical composition is a semi-solid at room temperature.

[0106] Suitably, there is provided a pharmaceutical composition for oral use comprising as an active substance Compound I, or a pharmaceutically acceptable salt thereof, and a non-aqueous solvent for the active substance wherein the active substance is homogenously distributed throughout the non-aqueous solvent and the active substance is stable in the pharmaceutical composition for at least about 2 weeks, about 1 month, about 2 months, about 3 months, about 6 months, about 12 months, or about 24 months.

[0107] Suitably, there is provided a pharmaceutical composition for oral use comprising as an active substance N-(2-(tert-butyl)-1-((4,4-difluorocyclohexyl)methyl)-1H-benzimidazol-5-yl)ethanesulfonamide, or a pharmaceutically acceptable salt thereof, and a non-aqueous solvent for the active substance wherein the active substance is homogenously distributed throughout the non-aqueous solvent and wherein at least about 75% of the total amount of the active substance contained in the pharmaceutical composition is released within about the first 45 minutes when the pharmaceutical composition is subjected to an in vitro dissolution test employing 0.1 M HCl or pH 6.8 phosphate buffer as the dissolution medium and the dissolution profile is determined as described in the United States Pharmacopeia at 37°C using a rotation speed of 50 rpm.PHARMACEUTICAL FORMULATIONS

[0108] In one aspect, there is provided a pharmaceutical formulation comprising the pharmaceutical composition as defined herein.

[0109] In a further aspect, there is provided an immediate release pharmaceutical formulation for oral use comprising the pharmaceutical composition according to the claims.

[0110] Suitably, the immediate release pharmaceutical formulation comprises a capsule shell and the pharmaceutical composition according to the claims.

[0111] Suitably, the immediate release pharmaceutical formulation consists of the pharmaceutical composition.

[0112] Suitably, there is provided an immediate release pharmaceutical formulation for oral use comprising the pharmaceutical composition according to the claims wherein when the immediate release pharmaceutical formulation is subjected to a content uniformity test as described in the European Pharmacopoeia the acceptance value is less than 15.

[0113] Advantageously, having a good content uniformity ensures each dosage form of the immediate release pharmaceutical formulation contains the intended quantity of the active substance. This is critical from a patient safety and efficacy perspective.

[0114] Suitably, there is provided an immediate release pharmaceutical formulation for oral use comprising the pharmaceutical composition according to the claims wherein the immediate release pharmaceutical formulation is an immediate release capsule formulation. Suitably, the immediate release capsule formulation comprises a capsule shell.

[0115] Suitably, there is provided an immediate release pharmaceutical formulation for oral use comprising the pharmaceutical composition according to the claims wherein the immediate release pharmaceutical formulation is an immediate release spray formulation.

[0116] Suitably, there is provided an immediate release pharmaceutical formulation for oral use comprising the pharmaceutical composition according to the claims wherein the immediate release formulation comprises between about 10 µg and about 1000 µg of the active substance, such as between about 10 µg and about 500 µg, about 20 µg and about 500 µg, about 30 µg and about 300 µg, or about 40 µg and about 250 µg.

[0117] Suitably, there is provided an immediate release pharmaceutical formulation for oral use comprising the pharmaceutical composition according to the claims wherein the immediate release formulation comprises about 50 µg or about 200 µg of the active substance Suitably, there is provided an immediate release pharmaceutical formulation for oral use comprising a pharmaceutical composition wherein the pharmaceutical composition comprises as an active substance Compound I, or a pharmaceutically acceptable salt thereof, and a non-aqueous solvent for the active substance.

[0118] Suitably, there is provided an immediate release pharmaceutical formulation for oral use comprising a pharmaceutical composition wherein the pharmaceutical composition comprises as an active substance Compound I, or a pharmaceutically acceptable salt thereof, and a non-aqueous solvent for the active substance, and wherein the immediate release pharmaceutical formulation is an immediate release capsule formulation.

[0119] Suitably, there is provided an immediate release pharmaceutical formulation for oral use comprising a pharmaceutical composition wherein: a. the pharmaceutical composition comprises as an active substance Compound I, or a pharmaceutically acceptable salt thereof and a non-aqueous solvent for the active substance; and b. the non-aqueous solvent comprises polyethylene glycol.

[0120] Suitably, there is provided an immediate release pharmaceutical formulation for oral use comprising a pharmaceutical composition wherein: a. the pharmaceutical composition comprises as an active substance Compound I, or a pharmaceutically acceptable salt thereof and a non-aqueous solvent for the active substance; b. the non-aqueous solvent is polyethylene glycol wherein the polyethylene glycol has an average molecular weight between about 1000 and about 6000 g / mol; c. the pharmaceutical composition comprises between about 50 and about 99.99% w / w of the non-aqueous solvent by weight of the total pharmaceutical composition; and d. the pharmaceutical composition comprises between about 0.01 and about 0.8% w / w of the active substance by weight of the total pharmaceutical composition.

[0121] Suitably, there is provided an immediate release pharmaceutical formulation for oral use comprising a pharmaceutical composition wherein: a. the pharmaceutical composition comprises as an active substance Compound I, or a pharmaceutically acceptable salt thereof and a non-aqueous solvent for the active substance; b. the non-aqueous solvent is polyethylene glycol wherein the polyethylene glycol has an average molecular weight between 1000 and 6000 g / mol; c. the pharmaceutical composition comprises between 50 and 99.99% w / w of the non-aqueous solvent by weight of the total pharmaceutical composition; and d. the pharmaceutical composition comprises between 0.01 and 0.8% w / w of the active substance by weight of the total pharmaceutical composition.

[0122] Suitably, there is provided an immediate release pharmaceutical formulation for oral use comprising a pharmaceutical composition wherein the pharmaceutical composition comprises as an active substance Compound I, or a pharmaceutically acceptable salt thereof, and wherein the pharmaceutical composition is a semi-solid at room temperature.

[0123] Suitably, there is provided an immediate release pharmaceutical formulation for oral use comprising a pharmaceutical composition wherein: a. the pharmaceutical composition comprises as an active substance Compound I, or a pharmaceutically acceptable salt thereof; and b. the active substance is stable in the pharmaceutical composition for at least about 2 weeks, about 1 month, about 2 months, about 3 months, about 6 months, about 12 months, or about 24 months.

[0124] Suitably, there is provided an immediate release pharmaceutical formulation for oral use comprising a pharmaceutical composition wherein: a. the pharmaceutical composition comprises as an active substance Compound I, or a pharmaceutically acceptable salt thereof; and b. at least about 75% of the total amount of the active substance contained in the immediate release pharmaceutical formulation is released within about the first 45 minutes when the pharmaceutical composition is subjected to an in vitro dissolution test employing 0.1 M HCl or pH 6.8 phosphate buffer as the dissolution medium and the dissolution profile is determined as described in the United States Pharmacopeia at 37°C using a rotation speed of 50 rpm.

[0125] Suitably, there is provided an immediate release pharmaceutical formulation for oral use comprising a pharmaceutical composition wherein: a. the pharmaceutical composition comprises as an active substance Compound I, or a pharmaceutically acceptable salt thereof; and b. at least about 75% of the total amount of the active substance contained in the pharmaceutical composition is released within about the first 45 minutes when the pharmaceutical composition is subjected to an in vitro dissolution test employing 0.1 M HCl or pH 6.8 phosphate buffer as the dissolution medium and the dissolution profile is determined as described in the United States Pharmacopeia at 37°C using a rotation speed of 50 rpm.

[0126] Suitably, there is provided an immediate release pharmaceutical formulation for oral use comprising a pharmaceutical composition wherein: a. the pharmaceutical composition comprises as an active substance Compound I, or a pharmaceutically acceptable salt thereof and a non-aqueous solvent for the active substance; and b. the active substance is homogenously distributed throughout the non-aqueous solvent. Active substance

[0127] 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.

[0128] According to the claims, the pharmaceutical composition comprises between about 0.001 and about 0.8% w / w of the active substance by weight of the total pharmaceutical composition, such as between about 0.01 and about 0.8% w / w, about 0.05 and about 0.6% w / w, about 0.08 and about 0.5% w / w, or about 0.1 and about 0.4% w / w. Suitably, the pharmaceutical composition comprises between 0.001 and 0.8% w / w of the active substance by weight of the total pharmaceutical composition, such as between 0.01 and 0.8% w / w, 0.05 and 0.6% w / w, 0.08 and 0.5% w / w, or 0.1 and 0.4% w / w.

[0129] Suitably, the pharmaceutical composition comprises about 0.1% w / w of the active substance by weight of the total pharmaceutical composition. Suitably, the pharmaceutical composition comprises about 0.4% w / w of the active substance by weight of the total pharmaceutical composition. Suitably, the pharmaceutical composition comprises 0.1% w / w of the active substance by weight of the total pharmaceutical composition. Suitably, the pharmaceutical composition comprises 0.4% w / w of the active substance by weight of the total pharmaceutical composition.

[0130] According to the claims, the pharmaceutical composition comprises between about 0.001 and about 0.8% w / w of the active substance by weight of the total pharmaceutical composition and at least 20% w / w of the non-aqueous solvent by weight of the total pharmaceutical composition. Suitably, the pharmaceutical composition comprises between 0.001 and 0.8% w / w of the active substance by weight of the total pharmaceutical composition and at least 20% w / w of the non-aqueous solvent by weight of the total pharmaceutical composition.

[0131] Suitably, the pharmaceutical composition comprises between about 0.001 and about 0.8% w / w of the active substance by weight of the total pharmaceutical composition and at least about 50% w / w of the non-aqueous solvent by weight of the total pharmaceutical composition. Suitably, the pharmaceutical composition comprises between 0.001 and 0.8% w / w of the active substance by weight of the total pharmaceutical composition and at least 50% w / w of the non-aqueous solvent by weight of the total pharmaceutical composition.

[0132] Suitably, the pharmaceutical composition comprises between about 0.01 and about 0.8% w / w of the active substance by weight of the total pharmaceutical composition and at least about 50% w / w of the non-aqueous solvent by weight of the total pharmaceutical composition. Suitably, the pharmaceutical composition comprises between 0.01 and 0.8% w / w of the active substance by weight of the total pharmaceutical composition and at least 50% w / w of the non-aqueous solvent by weight of the total pharmaceutical composition.

[0133] Suitably, the pharmaceutical composition comprises between about 0.001 and about 0.8% w / w of the active substance by weight of the total pharmaceutical composition and at least about 90% w / w of the non-aqueous solvent by weight of the total pharmaceutical composition. Suitably, the pharmaceutical composition comprises between 0.001 and 0.8% w / w of the active substance by weight of the total pharmaceutical composition and at least 90% w / w of the non-aqueous solvent by weight of the total pharmaceutical composition.

[0134] Suitably, the pharmaceutical composition comprises between about 0.1 and about 0.4% w / w of the active substance by weight of the total pharmaceutical composition and at least about 90% w / w of the non-aqueous solvent by weight of the total pharmaceutical composition. Suitably, the pharmaceutical composition comprises between 0.1 and 0.4% w / w of the active substance by weight of the total pharmaceutical composition and at least 90% w / w of the non-aqueous solvent by weight of the total pharmaceutical composition.Non-aqueous solvent for the active substance

[0135] Suitably, there is provided a pharmaceutical composition for oral use comprising as an active substance N-(2-(tert-butyl)-1-((4,4-difluorocyclohexyl)methyl)-1H-benzimidazol-5-yl)ethanesulfonamide, or a pharmaceutically acceptable salt thereof, and a non-aqueous solvent for the active substance.

[0136] Suitably, the pharmaceutical composition comprises at least one non-aqueous solvent, such as at least two, at least three, or at least four. Suitably, the pharmaceutical composition comprises one non-aqueous solvent, two non-aqueous solvents, three non-aqueous solvents or four non-aqueous solvents. Suitably, the pharmaceutical composition comprises a mixture of non-aqueous solvents.

[0137] Suitably, the active substance has a solubility in the non-aqueous solvent of at least about 0.1% w / w at room temperature, such as at least about 0.2% w / w, at least about 0.5% w / w, or at least about 1.0% w / w. Suitably, the active substance has a solubility in the non-aqueous solvent of about 0.1% w / w to about 50% w / w, such as about 0.1% w / w to about 25% w / w, or about 0.1% w / w to about 10% w / w. Suitably, the active substance has a solubility in the non-aqueous solvent of at least 0.1% w / w at room temperature, such as at least 0.2% w / w, at least 0.5% w / w, or at least 1.0% w / w. Suitably, the active substance has a solubility in the non-aqueous solvent of 0.1% w / w to 50% w / w, such as 0.1% w / w to 25% w / w, or 0.1% w / w to 10% w / w.

[0138] Suitably, the active substance is dispersed in the non-aqueous solvent at room temperature.

[0139] Suitably, the active substance is dissolved in the non-aqueous solvent at room temperature.

[0140] Suitably, at least about 85% by weight of the active substance is dissolved in the non-aqueous solvent at room temperature, such as at least about 90% by weight, at least about 95% by weight, at least about 99% by weight, or at least about 99.9% by weight. Suitably, at least 85% by weight of the active substance is dissolved in the non-aqueous solvent at room temperature, such as at least 90% by weight, at least 95% by weight, at least 99% by weight, or at least 99.9% by weight Suitably, all of the active substance is dissolved in the non-aqueous solvent at room temperature. The skilled person would know how to assess whether the active substance is dissolved in the non-aqueous solvent, for example, this may be assessed by eye or microscopy.

[0141] Suitably, the non-aqueous solvent comprises polyethylene glycol, propylene glycol, ethanol, glycerol, stearoyl polyoxylglyceride, polyoxyethylene stearate, long chain triglyceride, medium chain triglyceride, long chain fatty acid, medium chain fatty acid, long chain monoglyceride, long chain diglyceride, medium chain monoglyceride, medium chain diglyceride, polyoxyethylene castor oil derivative, polyoxyethylene sorbitan fatty acid ester, polyoxyethylated 12-hydroxystearic acid, caprylocaproyl polyoxylglyceride, linoleoyl polyoxylglyceride, oleoyl polyoxylglyceride, propylene glycol mono fatty ester, propylene glycol di fatty acid ester, soybean oil, glyceryl palmitostearate, diethylene glycol monoethyl ether, sorbitan ester, poloxamer, vitamin E TPGS or combinations thereof. According to the claims, the non-aqueous solvent comprises polyethylene glycol.

[0142] Suitably, the non-aqueous solvent comprises polyethylene glycol, propylene glycol, ethanol, glycerol, stearoyl polyoxylglyceride, polyoxyethylene stearate, long chain triglyceride, medium chain triglyceride, long chain fatty acid, medium chain fatty acid, long chain monoglyceride, long chain diglyceride, medium chain monoglyceride, medium chain diglyceride, polyoxyethylene castor oil derivative, polyoxyethylene sorbitan fatty acid ester, polyoxyethylated 12-hydroxystearic acid, caprylocaproyl polyoxylglyceride, linoleoyl polyoxylglyceride, oleoyl polyoxylglyceride, propylene glycol mono fatty ester, propylene glycol di fatty acid ester, soybean oil, glyceryl palmitostearate, diethylene glycol monoethyl ether, sorbitan ester, poloxamer, or combinations thereof. According to the claims, the non-aqueous solvent comprises polyethylene glycol.

[0143] Suitably, the non-aqueous solvent comprises polyethylene glycol, ethanol, stearoyl polyoxylglyceride, polyoxyethylene stearate, medium chain fatty acid, long chain monoglyceride, long chain diglyceride, medium chain monoglyceride, medium chain diglyceride, polyoxyethylene castor oil derivative, polyoxyethylene sorbitan fatty acid ester, polyoxyethylated 12-hydroxystearic acid, caprylocaproyl polyoxylglyceride, oleoyl polyoxylglyceride, propylene glycol mono fatty ester, propylene glycol di fatty acid ester, diethylene glycol monoethyl ether, poloxamer, or vitamin E TPGS or combinations thereof. Suitably, the polyoxyethylene castor oil derivative comprises polyoxyl 40 hydrogenated castor oil. Suitably, the polyoxyethylene castor oil derivative is polyoxyl 40 hydrogenated castor oil. According to the claims, the non-aqueous solvent comprises polyethylene glycol.

[0144] Suitably, the non-aqueous solvent comprises polyethylene glycol, stearoyl polyoxylglyceride, polyoxyethylene stearate, medium chain fatty acid, long chain monoglyceride, long chain diglyceride, medium chain monoglyceride, medium chain diglyceride, polyoxyethylene castor oil derivative, polyoxyethylene sorbitan fatty acid ester, polyoxyethylated 12-hydroxystearic acid, caprylocaproyl polyoxylglyceride, propylene glycol mono fatty ester, propylene glycol di fatty acid ester, diethylene glycol monoethyl ether, poloxamer, vitamin E TPGS or combinations thereof. Suitably, the polyoxyethylene castor oil derivative comprises polyoxyl 40 hydrogenated castor oil. Suitably, the polyoxyethylene castor oil derivative is polyoxyl 40 hydrogenated castor oil. According to the claims, the non-aqueous solvent comprises polyethylene glycol.

[0145] Suitably, the non-aqueous solvent comprises polyethylene glycol, stearoyl polyoxylglyceride, polyoxyethylene stearate, medium chain fatty acid, long chain monoglyceride, long chain diglyceride, medium chain monoglyceride, medium chain diglyceride, polyoxyethylene castor oil derivative, polyoxyethylene sorbitan fatty acid ester, polyoxyethylated 12-hydroxystearic acid, caprylocaproyl polyoxylglyceride, propylene glycol mono fatty ester, propylene glycol di fatty acid ester, diethylene glycol monoethyl ether, or poloxamer or combinations thereof, wherein the polyethylene glycol has an average molecular weight of 400 g / mol or about 1500 g / mol and is super-refined as defined herein. According to the claims, the non-aqueous solvent comprises polyethylene glycol.

[0146] Suitably, the non-aqueous solvent comprises polyethylene glycol, stearoyl polyoxylglyceride, polyoxyethylene stearate, medium chain fatty acid, long chain monoglyceride, long chain diglyceride, medium chain monoglyceride, medium chain diglyceride, polyoxyethylene castor oil derivative, polyoxyethylene sorbitan fatty acid ester, polyoxyethylated 12-hydroxystearic acid, caprylocaproyl polyoxylglyceride, propylene glycol mono fatty ester, propylene glycol di fatty acid ester, diethylene glycol monoethyl ether, or poloxamer or combinations thereof, wherein the polyethylene glycol is has an average molecular weight between about 1000 and about 6000 g / mol, about 1200 and about 1800 g / mol, about 1400 and about 1600 g / mol. According to the claims, the non-aqueous solvent comprises polyethylene glycol.

[0147] Suitably, the non-aqueous solvent comprises polyethylene glycol, stearoyl polyoxylglyceride, medium chain fatty acid, medium chain monoglyceride, medium chain diglyceride, polyoxyethylene castor oil derivative, polyoxyethylene sorbitan fatty acid ester, polyoxyethylated 12-hydroxystearic acid, propylene glycol di fatty acid ester, diethylene glycol monoethyl ether, or poloxamer or combinations thereof. Suitably, the polyoxyethylene castor oil derivative comprises polyoxyl 40 hydrogenated castor oil. Suitably, the polyoxyethylene castor oil derivative is polyoxyl 40 hydrogenated castor oil. According to the claims, the non-aqueous solvent comprises polyethylene glycol.

[0148] Suitably, the non-aqueous solvent comprises polyethylene glycol, stearoyl polyoxylglyceride, polyoxyethylene stearate, medium chain monoglyceride, medium chain diglyceride, polyoxyethylene sorbitan fatty acid ester, propylene glycol di fatty acid ester, or combinations thereof. According to the claims, the non-aqueous solvent comprises polyethylene glycol.

[0149] Suitably, the non-aqueous solvent comprises polyethylene glycol, stearoyl polyoxylglyceride, polyoxyethylene stearate, medium chain fatty acid, long chain monoglyceride, long chain diglyceride, medium chain monoglyceride, medium chain diglyceride, polyoxyethylene castor oil derivative, polyoxyethylene sorbitan fatty acid ester, polyoxyethylated 12-hydroxystearic acid, caprylocaproyl polyoxylglyceride, propylene glycol mono fatty ester, propylene glycol di fatty acid ester, diethylene glycol monoethyl ether, or poloxamer or combinations thereof. According to the claims, the non-aqueous solvent comprises polyethylene glycol.

[0150] Suitably, the non-aqueous solvent comprises polyethylene glycol, stearoyl polyoxylglyceride, medium chain fatty acid, long chain monoglyceride, long chain diglyceride, medium chain monoglyceride, medium chain diglyceride, polyoxyethylene sorbitan fatty acid ester, caprylocaproyl polyoxylglyceride, propylene glycol mono fatty ester, propylene glycol di fatty acid ester, diethylene glycol monoethyl ether, or poloxamer or combinations thereof. According to the claims, the non-aqueous solvent comprises polyethylene glycol.

[0151] Suitably, the non-aqueous solvent comprises polyethylene glycol, polyoxyethylene stearate, polyoxyethylene castor oil derivative, polyoxyethylated 12-hydroxystearic acid, diethylene glycol monoethyl ether, or poloxamer, vitamin E TPGS, or combinations thereof. According to the claims, the non-aqueous solvent comprises polyethylene glycol.

[0152] Suitably, the non-aqueous solvent comprises polyethylene glycol, polyoxyethylene castor oil derivative, polyoxyethylated 12-hydroxystearic acid, diethylene glycol monoethyl ether, or poloxamer, or combinations thereof. According to the claims, the non-aqueous solvent comprises polyethylene glycol.

[0153] Suitably, the non-aqueous solvent comprises polyethylene glycol, propylene glycol, glycerol, stearoyl polyoxylglyceride, polyoxyethylene stearate, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid ester, polyoxyethylated 12-hydroxystearic acid, caprylocaproyl polyoxylglyceride, linoleoyl polyoxylglyceride, oleoyl polyoxylglyceride, or sorbitan ester or combinations thereof. According to the claims, the non-aqueous solvent comprises polyethylene glycol.

[0154] Suitably, the non-aqueous solvent comprises polyethylene glycol, stearoyl polyoxylglyceride, or polyoxyethylene stearate or combinations thereof. According to the claims, the non-aqueous solvent comprises polyethylene glycol.

[0155] Suitably, the non-aqueous solvent is water soluble. Solubility is determined at room temperature. Water solubility in this context is defined as at least 1 part of the non-aqueous solvent is soluble in 10 to 30 parts of water, for example at least 1 part of the non-aqueous solvent is soluble in 1 to 10 parts of water, or at least 1 part of the non-aqueous solvent is soluble in less than 1 part of water. Sparingly soluble is defined as 1 part of the non-aqueous solvent is soluble in 30 to 100 parts of water. Slightly soluble is defined as 1 part of the non-aqueous solvent is soluble in 100 to 1000 parts of water. Very slightly soluble is defined as 1 part of the non-aqueous solvent is soluble in 1000 to 10000 parts of water. Practically insoluble or insoluble is defined as 1 part of the non-aqueous solvent is soluble in more than 10000 parts of water.

[0156] Suitably, the non-aqueous solvent is miscible with water. Miscibility is herein defined as when the non-aqueous solvent forms a homogeneous mixture when added to water at room temperature.

[0157] Suitably, the non-aqueous solvent comprises polyethylene glycol, propylene glycol, ethanol, glycerol, polyoxyethylene castor oil derivative, polyoxyethylene sorbitan fatty acid ester, polyoxyethylated 12-hydroxystearic acid, or poloxamer or combinations thereof.. According to the claims, the non-aqueous solvent comprises polyethylene glycol.

[0158] According to the claims, the non-aqueous solvent comprises polyethylene glycol.

[0159] Suitably, the non-aqueous solvent consists essentially of polyethylene glycol.

[0160] Suitably, the non-aqueous solvent consists of polyethylene glycol.

[0161] Suitably, the polyethylene glycol has an average molecular weight between 400 and about 6000 g / mol, about 1000 and about 6000 g / mol, about 1200 and about 1800 g / mol, about 1400 and about 1600 g / mol. Suitably, the polyethylene glycol has an average molecular weight between 400 and 6000 g / mol, 1000 and 6000 g / mol, 1200 and 1800 g / mol, or 1400 and 1600 g / mol.

[0162] The skilled person would be able to determine the average molecular weight of polyethylene glycol. For example, molecular weight assay analytical tests are disclosed in US Pharmacopeia Monograph for polyethylene glycol.

[0163] Suitably, the average molecular weight of polyethylene glycol can be determined using the following assay: Phthalic anhydride solution: Place 49.0 g of phthalic anhydride into an amber bottle, and dissolve in 300 mL of pyridine from a freshly opened bottle or pyridine that has been freshly distilled over phthalic anhydride. Shake vigorously until completely dissolved. Add 7 g of imidazole, swirl carefully to dissolve, and allow to stand for 16 h before using. Sample solution for liquid Polyethylene Glycols: Carefully introduce 25.0 mL of the Phthalic anhydride solution into a dry, heat-resistant pressure bottle. Add an amount of the specimen equivalent to its expected average molecular weight divided by 160. Insert the stopper in the bottle, and wrap it securely in a cloth bag. Sample solution for solid Polyethylene Glycols: Carefully introduce 25.0 mL of Phthalic anhydride solution into a dry, heat-resistant pressure bottle. Add an amount of the specimen equivalent to its expected molecular weight divided by 160; however, because of limited solubility, do not use more than 25 g. Add 25 mL of pyridine, from a freshly opened bottle or pyridine that has been freshly distilled over phthalic anhydride. Swirl to dissolve, insert the stopper in the bottle, and wrap it securely in a cloth bag. Blank: 25.0 mL of Phthalic anhydride solution plus any additional pyridine added to the bottle Analysis: Immerse the bottle in a water bath maintained at a temperature between 96° and 100°, to the same depth as that of the mixture in the bottle. Remove the bottles the bath after 5 min and, without unwrapping, swirl for 30 s to homogenize. Heat in the water bath for 30 min (60 min for Polyethylene Glycols having molecular weights of 3000 or more), then remove from the bath, and allow it to cool to room temperature. Uncap the bottle carefully to release any pressure, remove from the bag, add 10 mL of water and swirl thoroughly. Wait 2 min, add 0.5 mL of a solution of phenolphthalein in pyridine (1 in 100), and titrate with 0.5 N sodium hydroxide VS to the first pink colour that persists for 15 s. Perform a blank determination. Calculate the average molecular weight taken: Result = 2000 × W / V B − V S × N W = weight of the Polyethylene Glycol taken for the Sample solution (g) V B = volume of 0.5 N sodium hydroxide consumed by the Blank (mL) V S = volume of 0.5 N sodium hydroxide consumed by the specimen (mL) N = normality of the sodium hydroxide solution

[0164] Suitably, the polyethylene glycol has an average molecular weight of 400, about 1000, about 1500, about 1540, about 2000, about 3000, about 4000, about 6000, or about 8000 g / mol. Suitably, the polyethylene glycol has an average molecular weight of 400, 1000, 1500, 1540, 2000, 3000, 4000, 6000, or 8000 g / mol.

[0165] Suitably, the polyethylene glycol has an average molecular weight of 400, about 1500, about 4000, or about 6000 g / mol. Suitably, the polyethylene glycol has an average molecular weight of 400, 1500, 4000, or 6000 g / mol.

[0166] Suitably, the polyethylene glycol has an average molecular weight of 400 g / mol. Suitably, the polyethylene glycol has an average molecular weight of about 1500 g / mol. Suitably, the polyethylene glycol has an average molecular weight of about 4000 g / mol. Suitably, the polyethylene glycol has an average molecular weight of about 6000 g / mol. Suitably, the polyethylene glycol has an average molecular weight of 400 g / mol. Suitably, the polyethylene glycol has an average molecular weight of 1500 g / mol. Suitably, the polyethylene glycol has an average molecular weight of 4000 g / mol. Suitably, the polyethylene glycol has an average molecular weight of 6000 g / mol.

[0167] Suitably, the non-aqueous solvent comprises polyethylene glycol having an average weight of about 1500 g / mol. Suitably, the non-aqueous solvent comprises polyethylene glycol having an average weight of 1500 g / mol.

[0168] Suitably, the non-aqueous solvent consists essentially of polyethylene glycol having an average weight of about 1500 g / mol. Suitably, the non-aqueous solvent consists essentially of polyethylene glycol having an average weight of 1500 g / mol.

[0169] Suitably, the non-aqueous solvent consists of polyethylene glycol having an average weight of about 1500 g / mol. Suitably, the non-aqueous solvent consists of polyethylene glycol having an average weight of 1500 g / mol.

[0170] Suitably, the non-aqueous solvent comprises polyethylene glycol having an average weight of about 4000 g / mol. Suitably, the non-aqueous solvent comprises polyethylene glycol having an average weight of 4000 g / mol.

[0171] Suitably, the non-aqueous solvent consists essentially of polyethylene glycol having an average weight of about 4000 g / mol. Suitably, the non-aqueous solvent consists essentially of polyethylene glycol having an average weight of 4000 g / mol.

[0172] Suitably, the non-aqueous solvent consists of polyethylene glycol having an average weight of about 4000 g / mol. Suitably, the non-aqueous solvent consists of polyethylene glycol having an average weight of 4000 g / mol.

[0173] Suitably, the non-aqueous solvent comprises polyethylene glycol having an average weight of about 6000 g / mol. Suitably, the non-aqueous solvent comprises polyethylene glycol having an average weight of 6000 g / mol.

[0174] Suitably, the non-aqueous solvent consists essentially of polyethylene glycol having an average weight of about 6000 g / mol. Suitably, the non-aqueous solvent consists essentially of polyethylene glycol having an average weight of 6000 g / mol.

[0175] Suitably, the non-aqueous solvent consists of polyethylene glycol having an average weight of about 6000 g / mol. Suitably, the non-aqueous solvent consists of polyethylene glycol having an average weight of 6000 g / mol.

[0176] Suitably, the non-aqueous solvent comprises polyethylene glycol having an average weight of 400 g / mol.

[0177] Suitably, the non-aqueous solvent consists essentially of polyethylene glycol having an average weight of 400 g / mol.

[0178] Suitably, the non-aqueous solvent consists of polyethylene glycol having an average weight of 400 g / mol.

[0179] Suitably, the polyethylene glycol is a super refined polyethylene glycol. Suitably, the super refined polyethylene glycol has an average molecular weight between 400 and about 6000 g / mol, between about 1000 and about 6000 g / mol, between about 1200 and about 1800 g / mol, or between about 1400 and about 1600 g / mol. Suitably, the super refined polyethylene glycol has an average molecular weight of 400 g / mol.

[0180] Suitably, the super refined polyethylene glycol: (a) has a pH of between 4.5 and 7.5, such as between 4.0 and 7.0; (b) contains between 0 and 10 ppm ethylene oxide, such as between 0 and 1 ppm; (c) contains between 0 and 10 ppm dioxane; (d) contains between 0.0 and 0.4% ethylene glycol, such as between 0.00 and 0.25%; (e) contains between 0.0 and 0.4% diethylene glycol, such as between 0.00 and 0.25%, such as no more than 0.062%; (f) contains no more than 0.25% of ethylene glycol and diethylene glycol combined; (g) contains no more than 30 ppm formaldehyde, such as no more than 15 ppm; (h) contains between 0.0 and 2.0% water, such as no more than 1.0%; (i) contains no more than 0.5% acetic acid; and / or (j) has a peroxide value of between 0.0 and 5.0 meqO2 / kg.

[0181] Suitably, the non-aqueous solvent comprises two different polyethylene glycols, wherein the first polyethylene glycol has an average weight of less than about 1000 g / mol, such as less than about 800 g / mol, or such as less than about 600 g / mol, and wherein the second polyethylene glycol has an average weight of at least about 1000 g / mol, such as at least about 1200 g / mol, or such as at least about 1400 g / mol.

[0182] Suitably, the non-aqueous solvent comprises two different polyethylene glycols, wherein the first polyethylene glycol has an average weight of between 400 and 800 g / mol, and wherein the second polyethylene glycol has an average weight of between 1200 and 10000 g / mol, such as between 1200 and 6000 g / mol.

[0183] Suitably, the non-aqueous solvent comprises two different polyethylene glycols, wherein the first polyethylene glycol has an average weight 400 g / mol, and wherein the second polyethylene glycol has an average weight of about 1500, 4000 or 6000 g / mol.

[0184] Suitably, the weight ratio of the first polyethylene glycol to the second polyethylene glycol is between 1:20 and 20:1, such as between 1:10 and 10:1, such as between 1:9 and 9:1.

[0185] Suitably, the first polyethylene glycol is a super refined polyethylene glycol.

[0186] Suitably, the pharmaceutical composition comprises two non-aqueous solvents, wherein the first non-aqueous solvent comprises vitamin E TPGS and the second non-aqueous solvent is polyethylene glycol. Suitably, the polyethylene glycol has an average weight of at least about 1000 g / mol, such as at least about 1200 g / mol, or such as at least about 1400 g / mol. Suitably, the polyethylene glycol has an average weight of between 1200 and 10000 g / mol, such as between 1200 and 6000 g / mol. Suitably, the polyethylene glycol has an average weight of about 1500, 4000 or 6000 g / mol. Suitably, the weight ratio of the polyethylene glycol to vitamin E TPGS is between 1:20 and 20:1, such as between 1:10 and 10:1, such as between 1:9 and 9:1.

[0187] Suitably, the polyoxyethylene stearate is PEG-32 stearate or polyethylene glycol monostearate or a mixture thereof.

[0188] Glycerol has three hydroxyl functional groups, which can be esterified with one, two, or three fatty acids to form mono-, di-, or triglycerides respectively. Mono-, di-, and triglycerides comprise fatty acids in a bound state.

[0189] A long chain triglyceride is a triglyceride with three fatty acids having aliphatic tails of 13 to 21 carbons. Suitably, the long chain triglyceride comprises a fatty acid with an aliphatic tail of 13 to 21 carbons. Suitably, the long chain triglyceride comprises a fatty acid with an aliphatic tail of 16 to 20 carbons. Suitably, the long chain triglyceride comprises oleic acid. Suitably, the long chain triglyceride is selected from corn oil and soy bean oil A medium chain triglyceride is a triglyceride with three fatty acids having aliphatic tails of 6 to 12 carbons. Suitably, the medium chain triglyceride comprises a fatty acid with an aliphatic tail of 6 to 12 carbons. Suitably, the medium chain triglyceride comprises caprylic acid or capric acid or a mixture thereof.

[0190] A long chain monoglyceride is a monoglyceride with one fatty acid having an aliphatic tail of 13 to 21 carbons. Suitably, the long chain monoglyceride comprises a fatty acid with an aliphatic tail of 13 to 21 carbons. Suitably, the long chain monoglyceride comprises a fatty acid with an aliphatic tail of 16 to 20 carbons. Suitably, the long chain monoglyceride is glyceryl monooleate.

[0191] A medium chain monoglyceride is a monoglyceride with one fatty acid having an aliphatic tail of 6 to 12 carbons. Suitably, the medium chain monoglyceride comprises a fatty acid with an aliphatic tail of 6 to 12 carbons. Suitably, the medium chain monoglyceride comprises a fatty acid with an aliphatic tail of 8 to 12 carbons. Suitably, the medium chain monoglyceride is glyceryl monocaprylate.

[0192] A long chain fatty acid is a free fatty acid (i.e., not bound to another molecule, for example, a glycerol molecule in a mono-, di-, or tri-glyceride) with an aliphatic tail of at least 13 carbon atoms, suitably 13 to 21 carbons. Suitably, the long chain fatty acid has an aliphatic chain comprising 13 to 21 carbons. Suitably, the long chain fatty acid has an aliphatic chain comprising 16 to 20 carbons. Suitably, the long chain fatty acid is a very long chain fatty acid. Suitably, the long chain fatty acid is a free fatty acid with an aliphatic tail at least 22 carbons. Suitably, the long chain fatty acid is a saturated long chain fatty acid. Suitably, the long chain fatty acid is an unsaturated long chain fatty acid. Suitably, the long chain fatty acid is oleic acid, palmitic acid, stearic acid, arachidic acid, palmitoleic acid, nervonic acid, linoleic acid, alpha-linolenic acid, arachidonic acid, or eicosapentaenoic acid.

[0193] A medium chain fatty acid is a free fatty acid (i.e., not bound to another molecule, for example, a glycerol molecule in a mono-, di-, or tri-glyceride) with an aliphatic tail of 6 to 12 carbons. Suitably, the medium chain fatty acid has an aliphatic chain comprising 6 to 12 carbons. Suitably, the medium chain fatty acid has an aliphatic chain comprising 6 to 10 carbons. Suitably, the medium chain fatty acid is a saturated medium chain fatty acid. Suitably, the medium chain fatty acid is an unsaturated medium chain fatty acid. Suitably, the medium chain fatty acid is caprylic acid, capric acid or lauric acid.

[0194] Polyoxyethylene castor oil derivatives are obtained by reacting varying amounts of ethylene oxide with either castor oil or hydrogenated castor oil. Suitably, the polyoxyethylene castor oil derivative comprises polyoxyl 40 hydrogenated castor oil, polyoxyl-35 castor oil, or a mixture thereof. Suitably, the polyoxyethylene castor oil derivative is polyoxyl 40 hydrogenated castor oil, polyoxyl-35 castor oil, or a mixture thereof. Suitably, the polyoxyethylene castor oil derivative comprises polyoxyl 40 hydrogenated castor oil. Suitably, the polyoxyethylene castor oil derivative is polyoxyl 40 hydrogenated castor oil.

[0195] Suitably, the polyoxyethylene sorbitan fatty acid ester is polysorbate 20, polysorbate 80, or a mixture thereof. Suitably, the polyoxyethylene sorbitan fatty acid is polysorbate 20.

[0196] Suitably, the propylene glycol mono fatty ester is propylene glycol monocaprylate.

[0197] Suitably, the propylene glycol di fatty acid ester is propylene glycol dilaurate.

[0198] A poloxamer is non-ionic triblock copolymers composed of a central hydrophobic chain of polyoxypropylene (poly(propylene oxide)) flanked by two hydrophilic chains of polyoxyethylene (poly(ethylene oxide)). Suitably, the poloxamer is poloxamer 124, poloxamer 188, poloxamer 237, poloxamer 338, or poloxamer 407.

[0199] Suitably, the non-aqueous solvent comprises more than one non-aqueous solvent, for example two, three or four non-aqueous solvents.

[0200] According to the claims, the pharmaceutical composition comprises at least 20% w / w of the non-aqueous solvent by weight of the total pharmaceutical composition, such as at least about 30% w / w, at least about 40% w / w, at least about 50% w / w, at least about 60% w / w, at least about 70% w / w, at least about 80% w / w, at least about 90% w / w, at least about 95% w / w, at least about 96% w / w, at least about 97% w / w, at least about 98% w / w, at least about 99% w / w, at least about 99.2% w / w, or at least about 99.5% w / w. Suitably, the pharmaceutical composition comprises at least 20% w / w of the non-aqueous solvent by weight of the total pharmaceutical composition, such as at least 30% w / w, at least 40% w / w, at least 50% w / w, at least 60% w / w, at least 70% w / w, at least 80% w / w, at least 90% w / w, at least 95% w / w, at least 96% w / w, at least 97% w / w, at least 98% w / w, at least 99% w / w, at least 99.2% w / w, or at least 99.5% w / w.

[0201] Suitably, the pharmaceutical composition comprises between 20 and about 99.99% w / w of the non-aqueous solvent by weight of the total pharmaceutical composition, such as between about 30 and about 99.99% w / w, about 40 and about 99.99% w / w, about 50 and about 99.99% w / w, about 60 and about 99.99% w / w, about 70 and about 99.99% w / w, about 80 and about 99.99% w / w, about 90 and about 99.99% w / w, about 95 and about 99.99% w / w, about 96 and about 99.99% w / w, about 97 and about 99.99% w / w, about 98 and about 99.99% w / w, about 99 and about 99.99% w / w, about 99.2 and about 99.99% w / w, or about 99.5 and about 99.99% w / w. Suitably, the pharmaceutical composition comprises between 20 and 99.99% w / w of the non-aqueous solvent by weight of the total pharmaceutical composition, such as between 30 and 99.99% w / w, 40 and 99.99% w / w, 50 and 99.99% w / w, 60 and 99.99% w / w, 70 and 99.99% w / w, 80 and 99.99% w / w, 90 and 99.99% w / w, 95 and 99.99% w / w, 96 and 99.99% w / w, 97 and 99.99% w / w, 98 and 99.99% w / w, 99 and 99.99% w / w, 99.2 and 99.99% w / w, or 99.5 and 99.99% w / w.

[0202] Suitably, the pharmaceutical composition comprises about 99.6% w / w of the non-aqueous solvent by weight of the total pharmaceutical composition. Suitably, the pharmaceutical composition comprises about 99.9% w / w of the non-aqueous solvent by weight of the total pharmaceutical composition.

[0203] Suitably, the non-aqueous solvent is a semi-solid at room temperature. A semi-solid is any material which at room temperature is a solid and at a temperature above room temperature is a liquid.

[0204] Suitably, the non-aqueous solvent has a melting point of at least 30°C, such as at least 35°C, at least 40°C. Suitably, the non-aqueous solvent has a melting point of at least about 30°C, such as at least about 35°C, at least about 40°C.

[0205] Suitably, the non-aqueous solvent has a melting point between about 35°C and about 80°C, such as between about 35°C and about 70°C, about 35°C and about 60°C, about 35°C and about 50°C, or about 40°C and about 50°C. Suitably, the non-aqueous solvent has a melting point between 35°C and 80°C, such as between 35°C and 70°C, 35°C and 60°C, 35°C and 50°C, or 40°C and 50°C.Additional excipients in the pharmaceutical composition

[0206] Optionally, additional excipients may be included in the pharmaceutical composition according to the present disclosure.

[0207] Suitably, the pharmaceutical composition further comprises vitamin E TPGS or lauroyl polyoxylglyceride. Suitably, the pharmaceutical composition comprises vitamin E TPGS.

[0208] Suitably, the weight ratio of the non-aqueous solvent to vitamin E TPGS is between 1:20 and 20:1, such as between 1:10 and 10:1, such as between 1:9 and 9:1.

[0209] Suitably, the pharmaceutical composition comprises a non-aqueous solvent and vitamin E TPGS, wherein the non-aqueous solvent comprises polyethylene glycol. Suitably, the polyethylene glycol has an average weight of at least about 1000 g / mol, such as at least about 1200 g / mol, or such as at least about 1400 g / mol. Suitably, the polyethylene glycol has an average weight of between 1200 and 10000 g / mol, such as between 1200 and 6000 g / mol. Suitably, the polyethylene glycol has an average weight of about 1500, 4000 or 6000 g / mol. Suitably, the weight ratio of the polyethylene glycol to vitamin E TPGS is between 1:20 and 20:1, such as between 1:10 and 10:1, such as between 1:9 and 9:1.

[0210] Suitably, the pharmaceutical composition further comprises a viscosity modifier, opacifier, colouring, sweetening flavouring, and / or a preservatives agent such as an antioxidant.

[0211] The viscosity modifier is an excipient which gives the pharmaceutical composition suitable viscosity properties to allow consistent manufacturing, for example, to modify the viscosity of the pharmaceutical composition so that the pharmaceutical composition has the desired flow properties during manufacture to ensure the desired volumes of the pharmaceutical composition is dispensed. Suitably, the viscosity modifier is a liquid at room temperature. Suitably, the viscosity modifier is vitamin E TPGS and / or polyethylene glycol having an average weight of less than 1000 g / mol, such as less than 600 g / mol. Suitably, the polyethylene glycol has an average weight between about 200 and about 1000 g / mol, such as between about 300 and 500 g / mol. Suitably, the polyethylene glycol has an average weight of about 400 g / mol.

[0212] An opacifier is an excipient which makes the pharmaceutical composition opaque.

[0213] Suitably, the antioxidant comprises butylated hydroxyanisole, butylated hydroxytoluene, ascorbic acid, or alpha tocopherol.Semi-solid pharmaceutical composition

[0214] Suitably, the pharmaceutical composition is a semi-solid at room temperature. A semi-solid is any material which at room temperature is a solid and at a temperature above room temperature is a liquid.

[0215] Suitably, the pharmaceutical composition has a melting point of at least about 30°C, such as at least about 35°C, at least about 40°C. Suitably, the pharmaceutical composition has a melting point of at least 30°C, such as at least 35°C, at least 40°C.

[0216] Suitably, the pharmaceutical composition has a melting point between about 35°C and about 80°C, such as between about 35°C and about 70°C, about 35°C and about 60°C, about 35°C and about 50°C, or about 40°C and about 50°C. Suitably, the pharmaceutical composition has a melting point between 35°C and 80°C, such as between 35°C and 70°C, 35°C and 60°C, 35°C and 50°C, or 40°C and 50°C.

[0217] Advantageously, having a pharmaceutical composition which is a semi-solid at room temperature whose melting point is between 35°C and 80°C means that the active substance is not exposed to elevated temperatures during manufacture and thereby minimising degradation of the active substance during manufacture. Furthermore, a pharmaceutical composition which can be melted facilitates the transfer of the desired quantity of the pharmaceutical composition, for example into a capsule shell.Stability of the pharmaceutical composition

[0218] Suitably, the active substance is stable in the pharmaceutical composition. Suitably, the active substance is stable in the pharmaceutical composition for at least about 2 weeks, about 1 month, about 2 months, about 3 months, about 6 months, about 12 months, or about 24 months. Suitably, the active substance is stable in the pharmaceutical composition for at least 2 weeks, 1, 2, 3, 6, 12, or 24 months.

[0219] Suitably, 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. Suitably, the active substance is chemically stable in the pharmaceutical composition for at least 2 weeks, 1, 2, 3, 6, 12, or 24 months.

[0220] Advantageously, the active substance is stable within the pharmaceutical composition during the lifetime of the pharmaceutical composition, for example during the manufacture of the pharmaceutical composition and at least until the pharmaceutical composition is administered to a patient. Stability is an important safety aspect of a pharmaceutical composition as a stable pharmaceutical composition results in the assay of the active substance being consistent over time which inturn allows for consistent dosing of the active substance to a patient. Therefore, resulting in the desired dose being administered to the patient. Furthermore, the degradation products of the active substance in a stable pharmaceutical composition are at minimal levels which ensures the end user, for example the patient, is not administered degradation products of the active substance. Stability of the active substance within the pharmaceutical composition is critical from a patient safety and efficacy perspective.

[0221] Suitably, the active substance is stable in the pharmaceutical composition for at least about 2 weeks, about 1 month, about 2 months, about 3 months, about 6 months, about 12 months, or about 24 months when the pharmaceutical composition is stored at 25°C / 60%RH and / or 40°C / 75%RH. Suitably, the active substance is stable in the pharmaceutical composition for at least 2 weeks, 1, 2, 3, 6, 12, or 24 months when the pharmaceutical composition is stored at 25°C / 60%RH and / or 40°C / 75%RH.

[0222] Suitably, the active substance is stable in the pharmaceutical composition for at least about 2 weeks, about 1 month, about 2 months, about 3 months, about 6 months, about 12 months, or about 24 months when the pharmaceutical composition is stored at 25°C / 60%RH and / or 40°C / 75%RH. Suitably, the active substance is stable in the pharmaceutical composition for 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.

[0223] Suitably, the total amount of degradation products of the active substance is less than or equal to about 4 area% as determined by a chromatographic method 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 degradation products of the active substance is less than or equal to 4 area% as determined by a chromatographic method 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.

[0224] Suitably, the total amount of degradation products of the active substance is less than or equal to about 3 area% as determined by a chromatographic method 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 degradation products of the active substance is less than or equal to 3 area% as determined by a chromatographic method 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.

[0225] Suitably, the total amount of degradation products of the active substance is less than or equal to about 2 area% as determined by a chromatographic method 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 degradation products of the active substance is less than or equal to 2 area% as determined by a chromatographic method 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.

[0226] Suitably, the pharmaceutical composition does not contain more than about 1 area% of a single degradation product of the active substance as determined by a chromatographic method 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 pharmaceutical composition does not contain more than 1 area% of a single degradation product of the active substance as determined by a chromatographic method 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.

[0227] A degradation product of the active substance is an impurity which forms upon storage of the active substance (or during manufacture of the pharmaceutical composition). The degradation product may be formed from exposure of the active substance to water, oxygen, peroxides, or UV light.

[0228] Suitably, the assay of the active substance is about 90 to about 110% of nominal as determined by a chromatographic method 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 assay of the active substance is 90 to 110% of nominal as determined by a chromatographic method 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.

[0229] Suitably, the assay of the active substance is about 95 to about 105% of nominal as determined by a chromatographic method 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 assay of the active substance is 95 to 105% of nominal as determined by a chromatographic method 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.

[0230] Suitably, the assay of the active substance is about 98 to about 102% of nominal as determined by a chromatographic method 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 assay of the active substance is 98 to 102% of nominal as determined by a chromatographic method 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.

[0231] Suitably, the total amount of degradation products of the active substance is less than or equal to about 4 area% as determined by a chromatographic method and the assay of the active substance is about 90 to about 110% of nominal as determined by a chromatographic method 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 degradation products of the active substance is less than or equal to 4 area% and the assay of the active substance is 90 to 110% of nominal as determined by a chromatographic method 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.

[0232] Suitably, the active substance is stable in the pharmaceutical composition for at least about 2 weeks, about 1 month, about 2 months, about 3 months, about 6 months, about 12 months, or about 24 months when the pharmaceutical composition is protected from light, suitably UV radiation. Suitably, the active substance is stable in the pharmaceutical composition for at least 2 weeks, 1, 2, 3, 6, 12, or 24 months when the pharmaceutical composition is protected from light, suitably UV radiation.

[0233] Suitably, the chromatographic method is a HPLC method. HPLC in this context includes UPLC.

[0234] Suitably the HPLC method comprises a UV detector. Suitably, the UV detector measures the assay and / or degradation products of the active substance at about 256 nm.

[0235] Suitably, the HPLC method is a reverse phase HPLC method. Suitably, the reverse phase HPLC method comprises two eluents wherein the ratio of the two eluents changes during the course of the HPLC analysis. Suitably, the first eluent comprises water and the second eluent comprises acetonitrile. Suitably, the first eluent comprises water and ammonium acetate and the second eluent comprises acetonitrile. Suitably, the first eluent comprises water and 10 mM ammonium acetate and the second eluent comprises acetonitrile.

[0236] Suitably, the reverse phase HPLC method comprises a HPLC column. Suitably, the HPLC column comprises a C18 stationary phase. Suitably, the HPLC column temperature is at about 40°C.

[0237] Suitably, the eluents flow through the HPLC column at about 0.3 mL / min.

[0238] Suitably, the chromatographic method is a reverse phase HPLC method wherein the reverse phase HPLC method comprises: a. a UV detector; b. a HPLC column; and c. two eluents wherein the ratio of the two eluents changes during the course of the HPLC analysis. Release rate of the active substance from the pharmaceutical composition

[0239] Suitably, at least about 75% of the total amount of the active substance contained in the pharmaceutical composition is released within about the first 45 minutes when the pharmaceutical composition is subjected to an in vitro dissolution test employing 0.1 M HCl or pH 6.8 phosphate buffer as the dissolution medium and the dissolution profile is determined at about 37°C using a rotation speed of about 50 rpm. Suitably, at least 75% of the total amount of the active substance contained in the pharmaceutical composition is released within the first 45 minutes when the pharmaceutical composition is subjected to an in vitro dissolution test employing 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.

[0240] Advantageously, such a release profile provides optimal absorption of the active substance when administered to a patient.

[0241] Suitably, at least about 75% of the total amount of the active substance contained in the pharmaceutical composition is released within about the first 30 minutes when the pharmaceutical composition is subjected to an in vitro dissolution test employing 0.1 M HCl or pH 6.8 phosphate buffer as the dissolution medium and the dissolution profile is determined at about 37°C using a rotation speed of about 50 rpm. Suitably, at least 75% of the total amount of the active substance contained in the pharmaceutical composition is released within the first 30 minutes when the pharmaceutical composition is subjected to an in vitro dissolution test employing 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.

[0242] Suitably, at least about 85% of the total amount of the active substance contained in the pharmaceutical composition is released within about the first 15 minutes when the pharmaceutical composition is subjected to an in vitro dissolution test employing 0.1 M HCl or pH 6.8 phosphate buffer as the dissolution medium and the dissolution profile is determined at about 37°C using a rotation speed of about 50 rpm. Suitably, at least 85% of the total amount of the active substance contained in the pharmaceutical composition is released within the first 15 minutes when the pharmaceutical composition is subjected to an in vitro dissolution test employing 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.

[0243] Suitably, at least about 75% of the total amount of the active substance contained in the pharmaceutical composition is released within about the first 45 minutes when the pharmaceutical composition is subjected to an in vitro dissolution test employing 0.1 M HCl or pH 6.8 phosphate buffer as the dissolution medium and the dissolution profile is determined as described in the United States Pharmacopeia at about 37°C using a rotation speed of about 50 rpm. Suitably, at least 75% of the total amount of the active substance contained in the pharmaceutical composition is released within the first 45 minutes when the pharmaceutical composition is subjected to an in vitro dissolution test employing 0.1 M HCl or pH 6.8 phosphate buffer as the dissolution medium and the dissolution profile is determined as described in the United States Pharmacopeia at 37°C using a rotation speed of 50 rpm.

[0244] Suitably, at least about 75% of the total amount of the active substance contained in the pharmaceutical composition is released within about the first 30 minutes when the pharmaceutical composition is subjected to an in vitro dissolution test employing 0.1 M HCl or pH 6.8 phosphate buffer as the dissolution medium and the dissolution profile is determined as described in the United States Pharmacopeia at about 37°C using a rotation speed of about 50 rpm. Suitably, at least 75% of the total amount of the active substance contained in the pharmaceutical composition is released within the first 30 minutes when the pharmaceutical composition is subjected to an in vitro dissolution test employing 0.1 M HCl or pH 6.8 phosphate buffer as the dissolution medium and the dissolution profile is determined as described in the United States Pharmacopeia at 37°C using a rotation speed of 50 rpm.

[0245] Suitably, at least about 75% of the total amount of the active substance contained in the pharmaceutical composition is released within about the first 15 minutes when the pharmaceutical composition is subjected to an in vitro dissolution test employing 0.1 M HCl or pH 6.8 phosphate buffer as the dissolution medium and the dissolution profile is determined as described in the United States Pharmacopeia at about 37°C using a rotation speed of about 50 rpm. Suitably, at least 75% of the total amount of the active substance contained in the pharmaceutical composition is released within the first 15 minutes when the pharmaceutical composition is subjected to an in vitro dissolution test employing 0.1 M HCl or pH 6.8 phosphate buffer as the dissolution medium and the dissolution profile is determined as described in the United States Pharmacopeia at 37°C using a rotation speed of 50 rpm.

[0246] Suitably, at least about 85% of the total amount of the active substance contained in the pharmaceutical composition is released within about the first 15 minutes when the pharmaceutical composition is subjected to an in vitro dissolution test employing 0.1 M HCl or pH 6.8 phosphate buffer as the dissolution medium and the dissolution profile is determined as described in the United States Pharmacopeia at about 37°C using a rotation speed of about 50 rpm. Suitably, at least 85% of the total amount of the active substance contained in the pharmaceutical composition is released within the first 15 minutes when the pharmaceutical composition is subjected to an in vitro dissolution test employing 0.1 M HCl or pH 6.8 phosphate buffer as the dissolution medium and the dissolution profile is determined as described in the United States Pharmacopeia at 37°C using a rotation speed of 50 rpm.

[0247] Suitably, the in vitro dissolution tests comprises a vessel filled with about 500 mL of dissolution medium wherein the dissolution medium is 0.1 M HCl or pH 6.8 phosphate buffer. Suitably, the in vitro dissolution tests comprises a vessel filled with 500 mL of dissolution medium wherein the dissolution medium is 0.1 M HCl or pH 6.8 phosphate buffer.

[0248] Suitably, the dissolution medium has a temperature of about 37°C. Suitably, the dissolution medium has a temperature of 37°C.

[0249] Suitably, the in vitro dissolution tests comprises a vessel filled with about 500 mL of dissolution medium wherein the dissolution medium is 0.1 M HCl or pH 6.8 phosphate buffer and the dissolution profile is determined as described in the United States Pharmacopeia at about 37°C using a rotation speed of about 50 rpm. Suitably, the in vitro dissolution tests comprises a vessel filled with 500 mL of dissolution medium wherein the dissolution medium is 0.1 M HCl or pH 6.8 phosphate buffer and the dissolution profile is determined as described in the United States Pharmacopeia at 37°C using a rotation speed of 50 rpm.

[0250] Suitably, the in vitro dissolution test comprises a vessel filled with about 500 mL of dissolution medium wherein the dissolution medium is 0.1 M HCl or pH 6.8 phosphate buffer and the dissolution profile is determined as described in the United States Pharmacopeia wherein a paddle rotates at about 50 rpm in the vessel, and wherein the dissolution medium has a temperature of about 37°C. Suitably, the in vitro dissolution test comprises a vessel filled with 500 mL of dissolution medium wherein the dissolution medium is 0.1 M HCl or pH 6.8 phosphate buffer and the dissolution profile is determined as described in the United States Pharmacopeia wherein a paddle rotates at 50 rpm in the vessel, and wherein the dissolution medium has a temperature of 37°C.

[0251] Suitably, the in vitro dissolution test comprises a vessel filled with about 500 mL of dissolution medium wherein the dissolution medium is 0.1 M HCl or pH 6.8 phosphate buffer and the dissolution profile is determined as described in the United States Pharmacopeia wherein a paddle rotates at about 50 rpm in the vessel for about the first 45 minutes of the test and then about 200 rpm after about 45 minutes, and wherein the dissolution medium has a temperature of about 37°C. Suitably, the in vitro dissolution test comprises a vessel filled with 500 mL of dissolution medium wherein the dissolution medium is 0.1 M HCl or pH 6.8 phosphate buffer and the dissolution profile is determined as described in the United States Pharmacopeia wherein a paddle rotates at 50 rpm in the vessel for the first 45 minutes of the test and then 200 rpm after 45 minutes, and wherein the dissolution medium has a temperature of 37°C.

[0252] Suitably, the in vitro dissolution test comprises a paddle wherein the paddle rotates. Suitably, the in vitro dissolution test comprises a paddle wherein the paddle rotates at about 50 rpm. Suitably, the in vitro dissolution test comprises a paddle wherein the paddle rotates at about 50 rpm for about the first 45 minutes of the test and then about 200 rpm after about 45 minutes. Suitably, the in vitro dissolution test comprises a paddle wherein the paddle rotates at 50 rpm. Suitably, the in vitro dissolution test comprises a paddle wherein the paddle rotates at 50 rpm for the first 45 minutes of the test and then 200 rpm after 45 minutes.

[0253] Suitably, the in vitro dissolution test comprises a basket wherein the basket rotates. Suitably, the in vitro dissolution test comprises a basket wherein the basket rotates at about 50 rpm. Suitably, the in vitro dissolution test comprises a basket wherein the basket rotates at about 50 rpm for about the first 45 minutes of the test and then about 200 rpm after about 45 minutes. Suitably, the in vitro dissolution test comprises a basket wherein the basket rotates at 50 rpm. Suitably, the in vitro dissolution test comprises a basket wherein the basket rotates at 50 rpm for the first 45 minutes of the test and then 200 rpm after 45 minutes.

[0254] Suitably, the in vitro dissolution test further comprises sinkers for the pharmaceutical composition. Suitably, the sinkers are O-ring sinkers.

[0255] Suitably, the in vitro dissolution test comprises a detector. Suitably the detector comprises a UV detector.

[0256] Suitably, the total amount of the active substance released from the pharmaceutical composition when the pharmaceutical composition is subjected to an in vitro dissolution profile is determined by a chromatographic method or UV spectroscopy. Suitably, the chromatographic method is a HPLC method. Suitably the HPLC method comprises a UV detector. Suitably, the UV detector measures the assay of the active substance at about 217 nm.

[0257] Suitably, the HPLC method is a reverse phase HPLC method. Suitably, the reverse phase HPLC method comprises two eluents wherein the ratio of the two eluents changes during the course of the HPLC analysis. Suitably, the first eluent comprises water and the second eluent comprises acetonitrile. Suitably, the first eluent comprises water and phosphoric acid and the second eluent comprises acetonitrile. Suitably, the first eluent comprises water and 0.1% phosphoric acid and the second eluent comprises acetonitrile.

[0258] Suitably, the reverse phase HPLC method comprises a HPLC column. Suitably, the HPLC column comprises a C18 stationary phase. Suitably, the HPLC column temperature is at about 40°C. Suitably, the eluents flow through the HPLC column at about 0.5 mL / min.

[0259] Suitably, the chromatographic method is a reverse phase HPLC method wherein the reverse phase HPLC method comprises: a. a UV detector; b. a HPLC column; and c. two eluents wherein the ratio of the two eluents changes during the course of the HPLC analysis. Uniformity of the active substance in the pharmaceutical composition

[0260] Suitably, the active substance is homogeneously distributed throughout the non-aqueous solvent. Suitably, the active substance is homogeneously distributed throughout the non-aqueous solvent at room temperature.

[0261] Advantageously, the active substance is homogeneously dispersed within the pharmaceutical composition. This ensures that the required amount of the active substance is present in the portion of pharmaceutical composition, for example, upon dosing of the pharmaceutical composition to a patient, or the use of the pharmaceutical composition in the preparation of an immediate release pharmaceutical formulation. This is critical from a patient safety and efficacy perspective.

[0262] In this context, homogeneously dispersed is defined as the uniform distribution of the active substance throughout the non-aqueous solvent. For example, if separate portions of the pharmaceutical composition were analysed to determine the active substance content within that portion, there would be minimal variability (i.e., less than about 10%, such as less than about 8%, less than about 6%, less than about 5%, less than about 4%, less than about 3%, less than about 2%, less than about 1%, or less than about 0.5% variability) in the active substance content determined for each portion).

[0263] Suitably, the active substance is homogeneously distributed throughout the non-aqueous solvent for at least about 2 weeks, about 1 month, about 2 months, about 3 months, about 6 months, about 12 months, or about 24 months. Suitably, the active substance is homogeneously distributed throughout the non-aqueous solvent for at least 2 weeks, 1, 2, 3, 6, 12, or 24 months.

[0264] Suitably, the active substance is homogeneously distributed throughout the non-aqueous solvent for at least about 2 weeks, about 1 month, about 2 months, about 3 months, about 6 months, about 12 months, or about 24 months upon storage of the pharmaceutical composition at room temperature. Suitably, the active substance is homogeneously distributed throughout the non-aqueous solvent for at least 2 weeks, 1, 2, 3, 6, 12, or 24 months upon storage of the pharmaceutical composition at room temperature.

[0265] Suitably, the active substance is homogeneously distributed throughout the non-aqueous solvent for at least about 2 weeks, about 1 month, about 2 months, about 3 months, about 6 months, about 12 months, or about 24 months upon storage of the pharmaceutical composition at 25°C / 60%RH and / or 40°C / 75%RH. Suitably, the active substance is homogeneously distributed throughout the non-aqueous solvent for at least 2 weeks, 1, 2, 3, 6, 12, or 24 months upon storage of the pharmaceutical composition at 25°C / 60%RH and / or 40°C / 75%RH.

[0266] Suitably, the homogeneous distribution of the active substance in the non-aqueous solvent is determined by an analytical method.

[0267] Suitably, the analytical method comprises determining the weight percentage of the active substance within a portion of the pharmaceutical composition.

[0268] Suitably, the analytical method comprises determining the weight percentage of the active substance within a portion of the pharmaceutical composition and wherein the weight percentage of the active substance within the portion of the pharmaceutical composition is ±5% of the expected value based on the total amount of the active substance added to the total amount of the pharmaceutical composition.

[0269] Suitably, the analytical method comprises determining the weight percentage of the active substance within a portion of the pharmaceutical composition and wherein the weight percentage of the active substance within the portion of the pharmaceutical composition is ±2% of the expected value based on the total amount of the active substance added to the total amount of the pharmaceutical composition.

[0270] Suitably, the analytical method comprises determining the weight percentage of the active substance within a portion of the pharmaceutical composition and wherein the weight

[0271] percentage of the active substance within the portion of the pharmaceutical composition is ±1% of the expected value based on the total amount of the active substance added to the total amount of the pharmaceutical composition.

[0272] Suitably, the analytical method comprises determining the weight percentage of the active substance within a portion of the pharmaceutical composition and wherein the weight percentage of the active substance within the portion of the pharmaceutical composition is ±0.5% of the expected value based on the total amount of the active substance added to the total amount of the pharmaceutical composition.

[0273] Suitably, the portion of the pharmaceutical composition is less than about 10% by the total weight of the pharmaceutical composition, such as less than about 5% by weight, about 4% by weight, about 3% by weight or about 2% by weight. Suitably, the portion of the pharmaceutical composition is less than 10% by the total weight of the pharmaceutical composition, such as less than 5% by weight, 4% by weight, 3% by weight or 2% by weight.

[0274] Suitably, the analytical method comprises a chromatographic method or a spectroscopic method.

[0275] Suitably, the spectroscopic method is NMR.

[0276] Suitably, the chromatographic method is HPLC or UPLC. Suitably the HPLC or UPLC method comprises a UV detector. Suitably, the UV detector measures the assay of the active substance at about 217 nm.

[0277] Suitably, the HPLC method is a reverse phase HPLC method. Suitably, the reverse phase HPLC method comprises two eluents wherein the ratio of the two eluents changes during the course of the HPLC analysis. Suitably, the first eluent comprises water and the second eluent comprises acetonitrile. Suitably, the first eluent comprises water and phosphoric acid and the second eluent comprises acetonitrile. Suitably, the first eluent comprises water and 0.1% phosphoric acid and the second eluent comprises acetonitrile.

[0278] Suitably, the reverse phase HPLC method comprises a HPLC column. Suitably, the HPLC column comprises a C18 stationary phase. Suitably, the HPLC column temperature is at about 40°C. Suitably, the eluents flow through the HPLC column at about 0.5 mL / min.

[0279] Suitably, the chromatographic method is a reverse phase HPLC method wherein the reverse phase HPLC method comprises: a. a UV detector; b. a HPLC column; and c. two eluents wherein the ratio of the two eluents changes during the course of the HPLC analysis. Pharmaceutical formulation

[0280] Suitably, there is provided an immediate release pharmaceutical formulation for oral use comprising the pharmaceutical composition according to the claims.

[0281] Suitably, the immediate release pharmaceutical formulation may be in a form suitable for oral use (for example, hard or soft capsules, suspensions, emulsions, syrups or elixirs, sprays).

[0282] Suitably, the immediate release pharmaceutical formulation, when subjected to a content uniformity test as described in the European Pharmacopoeia, the acceptance value is less than 15. Suitably, the immediate release pharmaceutical formulation, when subjected to a content uniformity test as described in the European Pharmacopoeia, the acceptance value is less than 10. Suitably, the content uniformity test comprises a chromatographic assay of the immediate release pharmaceutical formulation. Suitably, the chromatographic assay comprises HPLC. HPLC in this context includes UPLC.

[0283] Advantageously, the active substance in the pharmaceutical composition is uniformly distributed and meets the regulatory requirements. Thereby ensuring the correct dose of the active substance is present in each pharmaceutical formulation dosage unit. This is critical from a patient safety and efficacy perspective.

[0284] Suitably, the European Pharmacopoeia content uniformity test is 2.9.40.

[0285] Suitably, the content uniformity test comprises determining the amount of active substance in the immediate release pharmaceutical formulation. Suitably, the amount of active substance in the immediate release pharmaceutical formulation is determined using a chromatographic method. Suitably, the chromatographic method is a HPLC method. Suitably the HPLC method comprises a UV detector. Suitably, the UV detector measures the assay of the active substance at about 217 nm.

[0286] Suitably, the HPLC method is a reverse phase HPLC method. Suitably, the reverse phase HPLC method comprises two eluents wherein the ratio of the two eluents changes during the course of the HPLC analysis. Suitably, the first eluent comprises water and the second eluent comprises acetonitrile. Suitably, the first eluent comprises water and phosphoric acid and the second eluent comprises acetonitrile. Suitably, the first eluent comprises water and 0.1% phosphoric acid and the second eluent comprises acetonitrile.

[0287] Suitably, the reverse phase HPLC method comprises a HPLC column. Suitably, the HPLC column comprises a C18 stationary phase. Suitably, the HPLC column is at about 40°C. Suitably, the eluents flow through the HPLC column at about 0.5 mL / min.

[0288] Suitably, the chromatographic method is a reverse phase HPLC method wherein the reverse phase HPLC method comprises: a. a UV detector; b. a HPLC column; and c. two eluents wherein the ratio of the two eluents changes during the course of the HPLC analysis.

[0289] Suitably, the immediate release pharmaceutical formulation is added to a diluent and the active substance is dissolved in the diluent. Suitably, the diluent is 90:10 v / v 0.1M HCl:acetonitrile.

[0290] Suitably, the acceptance value is determined using the following formula: AV = M − X + ks wherein: X = Mean of individual contents (x 1 , x 2 ....x 3 ) expressed as a percentage of the label claim; k = acceptability constant. If n = 10 then k = 2.4, if n = 30 then 2.0 where n = sample size; s = Sample standard deviation; M = Reference Value wherein: for case 1 when T≤101.5: If 98.5%≤X≤101.5% then M = X (therefore AV = ks) If X<98.5% then M = 98.5% (therefore AV = 98.5 - X + ks) If X>101.5%, then M = 101.5% (therefore AV = X - 101.5 + ks) for case 2 when T>101.5: If 98.5%≤X≤T then M = X (therefore AV = ks) If X<98.5% then M = 98.5% (therefore AV = 98.5 - X + ks) If X>T, then M = T% (therefore AV = X - T + ks); and T = target test sample amount at time of manufacture.

[0291] Suitably, the immediate release pharmaceutical formulation is an immediate release capsule formulation comprising a capsule shell.

[0292] Suitably, the capsule shell comprises gelatin or HPMC.

[0293] Suitably, the capsule shell comprises gelatin, such as hard gelatin.

[0294] Suitably, the capsules shell is a size 2, 3 or 4 size capsule shell.

[0295] Suitably, the immediate release pharmaceutical formulation is a spray.

[0296] Suitably, the immediate release formulation comprises between about 10 and about 1000 µg of the active substance. Suitably, the immediate release formulation comprises between 10 and 1000 µg of the active substance. Suitably, the immediate release pharmaceutical formulation comprises between about 10 and about 650 µg of the active substance. Suitably, the immediate release pharmaceutical formulation comprises between 10 and 650 µg of the active substance. Suitably, the immediate release pharmaceutical formulation comprises between about 50 and about 200 µg of the active substance. Suitably, the immediate release pharmaceutical formulation comprises between 50 and 200 µg of the active substance. Suitably, the immediate release pharmaceutical formulation comprises between about 100 and about 650 µg of the active substance. Suitably, the immediate release pharmaceutical formulation comprises between 100 and 650 µg of the active substance. release pharmaceutical formulation comprises between 25 and 75 µg of the active substance. Suitably, the immediate release pharmaceutical formulation comprises between about 150 and about 250 µg of the active substance.

[0297] Suitably, the immediate release pharmaceutical formulation comprises about 50 µg of the active substance.

[0298] Suitably, the immediate release pharmaceutical formulation comprises about 200 µg of the active substance.

[0299] Suitably, the immediate release pharmaceutical formulation comprises about 650 µg of the active substance.Process of manufacture

[0300] Also disclosed but not claimed is a method of manufacturing the pharmaceutical composition described herein comprising the step of mixing as an active substance Compound I, or a pharmaceutically acceptable salt thereof, into a non-aqueous solvent.

[0301] Suitably, the non-aqueous solvent is a liquid in the mixing step.

[0302] Suitably, the step of mixing the active substance into the non-aqueous solvent is performed at a temperature greater than room temperature, such as between about 35°C and about 80°C, about 40°C and about 80°C, about 50°C and about 80°C, or about 60°C and about 80°C. Suitably, the step of mixing the active substance into the non-aqueous solvent is performed at a temperature greater than room temperature, such as between 35°C and 80°C, 40°C and 80°C, 50°C and 80°C, or 60°C and 80°C.

[0303] Suitably, the step of mixing the active substance into the non-aqueous solvent is performed at a temperature greater than the melting point of the non-aqueous solvent.

[0304] Suitably, the step of mixing the active substance into the non-aqueous solvent is performed under an inert atmosphere. Suitably, the inert atmosphere is a nitrogen atmosphere.

[0305] Suitably, the step of mixing the active substance into the non-aqueous solvent comprises protecting the active substance from light. Suitably, the step of mixing the active substance into the non-aqueous solvent is performed in a dark room. Suitably, the step of mixing the active substance into the non-aqueous solvent comprises using vessels for the active substance and non-aqueous solvent mixture wherein the vessels protect the contents of the vessel from light.

[0306] Advantageously, performing the mixing step in low light and / or under an inert atmosphere minimises the number of degradation products formed during manufacture and / or upon storage of the pharmaceutical composition.Therapeutic Uses and Applications

[0307] The present disclosure provides a pharmaceutical composition according to the claims or an immediate release pharmaceutical formulation according to the claims for use as a medicament.

[0308] The present disclosure provides a pharmaceutical composition according to the claims or an immediate release pharmaceutical formulation according to the claims for use in therapy.

[0309] The present disclosure provides a pharmaceutical composition according to the claims or an immediate release pharmaceutical formulation according to the claims for use in a disease state or disorder in which dysfunction of CB 1 and / or CB 2 receptors are present or implicated.

[0310] The present disclosure provides a pharmaceutical composition or an immediate release pharmaceutical formulation according to the claims for use in the treatment of an anorexia associated condition; a cachexia associated condition; or anorexia nervosa.

[0311] Suitably, the anorexia associated condition is anorexia associated with cancer, anorexia associated with HIV (Human Immunodeficiency Virus), anorexia associated with Chronic Kidney Disease, anorexia associated with dementia, or anorexia associated with chronic congestive heart failure.

[0312] Suitably, the anorexia associated condition is anorexia associated with cancer.

[0313] Suitably, the cachexia associated 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.

[0314] The present disclosure provides a pharmaceutical composition or an immediate release pharmaceutical formulation according to the claims for use in the treatment of a pain condition. Suitably, the pain condition is a pain condition in cancer, acute pain, chronic pain, neuropathic pain, back pain, cancer pain, visceral pain, pain caused by rheumatoid arthritis, migraine. Suitably, the pain condition in cancer is a pain condition in cancer associated with the reduction of opiate use, associated with the reduction in nausea and / or vomiting in cancer patients.

[0315] The present disclosure provides a pharmaceutical composition according to the claims or an immediate release pharmaceutical formulation according to the claims for use in the treatment of anxiety disorders, cancer, multiple sclerosis, Parkinson's disease, Huntington's chorea, Alzheimer's disease, AIDS (Acquired Immune Deficiency Syndrome), amyotrophic lateral sclerosis, gastrointestinal disorders, cardiovascular disorders, or insomnia.

[0316] The present disclosure provides a pharmaceutical composition according to the claims or an immediate release pharmaceutical formulation according to the claims for use as an immunomodulator. Suitably, the pharmaceutical composition according to the claims or the immediate release pharmaceutical formulation is for use in the treatment of autoimmune diseases such as arthritis, collagen diseases, or allergies. Suitably, the pharmaceutical composition according to the claims or the immediate release pharmaceutical formulation is for use in skin graft therapy, organ transplant therapy and other surgical needs. Suitably, the pharmaceutical composition according to the claims or the immediate release pharmaceutical formulation is for use as an anti-tumor agent or an anti-viral agent.

[0317] The present disclosure provides a pharmaceutical composition according to the claims or an immediate release pharmaceutical formulation according to the claims for use in the treatment of diarrhoea; depression; anxiety and stress-related disorders such as post-traumatic stress disorders, panic disorder, generalized anxiety disorder, social phobia, and obsessive compulsive disorder; urinary incontinence; premature ejaculation; various mental illnesses; cough; lung oedema; various gastro-intestinal disorders, e.g. constipation, functional gastrointestinal disorders such as Irritable Bowel Syndrome and Functional Dyspepsia; Parkinson's disease and other motor disorders; traumatic brain injury; stroke; cardioprotection following myocardial infarction; spinal injury and drug addiction including the treatment of alcohol, nicotine, opioid and other drug abuse; and for disorders of the sympathetic nervous system, such as hypertension.

[0318] The present disclosure provides a pharmaceutical composition according to the claims or an immediate release pharmaceutical formulation according to the claims for use as an analgesic agent, for example for use during general anaesthesia and monitored anaesthesia care. Combinations of agents with different properties are often used to achieve a balance of effects needed to maintain the anaesthetic state (e.g. amnesia, analgesia, muscle relaxation and sedation). Included in this combination are inhaled anaesthetics, hypnotics, anxiolytics, neuromuscular blockers and opioids.

[0319] Also disclosed but not claimed is a method of activating the CB 1 and / or CB 2 receptor in vitro or in vivo, said method comprising contacting a cell with an effective amount of a pharmaceutical composition as defined herein or an immediate release pharmaceutical formulation as defined herein.

[0320] Also disclosed but not claimed is a method of treating a disease or disorder in which dysfunction of CB 1 and / or CB 2 receptors are implicated in a patient in need of such treatment, said method comprising administering to said patient a therapeutically effective amount of a pharmaceutical composition as defined herein or an immediate release pharmaceutical formulation as defined herein.

[0321] A therapeutically effective amount of a pharmaceutical composition or immediate release pharmaceutical formulation comprising the active substance of the present disclosure for use in therapy is an amount to achieve a particular biological or therapeutic result such as, but not limited to, biological or therapeutic results disclosed, described, or exemplified herein. For example, to treat or prevent a disease or condition referred to herein, slow its progression and / or reduce the symptoms associated with the condition and / or disease.

[0322] The amount of the active substance that is combined with one or more excipients to produce the pharmaceutical composition or the immediate release pharmaceutical formulation will necessarily vary depending upon the individual treated and the particular route of administration. An immediate release formulation intended for oral administration to humans will generally contain, for example, from about 10 µg to about 1000 µg of the active substance (for example about 10 µg to about 650 µg) compounded with an appropriate and convenient amount of excipients which may vary from about 0.01 to about 99.99 percent by weight of the total pharmaceutical composition or the immediate release pharmaceutical formulation.

[0323] The size of the dose for therapeutic or prophylactic purposes of the active substance will naturally vary according to the nature and severity of the conditions, the age and sex of the animal or patient and the route of administration, according to well known principles of medicine.

[0324] Also disclosed but not claimed is a method of treating an anorexia associated condition, a cachexia associated condition or anorexia nervosa, said method comprising administering to said patient a therapeutically effective amount of a pharmaceutical composition as defined herein or the immediate release pharmaceutical formulation as defined herein.

[0325] Suitably, the anorexia associated condition is anorexia associated with cancer, anorexia associated with HIV, anorexia associated with Chronic Kidney Disease, anorexia associated with cancer dementia, or anorexia associated with chronic congestive heart failure.

[0326] Suitably, the anorexia associated condition is anorexia associated with cancer.

[0327] Suitably, the cachexia associated 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.

[0328] Also disclosed but not claimed is a method of treating a pain condition in a patient in need of such treatment, said method comprising administering to said patient a therapeutically effective amount of a pharmaceutical composition as defined herein or the immediate release pharmaceutical formulation as defined herein. Suitably, the pain condition is a pain condition in cancer, acute pain, chronic pain, neuropathic pain, back pain, cancer pain, visceral pain, pain caused by rheumatoid arthritis, migraine. Suitably, the pain condition in cancer is a pain condition in cancer associated with the reduction of opiate use, associated with the reduction in nausea and / or vomiting in cancer patients.

[0329] Also disclosed but not claimed is a method of treating anxiety disorders, cancer, multiple sclerosis, Parkinson's disease, Huntington's chorea, Alzheimer's disease, AIDS, amyotrophic lateral sclerosis, gastrointestinal disorders, cardiovascular disorders, or insomnia, said method comprising administering to said patient a therapeutically effective amount of a pharmaceutical composition as defined herein or the immediate release pharmaceutical formulation as defined herein.

[0330] Also disclosed but not claimed is a method of treating autoimmune diseases such as arthritis, collagen diseases, or allergies, said method comprising administering to said patient a therapeutically effective amount of a pharmaceutical composition or the immediate release pharmaceutical formulation as defined herein. Also disclosed but not claimed is 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 or the immediate release pharmaceutical formulation as defined herein.

[0331] Also disclosed but not claimed is a method of treating diarrhoea; depression; anxiety and stress-related disorders such as post-traumatic stress disorders, panic disorder, generalized anxiety disorder, social phobia, and obsessive compulsive disorder; urinary incontinence; premature ejaculation; various mental illnesses; cough; lung oedema; various gastro-intestinal disorders, e.g. constipation, functional gastrointestinal disorders such as Irritable Bowel Syndrome and Functional Dyspepsia; Parkinson's disease and other motor disorders; traumatic brain injury; stroke; cardioprotection following myocardial infarction; spinal injury and drug addiction including the treatment of alcohol, nicotine, opioid and other drug abuse; and for disorders of the sympathetic nervous system, such as hypertension, said method comprising administering to said patient a therapeutically effective amount of a pharmaceutical composition as defined herein or the immediate release pharmaceutical formulation as defined herein.

[0332] Also disclosed but not claimed is a method of providing an analgesic effect, for example for use during general anaesthesia and monitored anaesthesia care, said method comprising administering to said patient a therapeutically effective amount of a pharmaceutical composition as defined herein or the immediate release pharmaceutical formulation as defined herein. Combinations of agents with different properties are often used to achieve a balance of effects needed to maintain the anaesthetic state (e.g. amnesia, analgesia, muscle relaxation and sedation). Included in this combination are inhaled anaesthetics, hypnotics, anxiolytics, neuromuscular blockers and opioids.

[0333] Also disclosed but not claimed is use of a pharmaceutical composition as defined herein or an immediate release pharmaceutical formulation as defined herein for use in the manufacture of a medicament.

[0334] Also disclosed but not claimed is use of a pharmaceutical composition as defined herein or an immediate release pharmaceutical formulation as defined herein for use in the manufacture of a medicament for use in a disease state or disorder in which dysfunction of CB 1 and / or CB 2 receptors are present or implicated.

[0335] Also disclosed but not claimed is use of a pharmaceutical composition as defined herein or an immediate release pharmaceutical formulation as defined herein for use in the manufacture of a medicament for the treatment of an anorexia associated condition; a cachexia associated conditions; or anorexia nervosa.

[0336] Suitably, the anorexia associated condition is anorexia associated with cancer, anorexia associated with HIV, anorexia associated with Chronic Kidney Disease, anorexia associated with dementia, or anorexia associated with chronic congestive heart failure.

[0337] Suitably, the anorexia associated condition is anorexia associated with cancer.

[0338] Suitably, the cachexia associated 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.

[0339] Also disclosed but not claimed is use of a pharmaceutical composition as defined herein or an immediate release pharmaceutical formulation as defined herein for use in the manufacture of a medicament for the treatment of a pain condition. Suitably, the pain condition is a pain condition in cancer, acute pain, chronic pain, neuropathic pain, back pain, cancer pain, visceral pain, pain caused by rheumatoid arthritis, migraine. Suitably, the pain condition in cancer is a pain condition in cancer associated with the reduction of opiate use, associated with the reduction in nausea and / or vomiting in cancer patients.

[0340] Also disclosed but not claimed is use of a pharmaceutical composition as defined herein or an immediate release pharmaceutical formulation as defined herein for use in the manufacture of a medicament for the treatment of anxiety disorders, cancer, multiple sclerosis, Parkinson's disease, Huntington's chorea, Alzheimer's disease, AIDS, amyotrophic lateral sclerosis, gastrointestinal disorders, cardiovascular disorders, or insomnia.

[0341] Also disclosed but not claimed is use of a pharmaceutical composition as defined herein or an immediate release pharmaceutical formulation as defined herein for use in the manufacture of a medicament for use as an immunomodulator. Also disclosed but not claimed is use of a pharmaceutical composition as defined herein or an immediate release pharmaceutical formulation as defined herein for use in the manufacture of a medicament for the treatment of autoimmune diseases such as arthritis, collagen diseases, or allergies. Also disclosed but not claimed is use of a pharmaceutical composition as defined herein or an immediate release pharmaceutical formulation as defined herein for use in the manufacture of a medicament for use in skin graft therapy, organ transplant therapy and other surgical needs. Also disclosed but not claimed is use of a pharmaceutical composition as defined herein or an immediate release pharmaceutical formulation as defined herein for use in the manufacture of a medicament for use an anti-tumour agent or an anti-viral agent.

[0342] Also disclosed but not claimed is use of a pharmaceutical composition as defined herein or an immediate release pharmaceutical formulation as defined herein for use in the manufacture of a medicament for use in the treatment of diarrhoea; depression; anxiety and stress-related disorders such as post-traumatic stress disorders, panic disorder, generalized anxiety disorder, social phobia, and obsessive compulsive disorder; urinary incontinence; premature ejaculation; various mental illnesses; cough; lung oedema; various gastro-intestinal disorders, e.g. constipation, functional gastrointestinal disorders such as Irritable Bowel Syndrome and Functional Dyspepsia; Parkinson's disease and other motor disorders; traumatic brain injury; stroke; cardioprotection following myocardial infarction; spinal injury and drug addiction including the treatment of alcohol, nicotine, opioid and other drug abuse; and for disorders of the sympathetic nervous system, such as hypertension.

[0343] Also disclosed but not claimed is use of a pharmaceutical composition as defined herein or an immediate release pharmaceutical formulation as defined herein for use in the manufacture of a medicament for use as an analgesic agent, for example for use during general anaesthesia and monitored anaesthesia care. Combinations of agents with different properties are often used to achieve a balance of effects needed to maintain the anaesthetic state (e.g. amnesia, analgesia, muscle relaxation and sedation). Included in this combination are inhaled anaesthetics, hypnotics, anxiolytics, neuromuscular blockers and opioids.

[0344] In one embodiment, between about 25 and about 700 µg / dose / day of Compound I is administered to the patient, such as between about 50 and about 650 µg / dose / day. Suitably, about 50, 150, 250, 400 or 650 µg / dose / day of Compound I is administered to the patient,Routes of Administration

[0345] The pharmaceutical compositions or the immediate release pharmaceutical formulations of the disclosure may be administered to a subject by any convenient oral route of administration (e.g. by ingestion).Combination Therapies

[0346] The pharmaceutical compositions and / or pharmaceutical formulations of the present disclosure are useful for the treatment of conditions in which therapy with an agonist of CB1 and / or CB2 is beneficial. Examples of such conditions are outlined above in the therapeutic use section of the present disclosure.

[0347] The pharmaceutical compositions and pharmaceutical formulations of the present disclosure may be used in combination with one or more additional therapeutic agents for the treatment of the condition concerned.

[0348] An additional therapeutic agent may be included in the pharmaceutical composition or pharmaceutical formulation of the present disclosure with the Compound I, or a pharmaceutically acceptable salt thereof, as defined herein, or, alternatively, it may be administered separately, either at the same time as the pharmaceutical composition or pharmaceutical formulation of the present disclosure or at an earlier or later time.

[0349] Therefore, in a further aspect of the disclosure, there is provided a combination product comprising a pharmaceutical composition and / or pharmaceutical formulation of the present disclosure 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 and / or pharmaceutical formulation of the present disclosure and the pharmaceutical composition comprising the additional therapeutic agent are administered simultaneously, sequentially or separately.

[0350] According to this aspect of the disclosure there is provided a combination for use in the treatment of disease or condition in which therapy with a CB1 and / or CB2 agonist is beneficial (e.g. cancer anorexia), comprising a pharmaceutical composition or pharmaceutical formulation of the present disclosure as defined hereinbefore, and one or more additional therapeutic agents.

[0351] The present disclosure also provides a pharmaceutical composition and / or pharmaceutical formulation of the present disclosure and one or more additional therapeutic agents for use in the treatment of anorexia, especially cancer anorexia, wherein the pharmaceutical composition and / or formulation of the present disclosure and the additional therapeutic agent are administered simultaneously, sequentially or separately.

[0352] In certain embodiments, the pharmaceutical composition and / or pharmaceutical formulation of the present disclosure may be used for the treatment of cancer anorexia in patients undergoing cancer therapy. The cancer therapy may in the form of radiotherapy, surgical therapy, chemotherapy, immunotherapy or a combination thereof.

[0353] Herein, where the term "combination" is used it is to be understood that this 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. In a further aspect of the invention "combination" refers to sequential administration. Where the administration is sequential or separate, the delay in administering the second component should not be such as to lose the beneficial effect of the combination.

[0354] As indicated above, the combination therapy of the present disclosure may be achieved by way of the simultaneous, sequential, or separate dosing of the individual components of the treatment. Such combination products employ the compositions and formulations of the present disclosure within the dosage range described hereinbefore and one or more further pharmaceutically-active agents, wherein each additional agent is used within its approved dosage range.Examples

[0355] The following abbreviations have been used in the Examples: APIactive pharmaceutical ingredient, which in the present case is N-(2-(tert-butyl)-1-((4,4-difluorocyclohexyl)methyl)-1H-benzimidazol-5-yl)ethanesulfonamide (Compound I) AVacceptance value HPMChydroxypropyl methylcellulose n / anot applicable NMTnot more than PEGpolyethylene glycol Vitamin E TPGSD-α-Tocopherol polyethylene glycol succinate Example 1 - forced degradation study of N-(2-(tert-butyl)-1-((4,4-difluorocyclohexyl)methyl)-1H-benzimidazol-5-yl)ethanesulfonamide

[0356] A forced degradation of N-(2-(tert-butyl)-1-((4,4-difluorocyclohexyl)methyl)-1H-benzimidazol-5-yl)ethanesulfonamide study (active substance) was performed under a number of stressed conditions for up to 13 days. The active substance was shown to be stable to degradation as a solution at room temperature, at 100°C as a solid, under 1M acidic conditions at room temperature and at 60°C, under 0.5M basic conditions at room temperature and at 60°C, as a solution heated to 60°C, and under photostability conditions as a solid. The active substance showed slight degradation under peroxide conditions, under 1M acidic conditions and 0.5M basic conditions when these tests were extended to 80°C, and as a solution when heated to 80°C. Major degradation of the active substance as a solution under photostability conditions occurred.Materials

[0357] Active substanceN-(2-(tert-butyl)-1-((4,4-difluorocyclohexyl)methyl)-1H-benzimidazol-5-yl)ethanesulfonamideex- Onyx Scientific LtdBatch no: CB988ELCMS Waterex- Onyx Scientific LtdN / AAcetonitrileex- Sigma-AldrichLot no: - STBJ1963Ammonium acetateex- FlukaLot no: - H20106.0M Hydrochloric Acidex- FlukaLot no: - H13701M Sodium Hydroxideex- FisherLot no: - 187186830% Hydrogen peroxideex- Sigma-AldrichLot no: - MKBS2987V AnalysisHPLC Conditions

[0358] Instrument:Agilent 1100 / 1200Column:YMC Triart Phenyl, 4.6x150mm. 3µm particle size (ex-YMC P.N.TPH12S03-1546PTH)Mobile Phase:A - 10mM Ammonium acetate pH 6.0B - AcetonitrileFlow Rate:1.0ml.min-1Injection Volume:5µlDetection:UV @ 220nmColumn Temp:30°CPost Run:4 minutesGradient:Time (mins)%A%B080202035652659530.5595318020Diluent:Acetonitrile:deionised water (1:1)Standard Solution:Make up a solution of 0.2mg / ml. This is to be made up fresh prior to use at T=3 and T=7 days. Stock solution preparation

[0359] Accurately weigh 80 mg of the active substance into a 100 mL volumetric flask and dissolve in 50 mL of diluent. Dilute the resulting solution to volume with diluent and mix well.Procedure

[0360] Table 1 below details the different study tests performed. All solution samples are prepared and stored in sealed vials and heated samples are cooled to ambient prior to sampling to prevent evaporation. Analysis took place on days 3 and 7 after stressing initiation for solutions described for Tests 1-6 and once exposure was complete for samples described in Tests 7-10. Due to the low levels of degradation observed at 7 days, Tests 3, 4 and 5 were heated to 80°C for a further 4 days and analysed, and Test 6 was analysed after a further 6 days.

[0361] The photostability samples were exposed to a total of 1.92 million lux hours and an integrated near-UV energy of 374.6 Whm -2< . Table 1 - forced degradation study tests Test Description Sample preparation for analysis after study Test 1 - ControlAccurately pipette 5ml of stock solution and 5ml of diluent into a suitable container and leave at ambient temperature.Pipette 1ml of Control Solution into a 2ml volumetric flask, make up to volume with diluent and mix well.Test 2 - Solid stateStore 150mg of sample at 100°C.Dissolve in diluent to a concentration of 0.2 mg.ml -1< .Test 3 - Acid (1M)Accurately pipette 5ml of Stock Solution and 5ml of 2M HCl solution into a suitable container and leave at ambient temperature.Pipette 1ml of Acid Sample Solution into a 2ml volumetric flask, make up to volume with diluent and mix well.Test 3- Acid Blank (1M)Accurately pipette 5ml of diluent and 5ml of 2M HCl solution into a suitable container and leave at ambient temperature.Pipette 1ml of Acid Blank Solution into a 2ml volumetric flask, make up to volume with diluent and mix well.Test 3 - Acid (1M heated)Accurately pipette 5ml of Stock Solution and 5ml of 2M HCl solution into a suitable container and heat at 60°C.Pipette 1ml of Acid Sample Solution into a 2ml volumetric flask, make up to volume with diluent and mix well.Test 3 -Acid Blank (1M heated)Accurately pipette 5ml of diluent and 5ml of 2M HCl solution into a suitable container and heat at 60°C.Pipette 1ml of Acid Blank Solution into a 2ml volumetric flask, make up to volume with diluent and mix well.Test 4 - Base (0.5M)Accurately pipette 5ml of Stock Solution and 5ml of 1M NaOH solution into a suitable container and leave at ambient temperature.Pipette 1ml of Base Sample Solution into a 2ml volumetric flask, make up to volume with diluent and mix well.Test 4 - Base Blank (0.5M)Accurately pipette 5ml of diluent and 5ml of 1M NaOH solution into a suitable container and leave at ambient temperature.Blank - Pipette 1ml of Base Blank Solution into a 2ml volumetric flask, make up to volume with diluent and mix well.Test 4-Base (0.5M heated)Accurately pipette 5ml of Stock Solution and 5ml of 1M NaOH solution into a suitable container and heat at 60°C.Pipette 1ml of Base Sample Solution into a 2ml volumetric flask, make up to volume with diluent and mix well.Test 4 - Base Blank (0.5M heated)Accurately pipette 5ml of diluent and 5ml of 1M NaOH solution into a suitable container and heat at 60°C.Blank - Pipette 1ml of Base Blank Solution into a 2ml volumetric flask, make up to volume with diluent and mix well.Test 5 - Heat (60°C)Accurately pipette 5ml of Stock Solution and 5ml of diluent into a suitable container and heat at 60°C.Pipette 1.0 ml of heated sample solution into a 2ml volumetric flask, make up to volume with diluent and mix well.Test 6 - Peroxide (1.5%)Accurately pipette 5ml of Stock Solution and 5ml of 3% Hydrogen peroxide solution into a suitable container and leave at ambient temperature.Pipette 1.0ml of Peroxide Sample solution into a 2ml volumetric flask, make up to volume with diluent and mix well.Test 6 - Peroxide Blank (1.5%)Accurately pipette 5ml of diluent and 5ml of 3% Hydrogen peroxide solution into a suitable container and leave at ambient temperature.Pipette 1ml of Peroxide Blank Solution into a 2ml volumetric flask, make up to volume with diluent and mix well.Test 7 - Photostability (Solution Control)Accurately pipette 5ml of Stock Solution and 5ml of diluent into a suitable container, wrapped in aluminium foil. Expose to an overall illumination of no less than 1.2 million lux hours and integrated near-UV energy of no less than 200 watt hours per square metre.Once exposure is complete, pipette 1.0 ml of sample solution into a 2ml volumetric flask, make up to volume with diluent and mix well.Test 8 - Photostability (Solution Treated)Accurately pipette 5ml of Stock Solution and 5ml of diluent into a suitable container. Expose to an overall illumination of no less than 1.2 million lux hours and integrated near-UV energy of no less than 200 watt hours per square metre.Once exposure is complete, pipette 1.0 ml of sample solution into a 2ml volumetric flask, make up to volume with diluent and mix well.Test 9 - Photostability (Solid Control)Place a thin layer of the solid sample in a glass dish and wrap in aluminium foil. Expose to an overall illumination of no less than 1.2 million lux hours and an integrated near-UV energy of no less than 200 watt hours per square metre.Once exposure is complete, the sample is to be dissolved in diluent to a concentration of 0.2 mg.ml -1< .Test 10 - PhotostabilityPlace a thin layer of the solid sample in a glass dish. Expose to an overallOnce exposure is complete, the sample is to be dissolved(Solid Treated)illumination of no less than 1.2 million lux hours and an integrated near-UV energy of no less than 200 watt hours per square metre.in diluent to a concentration of 0.2 mg.ml -1< . ResultsObservations

[0362] Table 2: Forced degradation - observations Test Condition Sample observations 1ControlClear colourless solution. No change over study period.2Solid state 100°COff-white solid turning to very faint orange solid over study period.3AcidClear colourless solution. No change over study period.3Acid 60°CClear colourless solution. No change over study period.4BaseClear colourless solution. No change over study period.4Base 40°CClear colourless solution. No change over study period.5Heat 60°CClear colourless solution. No change over study period6PeroxideClear colourless solution. No change over study period7Photostability (Solution Control)Clear colourless solution. No change over study period.8Photostability (Solution Treated)Clear colourless solution turning to a clear yellow solution over study period.9Photostability (Solid Control)Off white solid. No change over study period.10Photostability (Solid Treated)Off-white solid turning to very faint orange solid over study period. Analysis

[0363] Table 3: forced degradation results for Tests 1-6 Test Assay of active substance (area %) Timepoint 0 days3 days7 days11 days13 days1 - solution control99.4099.4299.3099.392 - solid state at 100°C99.4399.403 - acid (1M) ambient temperature99.4099.413 - acid (1M) at 60°C until day 7, 80°C until day 1199.3799.3598.874 - base (0.5M) ambient temperature99.4099.374 - base (0.5M) at 60°C until day 7, 80°C until day 1199.3499.3299.165 - solution at 60°C until day 7, 80°C until day 1199.1399.3498.006 - peroxide (1.5%)98.5097.7596.58 Table 4: forced degradation results for Tests 7-10 Test Assay of active substance (area%) 7 - photocontrol solution99.408 - photo treated solution74.539 - photocontrol solid99.4010 - phototreated solid99.31 Example 2 - Preformulation Studies - compatibility of active ingredient with capsule shells and semi-solid excipients

[0364] A preformulation study was performed in order to select excipients for the development of an immediate release capsule containing a low dose of N-(2-(tert-butyl)-1-((4,4-difluorocyclohexyl)methyl)-1H-benzimidazol-5-yl)ethanesulfonamide in a semi-solid carrier. The chemical stability of N-(2-(tert-butyl)-1-((4,4-difluorocyclohexyl)methyl)-1H-benzimidazol-5-yl)ethanesulfonamide in the semi-solid carrier was evaluated for up to 28 days at 40°C and 50°C.

[0365] Both types of capsule shells evaluated (HPMC and PEG-softened hard gelatin shells) were compatible with the active ingredient. Of the three semi-solids tested the solubility of the active ingredient was sufficiently high (>0.1% w / w) so that a low dose capsule could be prepared. The active ingredient showed good chemical stability in PEG and Vitamin E TPGS over 28 days, however there was significant degradation of the active ingredient observed in Gelucire 44 / 14 at 40°C incubation.Methodology

[0366] While suspension formulations were not excluded per se, solution-based formulations were preferable in order to maximise the chances of achieving content uniformity. In order for a 200 µg dose strength to be delivered in a size 4 capsule a target solubility of >0.1 % w / w of the active ingredient in the excipient was set (max fill weight of Size 4 capsule is ~ 200 mg, 0.2 mg / 200 mg*100 = 0.1% w / w) and also to minimise the dose of excipient administered. This solubility would allow higher dose strengths to be manufactured in larger capsules should they be required as development progresses - for instance approximately 650 µg in a size 0 capsule.

[0367] The chemical compatibility of the active ingredient with excipients was assessed.Materials

[0368] Active Ingredient:(N-(2-(tert-butyl)-1-((4,4-difluorocyclohexyl)methyl)-1H-benzimidazol-5-yl)ethanesulfonamide)ex IPCASupplier Lot ID JCM1019BHMPC capsuleWhite Capsugel VCaps Plus size 4Hard Gelatin capsuleGreen / grey Qualicaps Quali-G PEG size 4)TPGSVitamin E TPGS from IsochemPolyethylene glycolPEG 1500, MerckPolyoxylglyceridesGelucire 44 / 14 Analytical MethodologyUPLC Conditions

[0369] Column:Waters Acquity BEH Shield100 x 2.1 mm, 1.7 µmColumn Temp.40°CSample manager wash (UPLC)AcetonitrileSample manager purge (UPLC)HPLC Water: ACN 50:50 % v / vMobile Phase A (for Semi-solids)pH 9.2 Sodium HydroxideMobile Phase A (for capsule shells)25% ammonia solutionMobile Phase BAcetonitrileMobile Phase C2-propanolFlow Rate0.3 mL / minInjection volume10 µL (for 0.01 mg / mL nominal concentration)5 µL (for 0.02 mg / mL nominal concentration)Wavelength215 nm Gradient program

[0370] Samples containing semi-solid excipient All other samples Time (min) MP* A (%)MP* B (%)MP* C (%)MP* A (%)MP* B (%)MP* C (%)0 955095510 5950595Not used10.1 5455095515 5455095515.1 955020 9550*MP = Mobile Phase Part 1 - active ingredient compatibility with capsule shells Prior to Day 0Preparation of a 3 mg / mL Doping solution

[0371] A 3 mg / mL active ingredient Doping Solution in ethanol was prepared by dispensing 89.5 to 90.5 mg of the active ingredient (avoid dispensing any agglomerates as these will slow dissolution) directly into a 30 mL amber bottle. A total of 30 mL of ethanol absolute was added to the bottle in a solvent fume cupboard. The contents of the bottle were stirred using a magnetic flea and stirrer plate until all solids had dissolved (a back light outside of the darkroom was briefly used and fibrous material in the bottle was ignored). The bottle was placed in a freezer until required for use.Day 0

[0372] The following stability vials were prepared and stored according to Table 5. Binary "Dry Excipient" and active ingredient: The dry excipient (HPMC capsule or hard gelatin capsule) is dispensed into a vial and 100 µL of the Doping Solution is applied. It was ensured that the doping solution fully contacted the dry excipient when added to the vial. The solvent was evaporated until a white film was formed. Placebo Control Samples: The dry excipient (HPMC capsule or hard gelatin capsule) is added to a vial, but no stock solution is applied to it. These served as controls to assist HPLC peak identification. Active Ingredient Only Control: 100 µL of the Doping Solution is added to an empty vial and the solvent evaporated. These showed the chemical stability of the active ingredient as a control.

[0373] For the above vials where solvent evaporation was required, the vials were left open overnight. Once the solvent had evaporated the vials were closed and placed in opaque plastic storage boxes. Table 5: Preformulation stability study vials prepared Dry Excipient Doping Solution added Storage Conditions (number of vials prepared) One HPMC capsuleYesStore at 20°C throughout (2)25°C for 14 days (2)25°C for 28 days (2)50°C for 14 days (2)50°C for 28 days (2)One Hard gelatin capsuleYesStore at 20°C throughout (2)25°C for 14 days (2)25°C for 28 days (2)50°C for 14 days (2)50°C for 28 days (2)NoneYesStore at 20°C throughout (2)25°C for 14 days (2)25°C for 28 days (2)50°C for 14 days (2)50°C for 28 days (2)One HPMC capsuleNoStore at 20°C throughout (1)25°C for 28 days (1)50°C for 14 days (1)One Hard gelatin capsuleNoStore at 20°C throughout (1)25°C for 28 days (1)50°C for 14 days (1)

[0374] At the timepoint specified in Table 5, the vials were removed in placed in a freezer until HPLC analysis was performed.Results

[0375] Table 6 shows the assay results of the active ingredient in HPMC and gelatin capsules. Table 6: Assay results of active ingredient in HPMC and gelatin capsules days vial HPMC Gelatin Incubation temperature Assay (%) Assay (%) n / a initial196.599.0299.0100.2mean97.899.625°C143N / A*97.4498.998.9mean95.898.128599.398.8699.099.4mean99.199.150°C14798.999.3898.799.4mean98.899.328998.899.41098.9N / A*mean98.989.3* Samples were spilt during preparation and so results are discounted.

[0376] Overall, the % assay for both sample sets appear consistent across all conditions and timepoints, indicating there is no degradation of the active ingredient for either HPMC or gelatin capsules.

[0377] The only two exceptions are low results for one of the replicates of HPMC at 25 °C after 14 days and one of the Gelatin replicates at 50 °C after 28 days. These results are not matched by the other replicate in either case, and so are considered to be outlier results.

[0378] The peak areas of potential active ingredient related substances are shown in Table 7. There is no evidence of active ingredient degradation in both capsule types since the total impurities remained below 1% with no increase with incubation time or temperature for any impurity. Table 7: Summary of related substances in HPMC and gelatin capsules Sample Condition Days Vial RRT 0.92 0.97 0.98 1.04 1.10 1.35 1.36 total HPMCn / ainitial10.08ND0.30.070.090.130.130.8120.07ND0.310.070.100.130.130.8225°C1430.08ND0.310.080.090.130.130.8240.07ND0.320.080.090.120.120.802850.08ND0.30.070.090.120.120.7960.08ND0.310.070.080.130.130.7950°C1470.07ND0.300.070.090.130.120.798<0.050.67*0.290.070.090.120.121.372890.07ND0.310.070.090.120.120.79100.07ND0.320.090.100.120.130.83Hard Gelatinn / ainitial10.06ND0.260.050.100.080.080.6220.05ND0.240.050.100.070.080.5825°C1430.05ND0.220.050.100.070.070.564<0.05ND0.18<0.050.090.070.080.422850.05ND0.18<0.050.080.070.080.476<0.05ND0.14<0.050.090.060.070.3640°C147<0.05ND0.14<0.050.090.060.070.378<0.05ND0.12<0.050.090.060.070.34289<0.05ND0.11<0.050.090.060.070.3310<0.05ND0.09<0.050.110.060.070.33* Appears to be a contamination peak since this high area at RRT 0.97 is not seen in the other replicate at this condition or at the later timepoint at the same (40 °C) storage condition. Part 2 - Solubility and stability assessment of active ingredient in the semi-solid excipient

[0379] The solubility of up to three aliquots of the active ingredient in each semi solid solution was evaluated with samples taken for stability evaluation, as follows: 1. While the semi-solid is molten at ~70°C, active ingredient aliquot 1 was added to the molten semi-solid, then homogenised using the Silverson mixer at 2000 RPM. 2. Following the dissolution of the first active ingredient aliquot, 10 stability and 10 'method development' samples were removed (200 µL per vial, not weighed) and placed on stability at 25 and 40 °C for up to 28 days 3. Because the active ingredient was apparently fully soluble in this experiment, active ingredient aliquots 2 and 3 were added then homogenised until dissolved into the remaining solution. 4. The appearance of the solution was recorded after adding each active ingredient aliquot

[0380] In order to ascertain the mass of semi-solid that had been volumetrically dispensed into the 20 vials in Step 2. the following procedure was employed: 1. The group mass of 5 "method development" vials was measured (mass G). 2. The vials were twice cleaned with ethanol (sonicating for 10 minutes each time) and allowed to dry for 1 hour - the vials were completely clean and dry. 3. The group mass of the 5 clean vials was measured (mass T). 4. The mean net weight of semi solid in the original vial was calculated = (G-T) / 5 where G and T.

[0381] Table 8 shows the level of active ingredient added to the three different semi-solids. Table 8: Semi-solid batch compositions (~80 mL batch size) Semi-Solid Batch ID N P Q Qty of ingredient: mass per vial and total % w / w of API (homogenisation times and temperatures in brackets)Vitamin E TPGS84.97 gPEG 150096.1 gGelucire 44 / 1485.0 gActive Ingredient Aliquot #121.2 mg, 0.025% (60 min @ 67.9-70.5°C)23.0mg,0.024% (18 min @73.6-71.1°C)20.7 mg,0.024% (19 min @ 63.5-73.1)Active Ingredient Aliquot #219.5 mg, 0.049% (30 min @ 62.7-71.4°C)16.1mg,0.041 (22 min @ 73.1-71.4 °C)16.3mg, 0.044% (20 min @ 65.7-68.6°C)Active Ingredient Aliquot #357.8 mg, 0.121% (18 min @ 70.2-72.1°C)54.9mg, 0.100% (1hr @ 64.5 - 71.3 °C)57.0mg, 0.115% (21 min @ 69.6-68.4°C) Results

[0382] All three active ingredient aliquots fully dissolved in each of the three molten semi-solids - Vitamin E TPGS, PEG 1500 and Gelucire 44 / 14. Clear solutions free from particles and opacity were achieved - only Vitamin E TPGS was slightly yellow while PEG 1500 and Gelucire 44 / 14 were colourless. The final concentration of API in each semi-solid was 0.10 to 0.12 % w / w, consistent with being able to fill the highest dose (200 µg) into the preferred sized capsule (Size 4).

[0383] Table 9 summarises the assay of the active ingredient in the semi-solids, sampled after the first aliquot addition only (i.e. active ingredient at 0.024-5% w / w which is the highest risk for stability) following a 28-day stability study at 25 and 40 °C. Table 9: Summary of the active ingredient assay in three different Semi-solids condition days vial Vitamin E TPGS PEG 1500 Gelucire 44 / 14 assay % assay % assay % n / a initial 194.4101.695.5294.2102.297.9mean94.3101.996.725°C 14 394.5102.798.6494.7103.098.5mean94.6102.998.628 595.3103.299.5694.9102.099.6mean95.1102.699.640°C 14 793.2124.2*89.5894.2107.691.0mean93.7115.990.328 995.0106.877.31096.2104.272.4mean95.6105.574.8* The high active ingredient peak area in this sample is believed to be associated with a high sample aliquot weight since the area of the main excipient peak was also 24% higher than for another representative replicate for PEG 1500 (#1 i.e. Initial).

[0384] The related substances for the three types of semi-solid excipients is presented in Table 10, Table 11 and Table 12.

[0385] Both Vitamin E TPGS and PEG 1500 appear to be stable with no significant effect of incubation time and temperature on assay. However, there is evidence for gross degradation in Gelucire 44 / 14 under accelerated stability conditions (40 °C). Table 10: Peak Areas (as % of Total) of API Related substances for Vitamin E TPGS Vitamin E TPGS condition days vial RRT 0.8 total n / a initial10.010.0120.020.0225°C 1430.020.0240.020.022850.020.0260.020.0240°C 1470.020.0280.020.022890.030.03100.030.03 Table 11: Peak Areas (as % of Total) of API Related substances for PEG1500 PEG1500 condition days vial RRT 0.56 1.20 total n / a initial10ND020ND025°C 1430ND040ND02850ND060ND040°C 1470.010.040.0480.020.030.052890.020.040.06100.010.040.05 Table 12: Peak Areas (as % of Total) of API Related substances for Gelucire Gelucire 44 / 14 Condition days vial RRT 0.20 0.82 0.85 total n / a initial 10.030.26ND0.2920.030.26ND0.2925°C 14 30.030.26ND0.2940.030.28ND0.3128 50.030.29ND0.3160.030.29ND0.3240°C 14 70.341.35ND1.7080.301.31ND1.6128 91.384.720.536.62101.897.000.889.77 Example 3 - Preparation, stability, and dissolution analysis of PEG1500 and Vitamin E TPGS based Immediate Release formulations

[0386] Semi-solid capsules containing the active ingredient in either Vitamin E TPGS or PEG were prepared at different doses (50 and 200 µg) and in different sized hard gelatin capsules (size 3 and 4). The prepared capsules were put on a 4-week stability study at 25°C and 40°C. Both types of semi-solid capsules (Vitamin E TPGS and PEG) were stable under the conditions tested. The PEG1500 formulations met the European Pharmacopoeia specification for a conventional immediate release dosage form (80% of the active ingredient releases within 45 minutes or less), however the Vitamin E TPGS formulations surprisingly did not in some instances.Methodology

[0387] Semi-solid capsule batches containing the active ingredient were prepared according to Table 13 and Table 14.

[0388] A suffix code is used in both tables to refer to the two concentrations of the active ingredient used in the PEG or Vitamin E TPGS solution: L denotes a low concentration (0.1%) of the active ingredient in the L-PEG and L-Vitamin E TPGS solutions H denotes a low concentration (0.4%) of the active ingredient in the H-PEG and H-Vitamin E TPGS solutions

[0389] The batches listed in Table 13 and Table 14 and were made at a batch size of approximately 80 g by performing the following processes in a darkroom without any environmental control of oxygen or RH levels: 1. Dissolve the active ingredient in molten Vitamin E TPGS or PEG 1500 using a Silverson homogeniser until a clear solution is formed. 2. Using a manual pipette (Gilson Repetman) to fill into the capsules (target fill weight specified in Table 13).

[0390] While the filling process worked well at a target temperature of 55 °C for the Vitamin E TPGS throughout, the operators noted that the PEG 1500 tended to solidify at this target temperature (high weight variability).

[0391] While weight uniformity was sub-optimal for the H-PEG and H- Vitamin E TPGS in the capsules that were analysed, it was able to improve this in later attempts under more controlled process conditions.

[0392] In addition to preparing the capsules, the active ingredient solutions were held for 24 hours at 55 °C to mimic a plausible process hold step.

[0393] Due to the some of the dissolution profiles of the Vitamin E TPGS capsules not meeting the European Pharmacopoeia specification for a conventional immediate release dosage form only the PEG1500 capsules were placed on a 4-week stability study at 25 °C and 40 °C and - 20 °C (all analysed together and -20 data used as initial). Table 13: Semi-solid PEG and Vitamin E TPGS formulations H-PEGL-PEGH- Vitamin E TPGSL- Vitamin E TPGSDose (µg)2002005020020050Composition of Capsule Fill (% w / w)Active ingredient0.40%0.10%0.40%0.10%PEG 1500 (Emprove ™< )99.60%99.90%99.60%-Vitamin E TPGS (Isochem)---99.90%Total100.00%100.00%100.00%0.10%Intended Weight of semi-solid per capsule (mg)50200505020050 Table 14: Process Variants assessed in semi-solid formulations H-PEGL-PEGH- Vitamin E TPGSL- Vitamin E TPGSAPI Solution Held at 55 C for 24-28hr prior to encapsulation?NoNoNoYesNoNoNoYesDose (µg)20020050502002005050Capsule TypeSize 3 white Quali-G PEGSize 4 green / gre y Quali-G PEGSize 3 white Quali-G PEGSize 4 green / grey Quali-G PEG Analytical methodsDissolution

[0394] ApparatusPaddles (USP apparatus II)Paddle Speed50 rpm200 rpm infinity speedDissolution Media0.1 M Hydrochloric acid / Phosphate pH 6.8 BufferMedia VolumeDose 50 µg: 500 mL (nominal concentration 0.1 µg / mL)Dose 200 µg: 500 mL (nominal concentration 0.4 µg / mL)Temperature37 ± 0.5 °CSinkersBand sinker with O-ring internal diameter suitable for capsule size testedSampling filters13 mm, 0.2 µm PVDF syringe filtersCannula filters10 µm cannula filters (P / N FIL010-CA-a)Sampling time points10, 20, 30 and 45 minutes at 50 rpm60 minutes (infinity speed at 200 rpm after the 45 minutes time point)DetectionHPLC / UPLC Preparation of 0.1 M HCl dissolution medium

[0395] Transfer 4000 mL of deionised water or HPLC water to a dissolution aspirator. Transfer 41 mL concentrated HCl to the aspirator using a measuring cylinder. Transfer a further 959 mL of deionised water or HPLC water to the same aspirator. Mix.Preparation of the pH 6.8 phosphate buffer dissolution medium

[0396] Dissolve 81.6 ± 0.5 g of anhydrous potassium phosphate monobasic (KH 2 PO 4 ) in 3000 mL deionised water (Preparation 1). Dissolve 214.8 ± 0.5 g of disodium hydrogen phosphate dodecahydrate (Na 2 HPO 4 ·12H 2 O) in 3000 mL of deionised water (Preparation 2). Combine 2550 mL of Preparation 1 with 2450 mL of Preparation 2. Measure the pH of the solution. The pH should be pH 6.8 ± 0.05. Adjust to pH 6.8 if necessary using either Preparation 1 or 2 (Preparation 1 to reduce pH or Preparation 2 to increase pH).Dissolution HPLC / UPLC

[0397] ColumnHalo C18 2.7 µm 3.0 x 50 mmColumn Temperature40°CSample manager wash (UPLC)HPLC Water: ACN 50:50 % v / vNeedle Wash (HPLC)HPLC Water: ACN 50:50 % v / vSample manager purge (UPLC)HPLC Water + 0.1% phosphoric acidMobile Phase AHPLC Water + 0.1% phosphoric acidMobile Phase B100% acetonitrileGradientTimeMobile Phase A (%)Mobile Phase B (%)0.0080200.5080203.0020803.012986.002986.0180209.508020Flow Rate0.5 mL / minInjection Volume10 µL (Dose 200 µg)25 µL (Dose 50 µg)Wavelength217 nm Standard preparation for HPLC / UPLC

[0398] The active ingredient is light sensitive and requires protection from light. High dose calibration standard: 0.1 M HCl Prepare a 0.4 µg / mL active ingredient standard in 90:10 v / v 0.1M HCl:acetonitrile Low dose calibration standard: 0.1 M HCl Prepare a 0.1 µg / mL active ingredient standard in 90:10 v / v 0.1M HCl:acetonitrile High dose calibration standard: pH 6.8 phosphate buffer Prepare a 0.4 µg / mL active ingredient standard in 90:10 v / v pH 6.8 phosphate buffer:acetonitrile Low dose calibration standard: pH 6.8 phosphate buffer Prepare a 0.1 µg / mL active ingredient standard in 90:10 v / v pH 6.8 phosphate buffer: acetonitrile Content uniformity

[0399] Weigh and record the mass of each capsule. Drop each capsule into separate 500 mL amber volumetric flask. Add approximately 200 mL of 90:10 v / v 0.1 M HCl:acetonitrile. Place on an orbital shaker set to approximately 200 rpm to allow sufficient agitation for 2 hours. Ensure the capsule has disintegrated. Allowed to equilibrate to room temperature and make to volume with 90:10 v / v 0.1 M HCl:acetonitrile. Seal flask and invert 15 times to ensure compete mixing. Take a portion of the sample out and place into an amber 8 mL vial. Centrifuge each sample at 4200 rpm for 30 minutes or until a clear supernatant is formed. Transfer 1.5 mL of the clear supernatant into an amber HPLC vial for analysis (see "Dissolution HPLC / UPLC" in Example 3 above. Calculate the acceptance value (AV) as per the Ph. Eur. 2.9.40 using the following formula: AV = M − X + ks Wherein X = Mean of individual contents (x 1 , x 2 ...x 3 ) expressed as a percentage of the label claim. k = acceptability constant. If n = 10 then k = 2.4, if n = 30 then 2.0 where n = sample size. s = Sample standard deviation M = Reference Value. For case 1 when T≤101.5: If 98.5%≤X≤101.5% then M = X (therefore AV = ks) If X<98.5% then M = 98.5% (therefore AV = 98.5 - X + ks) If X>101.5%, then M = 101.5% (therefore AV = X - 101.5 + ks) For case 2 when T>101.5: If 98.5%≤X≤T then M = X (therefore AV = ks) If X<98.5% then M = 98.5% (therefore AV = 98.5 - X + ks) If X>T, then M = T% (therefore AV = X - T + ks) T = target test sample amount at time of manufacture ResultsDissolution

[0400] Dissolution results were obtained from the various capsules in the 0.1M HCl (pH ~1) and in pH 6.8 phosphate buffer media, see Figures 1 to 12. PEG 1500 based formulations gave faster dissolution profiles for each dose in both media. Additionally, fill weight appeared to affect the rate of release of the active ingredient from TPGS containing capsules in 0.1M HCl. Release from some of the Vitamin E TPGS formulations in certain media did not meet the European Pharmacopoeia specification for a conventional immediate release dosage form (80% of active ingredient release within typically 45 min or less).Stability

[0401] Due to only some of the Vitamin E TPGS formulations meeting the European Pharmacopoeia specification for a conventional immediate release dosage form in certain dissolution media, only the PEG formulations were put down on stability and analysed.

[0402] The assay results for the PEG formulations are shown in Table 15. The assay results from the PEG-based capsules were all below nominal (~90% of target) across the stability study, possibly due to the method used where the semi-solid plugs were scraped out of the shells for analysis. However, there was no clear trend of assay or of the area of any of the impurity peaks with storage temperature (-20, 25 vs. 40 °C over 28 days) or change from the 24-28 hour hold of the API. Based on these results, there are no stability concerns. Table 15: Initial (-20) and stability assay results for PEG immediate release capsules Storage Condition -20 °C / 'Initial' 4 week @ 25 °C 4 weeks @ 40 °C Capsule Dose (µg) / Fill weight (mg) % Assay (RSD) 200 / 50 87.3 (1.3)88.1 (0.6)88.9 (1.5)200 / 200 89.8 (2.4)90.2 (1.0)87.0 (0.1)50 / 50 89.9 (2.6)92.0 (0.5)85.8 (4.9)50 / 50 plus 24 hours hold at 55 °C 86.1 (3.1)88.5 (2.3)81.4 (0.9) Content Uniformity

[0403] The content uniformity results for all capsules tested had an acceptance value (AV) < 15, see Table 16. Table 16: Content uniformity data for immediate release capsules Dose (µg)2002002002005050200200Solution CodeH-Vitamin E TPGSH-PEGL-Vitamin E TPGSL-PEGL-Vitamin E TPGSL-PEGH-Vitamin E TPGSH-PEGFill weight (mg)505020020050505050RepAssay (% nominal)Fill Weight (% target)199.69995.610099.9101.795.20%100.60%2104.698.894.8100.199.899104.60%95.20%398.597.796.199.899.6100.296.3095.404111.497.196.1100.998.7100.6109.6094.105103.199.595.799.798.696.5100.6098.80699.999.295.3100.597.9100.998.70101.907102.996.895.5100.599.295.5106.1097.80810092.896.910099.499.4103.6093.50999.7108.999.199.49999.597.20107.9010100.99894.7100.398.2100.1102.40100.70MEAN102.198.896100.19999.4101.4098.60RSD%3.74.11.30.40.71.94.64.5AV9.79.75.61.11.64.6-- Example 4 - Preparation and analysis of stability batches of PEG1500 immediate release capsules

[0404] Semi-solid capsules containing the active ingredient in PEG1500 were prepared at different doses (50 and 200 µg) and in different sized hard gelatin capsules (size 2 and 4). The prepared capsules were put on a stability study at 25°C and 40°C and for the timepoints analysed to date stability has been demonstrated. The formulations met the European Pharmacopoeia specification for a conventional immediate release dosage form (80% of the active ingredient releases within 45 minutes or less) and show good content uniformity.MethodologyMaterials

[0405] Active substance:(N-(2-(tert-butyl)-1 -((4,4-difluorocyclohexyl)methyl)-1H-benzimidazol-5-yl)ethanesulfonamide)Onyx (lot: JCM1019B)Polyethylene glycolPEG 1500 Merck, Lot: K51120505 950Gelatin capsuleGreen / Grey Size 4 Quali G capsulesQualicaps (ARE)Gelatin capsuleWhite Size 2 Quali G capsulesQualicaps (ARE)HPMC capsuleRed Size 4 Quali V CapsulesQualicaps (ARE)HPMC capsuleWhite Size 2 Quali V CapsulesQualicaps (ARE) Formulation compositions

[0406] The compositions prepared are summarised in Table 17. Table 17: Formulation compositions prepared Active Placebo Material %w / w g / batch %w / w g / batch *Uncorrected concentration *Corrected concentration *Uncorrected concentration *Corrected concentration High dose (200 µg) Matching high dose Active substance 0.40.40.840.85PEG 99.699.6209.16209.16100130Total 100 210 100 130 Capsules used White Size 2 Quali-G PEG ¥ Low dose (50 µg) Matching low dose Active substance 0.10.10.20.2PEG 99.999.9198.8199.8100130Total 100 200 100 130 Capsules used Green / grey Size 4 Quali-G PEG ¥ *'Uncorrected' values assume hypothetically pure API, 'corrected' values correct for the 98.92% potency of the API used ¥The placebo batches were also filled into White Size 2 and Red Size 4 Quali-V (HPMC) Capsules (TRI002 / 89PC-2H and -4H, respectively). 50 µg of active substance was also filled into Red Size 4 Quali- V capsules (TRI002 / 89P50-2H). QC testing was not performed on any of these HPMC capsules and they were not put on stability.

[0407] Two doses were prepared (50 µg and 200 µg) by melting the PEG 1500. All manufacture was performed in a dark room under Nitrogen (≤ 2 % Oxygen) as follows: A glycerol bath on a hot plate was used to melt the PEG 1500 and maintain a temperature of 60 - 66 °C throughout dispensing and encapsulation. The placebo formulation was made by melting PEG 1500 alone, and dispensing into capsules For the active formulations, once target temperature of the PEG 1500 was reached, the active substance was gradually added. The active substance was mixed until fully dissolved using a magnetic flea. A spatula was required to break apart the active substance agglomerates. A Repetman pipette was set to dose 50 mg of the filling fluid. Each formulation was filled into the capsule shells listed in Table 17. Quali - V capsules were eliminated from further studies (due to challenges with interference in the assay and related substance due to HPMC). Only the Quali-G PEG QC capsules were tested at T=0 and placed on stability. Analytical MethodologyDissolution

[0408] As per dissolution method described in Example 3. The HPLC / UPLC dissolution methodology used is as described in Example 3.Content Uniformity

[0409] As per content uniformity method described in Example 3.UPLC / HPLC parameters used for assay and related substances testing

[0410] ColumnHalo C18 2.7 µm 3.0 x 50 mmColumn Temperature40°CSample manager wash (UPLC)HPLC Water: ACN 50:50 % v / vSample manager purge (UPLC)HPLC Water: ACN 50:50 % v / vMobile Phase A10 mM ammonium acetate pH 7.0Mobile Phase B100% acetonitrileGradientTimeMobile Phase A (%)Mobile Phase B (%)0.009552.055457.150509.7188210.329821.029821.195526.0955Flow Rate0.3 mL / minInjection Volume12 or 38 µLWavelength256 nmDiluentAcetonitrileSample preparation:Assay analysis: nominal concentration of 0.01 g / mLRelated Substances: nominal concentration of 0.025 mg / mL Long Term stability study

[0411] The PEG1500 active and placebo batches were placed on stability as shown in Table 18. Table 18: Stability Study Summary for Capsules Strength (micrograms) Storage Conditions Stability Timepoints* (Months)[Optional] 50 and matching placebo5°C[0 a< , 1, 2, 3, 6, 12, 18, 24]25°C / 60%RH0 a< , 1, 2, 3, 6, 12 a< , 18, 24 a< 40°C / 75%RH0 a< , 1, 2, 3, 6 a< 200 and matching placebo5°C[0 a< , 1, 2, 3, 6, 12, 18, 24]25°C / 60%RH0 a< , 1, 2, 3, 6, 12 a< , 18, 24 a< 40°C / 75%RH0 a< , 1, 2, 3, 6 a< a Micro testing ResultsManufacturing Process evaluation

[0412] The four batches in Table 17 were successfully produced, two active formulations at 200 µg and 50 µg, and two matching placebos. During the manufacture, the following challenges were noted: I. Agglomeration of the active substance when added to the molten PEG, even when gradually added. The agglomeration was more apparent when more active substance was added (i.e. at the high dose). To aid dispersion of the active substance and therefore enhance active substance solubility, a spatula was used to breakdown agglomerates. The total time that took the API to fully dissolve was 1 hour 17 minutes and 1 hr 40 minutes for the low dose and the high dose, respectively. II. Rapid solidification of the molten formulation in the pipette tip or outer surface of the pipette tip was noted. Therefore, dispensing had to be carried out rapidly.

[0413] The process parameters for blend preparation and capsule filling are summarised in Table 19. Table 19: The process parameters during fluid preparation and capsule filling Placebo Active Parameters Matching low dose Matching high dose Low dose (50 µg) High dose (200 µg) Blend Preparation: Time to melt PEG and reach target temperature (60 - 65 °C) (hr:min) 01:1001:1501:4001:40Time to dissolve active substance (hr:min) 00:3300:55Mixing speed (RPM) 700600 -700Capsule filling: Pipette Set volume (µL) 46.5Total capsule filling Time (hr:min) 05:1803:0009:4505:56Temperature range during capsule filling (°C) 61.1-63.161.1 - 63.262.6 - 63.162.0 - 60.4Oxygen range (%) (throughout blend preparation and capsules filling) 0.2 - 1.80.3 - 1.8 Content Uniformity

[0414] The results for the 50 µg and 200 µg gelatin capsules (Green / grey size 4 Quali-G PEG and white size 2 Quali-G PEG respectively) are shown in Table 20 and Table 21. The acceptance value determined for both sets of capsules demonstrate good content uniformity. Table 20: Content uniformity for the 50 µg dose capsules Sample Replicate Assay weight (µg) % Label Claim Capsule Weight (mg) 149.999.992.07250.2100.491.04348.997.891.07449.599.190.57549.799.489.55649.498.889.47749.799.489.52852.3104.794.00949.799.491.631049.899.791.78Mean49.999.8Standard deviation0.91.8AV = 4.3 Table 21: Content uniformity for the 200 µg dose capsules Sample Replicate Assay weight (µg) % Label Claim Capsule Weight (mg) 1203.3101.6114.382206.1103.1114.683203.8101.9113.574204.2102.1112.595203.5101.7112.696206.9103.5114.307205.8102.9110.158203.9102.0110.309205.8102.9111.8210204.0102.0111.07Mean0.6102.4Standard deviation1.30.6AV = 2.3 Related Substances analysis

[0415] 10 of the Red Size 4 Quali-V (HPMC) capsules containing 50 µg of the active substance and 10 of the green / grey size 4 Quali-G (PEG) capsules containing 50 µg of the active substance were analysed by HPLC / UPLC according to the methodology above. It was observed that the HPMC capsule shells (Quali-V) caused a peak in the chromatogram which had a same relative retention time as a potential peroxide degradation peak. It was observed that strong peaks from the HPMC capsule (including placebo capsules) elute between ~1 and ~4 min, and hence could interfere with detection of this potential degradant. It is notable that gelatin capsules do not give any interference around 3.5 min (or indeed at any elution time).

[0416] In addition, a new peak was detected at a retention time of ~12 min in the active HPMC capsules, not seen in the placebo capsules. The concern is that this peak may grow further with storage. As such, the HPMC capsules were not progressed further (i.e., not tested at the initial time point or put down on stability).

[0417] It was discovered that upon incubation of the capsules incubated at 60°C a new peak in the chromatogram was observed at RRT 1.35. This peak was not seen during development or in the forced degradation study and appears to grow when the capsule is incubated at 60°C when under an air or a nitrogen atmosphere. This peak is not present in the capsules or the vial samples that had not been incubated at 60°C. The growth of this peak is demonstrated in Figure 13 - the area increases with increasing time of incubation, more so under air than under nitrogen (<1% O 2 ). This implies that processing the batch under nitrogen may help reduce chemical degradation of the batch.Stability Study Results

[0418] The stability study results are shown in Table 22, Table 23, Table 24 and Table 25. Dissolution profiles at the initial timepoint are shown in Figures 14 and 15; all capsules released 85% of the active substance by 15 minutes as determined by dissolution in 0.1 M HCl and pH 6.8 phosphate buffer. Table 22: Stability data for 50 micrograms capsules (25°C / 60% RH) Test Shelf-life Acceptance Criteria Initial 1 month AppearanceOpaque grey body / green cap capsule size 4 with no physical defectsCompliesCompliesAssay90.0%-110.0% of nominal99.1102.8Related substancesUnspecified impurity / degradation product*NMT 1.0%RRT0.94: 0.19RRT0.94: 0.22RRT1.05: 0.22RRT1.04: 0.18Total impurities / degradation productsNMT 4.0%Total: 0.41Total: 0.40DissolutionReport result105.199.5Microbial enumerationTAMCNMT 10 3< cfu / gCompliesNATYMCNMT 10 2< cfu / gCompliesNAEscherichia coliAbsent in 1 gCompliesNA* Only peaks ≥ 0.10% are reported Table 23: Stability data for 50 micrograms capsules (40°C / 75% RH) Test Shelf-life Acceptance Criteria Initial 1 month AppearanceOpaque grey body / green cap capsule size 4 with no physical defectsCompliesCompliesAssay90.0%-110.0% of nominal99.195.6Related substancesNMT 1.0%RRT0.94: 0.19RRT0.94: 0.20Unspecified impurity / degradation product*RRT1.05: 0.22RRT1.06: 0.26RRT: 1.45: 0.70Total impurities / degradation productsNMT 4.0%Total: 0.41Total: 1.21DissolutionReport result105.1100.2Microbial enumerationTAMCNMT 10 3< cfu / gCompliesNATYMCNMT 10 2< cfu / gCompliesNAEscherichia coliAbsent in 1 gCompliesNA * Only peaks ≥ 0.10% are reported Table 24: Stability data for 200 micrograms capsules (25°C / 60% RH) Test Shelf-life Acceptance Criteria Initial 1 month AppearanceWhite, opaque capsule size 2 with no physical defectsCompliesCompliesAssay90.0%-110.0% of nominal100.4100.3Related substancesUnspecified impurity / degradation product*NMT 1.0%RRT0.94: 0.19RRT0.94: 0.22RRT1.05: 0.23RRT1.05: 0.23Total impurities / degradation productsNMT 4.0%Total: 0.41Total: 0.45DissolutionReport result103.2104.0Microbial enumerationTAMCNMT 10 3< cfu / gCompliesNATYMCNMT 10 2< cfu / gCompliesNAEscherichia coliAbsent in 1 gCompliesNA * Only peaks ≥ 0.10% are reported Table 25: Stability data for 200 micrograms capsules (40°C / 75% RH) Test Shelf-life Acceptance Criteria Initial 1 month AppearanceWhite, opaque capsule size 2 with no physical defectsCompliesCompliesAssay90.0%-110.0% of nominal100.4100.1Related substancesNMT 1.0%RRT0.94: 0.19RRT0.94: 0.22Unspecified impurity / degradation product*RRT1.05: 0.23RRT1.05: 0.25RRT1.45: 0.15Total impurities / degradation productsNMT 4.0%Total: 0.41Total: 0.61DissolutionReport result103.2100.9Microbial enumerationTAMCNMT 10 3< cfu / gCompliesNATYMCNMT 10 2< cfu / gCompliesNAEscherichia coliAbsent in 1 gCompliesNA * Only peaks ≥ 0.10% are reported Example 5 - Solubility Study

[0419] The aim of this study was to assess the solubility of the N-(2-(tert-butyl)-1-((4,4-difluorocyclohexyl)methyl)-1H-benzimidazol-5-yl)ethanesulfonamide in a number of different excipients. Excipients which solubilised the active ingredient at ≥0.0125% w / w were assessed for their compatibility with the active ingredient (see Example 6) and dissolution performance (see Example 7).Materials

[0420] The materials used in this study are summarised in Table 26. Table 26: Materials used in Solubility Study. Material Function Manufacturer Compound IAPIOnyxPEG400 (Kollisolv)SolventBASF1,2 Propanediol (propylene glycol)MERCKGlycerolMERCKCorn oilSigmaKolliphor EL (cremophor EL)BASFPolysorbate 20SigmaPolysorbate 80SigmaLabrasol ALFGattefosseLabrafil M 2125 CSGattefosseMiglyol 812 (medium-chain triglycerides)IOI Oleo GmbHOctanoic acid (Caprylic Acid)SigmaPropylene glycol monocaprylate (Capmul MCM C-8)AbitecPropylene glycol dilaurate (Capmul PG-2L)AbitecDiethylene glycol monoethyl etherSigmaSoybean oilSigmaOleic acidSigmaKolliphor ELP (cremophor ELP)BASFPEG 4000MerckPEG 6000MerckCremophor RH40BASFKolliphor HS15BASFGelucire 50 / 13GattefosseGelucire 48 / 16GattefosseCapmul 808GAbitecSorbitan palmitateSigmaGlyceryl palmitostearateGattefosseGlyceryl monooleate (Capmul GMO-50)AbitecVitamin E TPGS 1000Isochem MethodologyPreparation of binary semi-solid compositions

[0421] The binary semi-solid compositions are summarised in Table 27.

[0422] The binary semi-solid composition mixtures were manufactured as follows: I. The semi solids were dispensed then molten overnight at ~ 60 °C (PEG 1500 and Vitamin E TPGS) or at ~80 °C (PEG 6000) II. PEG 400 was added the next day, as required, (when all the semi-solids were molten) III. Binary solvent mixture containing PEG 6000 were mixed at ~ 80 °C and the remaining binaries were mixed at ~ 70 °C, until homogenous Table 27 - Binary excipient composition Batch details %w:w / g PEG 400 PEG 1500 PEG 6000 Vitamin E TPGS Total PEG400: PEG 1500 (9:1)%w / w90.19.9100.09180.9219.78200.69PEG400: PEG 1500 (1:1)%w / w49.950.1100.0999.80100.06199.86PEG400: PEG 1500 (1:9)%w / w9.990.1100.0919.83180.06199.89PEG1500: PEG6000 (9:1)%w / w90.010.0100.09180.0219.91199.94PEG1500: PEG6000 (1:1)%w / w50.050.0100.09100.04100.00200.04PEG1500: PEG6000 (1:9)%w / w10.090.0100.0920.03180.09200.12PEG1500: TPGS (9:1)%w / w89.710.3100.09180.0120.69200.70PEG1500: TPGS (1:1)%w / w49.850.2100.09100.04100.86200.90PEG1500: TPGS (1:9)%w / w9.890.2100.0919.52179.77199.30 Solubility assessment methodology:

[0423] The quantities of API and solvents used in the solubility study (Parts 1 and 2) are summarised in Table 28. Table 28 - Quantities of API and solvents used in Part 1 and 2 of the solubility study. Part 1 Study Part 2 Study API dispensed (mg) 11.5 - 13.5 15 - 17 Solvent aliquot Aliquot 1Aliquot 2Aliquot 3Aliquot 1Aliquot 2Aliquot 3Aliquot 4Solvent volume to be added (mL) 2525502.02.02.49.6Total Cumulative Solvent volume (mL) 25501002.04.06.416Final concentration (%w / v) 0.050.0250.01250.80.40.250.1 Where required, the semi solids were melted prior to use (overnight). The solubility of the API in the selected solvents was assessed in two parts (Part 1 and Part 2 Studies) as follows: i. Solvent aliquots were added to pre-dispensed API while mixing using a magnetic flea and stirrer. ii. The temperature of the solvents was maintained as follows: a. Single-component liquids: Room temperature (ambient) b. TPGS and PEG 1500: ~60 °C c. PEG 6000 and binary solvent mixtures containing PEG 6000: ~80 °C iii. Solvents were mixed for a maximum of 1 hour between each aliquot addition. iv. The solvents were carefully inspected visually between aliquots. v. The addition of solvent was stopped when: a. After Aliquot 2 addition if API fully dissolve - (even if API dissolve after Aliquot 1, Aliquot 2 was added) b. After adding all the solvent aliquots in Table 28 vi. The number of solvent aliquots added and mixing times are summarised in Table 29. Table 29 - summary of solubility mixing times for each solvent Part 1 study Part 2 study Solvent Total mixing Time Total # aliquots added Total mixing Time Total # aliquots added Single-component liquids Octanoic acid2Hr22 Hr2 Propylene glycol monocaprylate2Hr22 Hr2 Diethylene glycol monoethyl ether2Hr2Over night (~15 Hrs)2 PEG 4002 Hr24 Hr4 Polysorbate 20Over night (~15 Hrs) #< 3 #< Over night (~15 Hrs) #< 4 Polysorbate 80Over night (~15 Hrs) #< 3 #< Over night (~15 Hrs) #< 4 Propylene glycol dilaurate4Hr3Over night (~15 Hrs)4 Labrasol ALF2Hr2Over night(~15 Hrs)4 1,2-propane diol3Hr^3^NAGlycerol3Hr^3^Corn oil3Hr^3^Kolliphor EL3Hr^3^Kolliphor ELP3Hr^3^Labrafil M 2125 CS3Hr^3^Miglyol 812 (Medium-chain Triglycerides)3Hr^3^Soybean oil3Hr^3^Oleic acid3Hr^3^ Single component Semi-Solids PEG 60002Hr22Hr2PEG 40002Hr12Hr2Cremophor RH402Hr #< 2 Only after Overnight Hold (~15 Hrs) #< 2Hr #< 2 #< Kolliphor HS152Hr22Hr2Glyceryl monooleate2Hr22Hr2Gelucire 50 / 132Hr24Hr4Capmul 808G2Hr24Hr4Gelucire 48 / 162Hr24Hr4Sorbitan palmitate4Hr^3^NAGlyceryl palmitostearate4Hr^3^ Binary solvent mixtures PEG400: PEG 1500 (9:1)2Hr22Hr2PEG400: PEG 1500 (1:1)2Hr22Hr2PEG400: PEG 1500 (1:9)2Hr22Hr2PEG1500: PEG6000 (1:1)2Hr40min21Hr10min2PEG1500: PEG6000 (9:1)2Hr22Hr2PEG1500: PEG6000 (1:9)3Hr33Hr2PEG1500: TPGS (9:1)2Hr22Hr2PEG1500: TPGS (1:1)2Hr22Hr2PEG1500: TPGS (1:9)3Hr33Hr2 #< excipients that only dissolved the API after stirring overnight ^Excipients that failed to dissolve the API Results:Single-component Liquids:

[0424] The liquid solvents used for the solubility study are shown in Table 30.

[0425] From Part 1 of the study the following can be noted: API had the highest solubility in diethylene glycol monoethyl ether where the API fully dissolved after the addition of the first aliquot PEG 400, octanoic acid, propylene glycol monocaprylate and Labrasol ALF dissolved the API following the addition of second solvent aliquot. Propylene glycol dilaurate, polysorbate 20 and polysorbate 80 dissolved the API but only after the addition of the third aliquot. The remaining solvents failed to dissolve the API even after the third aliquot addition.

[0426] For Part 2 Solubility the following can be noted: As per Part 1 of the solubility study, the API had the highest solubility in diethylene glycol monoethyl ether, octanoic acid and propylene glycol monocaprylate, dissolving in just two solvents aliquots. In order to dissolve the API in PEG 400, polysorbate 20, polysorbate 80, propylene glycol dilaurate and Labrasol ALF four solvent aliquots were required. However: ∘ Propylene glycol dilaurate, polysorbate 80, polysorbate 20 had to be mixed overnight (~15 hours) to dissolve the API ∘ For Labrasol ALF, the API dissolved after the third aliquot was added, and the solution remained clear with the addition of the 4th aliquot. However after 5 days standing at ambient it was observed on inspection that the API had precipitate out of solution. Table 30 - Summary results for API solubility in Liquid excipients Part 1 Study Part 2 Study Solubility range (% w / v) Aliquot whereFinal # aliquotNominal DoseAliquot whereNominalSolventAPI first fully dissolveds addedper vial (µg)API first fully dissolvedFinal # aliquots addedcapsule Dose (ug)AboveBelowOctanoic acid2nd268.92nd22290.40 %0.80%Propylene glycol monocaprylate2nd249.92nd22080.40 %0.80%Diethylene glycol monoethyl ether1st249.92nd22090.40 %0.80%PEG 4002nd248.74th41810.10 %0.25%Polysorbate 203rd #< 3 #< 34.54th Only after Overnight Hold #< 4 #< 1860.10 %N / KPolysorbate 803rd #< 3 #< 43.14th Only after Overnigt Hold #< 4 #< 2010.10 %N / KPropylene glycol dilaurate3rd #< 3 #< 22.44th Only after Overnight Hold #< 4 #< 2100.10 %N / KLabrasol ALF2nd #< 2 #< 74.63 rd< 4 #< Precipitate 5 days later1860.025%0.05%1,2-propane diolDND*NAGlycerolCorn oilKolliphor ELKolliphor ELPLabrafil M 2125 CSMiglyol 812 (Medium-chain Triglycerides)Soybean oilOleic acid *DND = Did not dissolve even after the addition of 3 aliquots ¥< N / K= Not known: in these cases, the API was found to dissolve after the addition of the 4 th< solvent aliquot (corresponding to 0.1% w / v - see Table 3) only after stirring overnight. Since these samples had not been stirred overnight following the 3 rd< solvent aliquot addition (corresponding to 0.25 %w / v), it cannot be assumed that the API solubility is below 0.25 %w / v. Hence the upper solubility limit is not known. #< excipients that only dissolved the API after stirring overnight Single-component Semi-Solids

[0427] The single-component semi-solid solvents used for Parts 1 and 2 of the solubility study are summarised in Table 31.

[0428] For Part 1 of the study the following observations can be noted: API had the highest solubility in PEG 4000, Kolliphor HS15, Capmul 808G and Gelucire 48 / 16 - The API fully dissolved after the addition of the first aliquot PEG 6000, Glyceryl monooleate, Gelucire 50 / 13 and Cremophor RH40 all dissolved the API following the addition of second solvent aliquot. However: ∘ API precipitation was observed next day in Gelucire 50 / 13 ∘ Cremophor RH40 had to be mixed overnight (~15 hours) to dissolve the API after the addition of the second aliquot. The remaining solvents (sorbitan palmitate and glyceryl palmitostearate) failed to dissolve the API even after third aliquot was added.

[0429] For Part 2 of the study the following observations can be noted: Notably different from Part 1 of the solubility study, the API had the highest solubility in PEG 6000. In addition, the API showed higher solubility in Gelucire 50 / 13 in Part 2 compared to Part 1. The higher solubility observed in Part 2 vs Part 1 may have occurred due to the smaller volume of this highly viscous solvent. Using this smaller volume: There is likely to be a more even spread of heat throughout the mixture (less chance of cold spots in the viscous fluid). The mixing energy per volume is higher allowing improved hydrodynamics for API dissolution. Controlled temperature and effective mixing are very critical when working with semi-solid that have high melting temperature and high viscosity, such as PEG 6000 and Gelucire 50 / 13 The solvents which required two aliquots to dissolve the API were PEG 4000, Cremophor RH40, Kolliphor HS15 and Glyceryl monooleate. ∘ Creophor RH40 had to be mixed overnight to dissolve the API To dissolve the API in Gelucire 50 / 13 and Capmul 808G three aliquots of the solvent had to be added. To dissolve the API in Gelucire 48 / 16 four aliquots of solvent were required. Table 31 - Summary results for API solubility in single component semisolid excipients SolventPart 1 Study Part 2 Study Solubility range (% w / v) Aliquot where API first fully dissolvedFinal # aliquots addedNominal Dose per vial (µg)Aliquot where API first fully dissolvedFinal # aliquots addedNominal capsule Dose (ug)AboveBelowPEG 60002nd286.61st21970.80%N / K ¥< PEG 40001st253.12nd21880.40%0.80%Cremophor RH402nd Only after Overnight Hold229.02nd #< 2 #< 2020.40%0.80%Kolliphor HS151st257.42nd21880.40%0.80%Glyceryl monooleate2nd251.02nd22030.40%0.80%Gelucire 50 / 132nd291.53rd42110.25%0.40%Capmul 808G1st248.43rd41990.25%0.40%Gelucire 48 / 161st245.54th41960.10%0.40%Sorbitan palmitateDND*NAGlyceryl palmito-stearate *DND = Did not dissolve ¥< N / k= Not known Binary Solvent Mixtures

[0430] The API solubility in the binary solvent mixtures is summarised in Table 32. The API showed high solubility in all the binary solvent mixtures for both Parts 1 and 2. With the exception of PEG1500:TPGS (1:9) and PEG1500: PEG6000 (1:9), the API fully dissolved after the addition of the first solvent aliquot. The API solubility in PEG 1500: TPGS (1:9) was unexpectedly lower than all the binary solvent mixtures. Three solvents aliquots were required to dissolve the API in Part 1 and two solvent aliquots were required to dissolve the API in Part 2. However, the API solubility in PEG 1500: TPGS solvent mixture at 1:9 ratio remained acceptable. Table 32- Summary results for API solubility in binary solvent mixtures. Part 1 Study Part 2 Study Solubility range (% w / v) Aliquot where API first fully dissolvedFinal # aliquots addedNominal Dose per vial (µg)Aliquot where API first fully dissolvedFinal # aliquots addedNominal capsule Dose (ug)SolventAboveBelowPEG400: PEG 1500 (9:1)1st246.61st21940.80%N / K ¥< PEG400: PEG 1500 (1:1)1st248.61st21870.80%N / K ¥< PEG400: PEG 1500 (1:9)1st251.71st21860.80%N / K ¥< PEG1500: PEG6000 (1:1)1st260.91st21830.80%N / K ¥< PEG1500: PEG6000 (9:1)1st250.01st21780.80%N / K ¥< PEG1500: PEG6000 (1:9)3rd323.81st21660.80%N / K ¥< PEG1500: TPGS (9:1)1st247.11st21920.80%N / K ¥< PEG1500: TPGS (1:1)1st248.51st21860.80%N / K ¥< PEG1500: TPGS (1:9)3rd322.62nd21970.40%0.80%*DND= Did Not Dissolve ¥< N / K= Not known Conclusions

[0431] For a semi-solid composition it is desirable that the API has some solubility, ideally fully soluble, in the excipients of the composition. Based on the predicted dose for this pharmaceutical product, excipients in which the API had sufficient solubility are: Octanoic acid, PEG 400, PEG 4000, PEG 6000, cremophor RH40, kolliphor HS15, Gelucire 50 / 13, polysorbate 20, Gelucire 48 / 16, polysorbate 80, capmul 808G, propylene glycol monocaprylate, propylene glycol dilaurate, diethylene glycol monoethyl, glyceryl monooleate, PEG 400:PEG 1500 (9:1), PEG 400:PEG 1500 (1:1), PEG 400:PEG 1500 (1:9), PEG 1500: PEG 6000 (1:1), PEG 1500: PEG 6000 (9:1), PEG 1500: PEG 6000 (1:9), PEG 1500: TPGS (9:1), PEG 1500: TPGS (1:1), and PEG 1500: TPGS (1:9).

[0432] These solvent systems were further studied in order to determine their compatibility with the API, see Example 6.Example 6 - Excipient compatibility

[0433] For the excipients tested in Example 5 which solubilised the API, samples of the excipient and API solutions were put down on a stability study in order to determine if the API was compatible with the excipient.Methodology

[0434] Based on the results from Example 5, if the API fully dissolved after addition of Aliquot 2 or 3, samples of the API solution were taken for excipient compatibility.

[0435] Duplicate active samples and single reps of their placebo controls (no API) were placed on station (-20 °C, 25 °C and 40 °C) for 14 and 28 days. Concentration of API in the excipient was 0.025% w / w. Once the incubation period was completed, samples were pulled and placed into a freezer pending their LC testing.UPLC method conditions:

[0436] Table 33 - UPLC methodology Parameter Value ColumnHalo C18 2.7 µm, 3.0 x 50 mm (PN: 92813-402)Column temperature40 °CSample manager wash (UPLC)HPLC Water: ACN 50:50 % v / vSample manager purge (UPLC)HPLC Water: ACN 50:50 % v / vMobile phase A10 mM Ammonium Acetate pH 7.0Mobile phase BAcetonitrileGradient programTime (minutes)Mobile Phase A (%)Mobile Phase B (%)09555.0072288.04554513.14505015.69188216.3129827.029827.195532.0955Flow rate0.3 mL / minRun time32 minutesSolution for injectionSolution in ACNHPLC water Auto-AdditionInjection volume12 µL38 µLWavelength256 nm3D data range190 to 400 nmSampling rate10 points / sec Results:Assay:

[0437] The assay results are presented in Table 34. Most of the samples had a low assay, generally < 85 %, but few samples had lower assays (<70 %). Those cases where the assay values decrease with incubation time and temperature are suggestive of API-excipient incompatibilities.

[0438] Apart from these cases, most assay values were consistently low over the course of the study. This has been attributed to poor extraction during sample preparation. The extraction method is optimised for PEG1500 and not the other excipients studied here.

[0439] For propylene glycol monocaprylate the API peak and the peak at RRT 0.93 are joined and as such an accurate assay result could not be determined. However, the UV spectrum, of the API peak in the samples does not match that of the standard UV spectrum. Propylene glycol monocaprylate is not compatible with the API.

[0440] The cases where the solvents contains at least 50% of PEG 400 showed evidence of gross degradation (i.e. assay values decreasing significantly (lowest for 28 days at 40 °C) with time and temperature) PEG 400, PEG 400:PEG 1500 (9:1) and (PEG 400:PEG 1500 (1:1).Related Substances:

[0441] The related substances detected for each excipient API system are presented in Tables 35-59 below.

[0442] Due to retention time shifts during the sequence, some of the excipient peaks did not always completely align with those in the active samples in the overlaid chromatograms. This is to be expected with excipient compatibility analysis. However, such retention times shifts were generally straightforward to account for.

[0443] Related substance peaks at RRT 0.96, 0.97, 1.02 & 1.03 / 1.04 are also present in the chromatogram of the standards. Each sample set is processed so that the API integration is consistent with the standard API peak for that sequence. In some sample sets, the RRT 1.02 and / or 1.03 / 1.04 peaks are indistinguishable from the API peak, and in some sets, the RRT 0.96 and / or 0.97 peaks are not well resolved due to e.g. interference from excipient peaks.

[0444] While all peaks reported are clearly distinguishable from the baseline, if a sample has a particularly low assay result (<50% of nominal) then the related substances % area reported may not be accurate as it will not be within the validated linearity range. This is acceptable for excipient compatibility analysis as results can still be trended.

[0445] For several families, peaks were detected in the samples tested at T=14 days but not at T=28 days. Because it is likely that genuine degradation peaks would increase in area from 14 to 28 days, it is unlikely that these peaks are degradation peaks. The potential reasons for the occurrence of these are: Inadvertent contamination of the vials during the LC dilution step (potentially not occurring at 28 days). More baseline noise at 28 days than at 14 days Use of different sequences and different placebo control samples to determine what is API / excipient related substances peaks at the 14 day vs 28-day timepoints. For example, where (excipient) peaks are seen in the placebo control sample at 28 days but not that (in the frozen control) at 14 days. This may indicate thermal degradation of the excipient at (40 °C for) 28 days. Related Substances Conclusions:

[0446] There was no evidence of related substances growth with incubation time and temperature for Polysorbate 20, Gelucire 50 / 13, Gelucire 48 / 16, Capmul 808G, propylene glycol monocaprylate, and propylene glycol dilaurate. However, it should be noted that all of these showed at least one peak (without a clear dependence of time or temperature) that were not present in the corresponding placebo control sample at the corresponding timepoint).

[0447] Comparing the areas of the related substance across all the PEG grades for the single-component solvents (see Tables 35-37), the following differences can be noted: PEG 400 showed several peaks that grew with incubation time and temperature: RRT 0.63, RRT 0.64, RRT 0.77, RRT 0.87, RRT 1.07 and RRT 1.08. The peaks at RRT 0.64 and RRT 0.77 had individual areas > 1 % after 28 days at 40 °C. PEG 4000 showed only one peak (RRT 1.18) which grew with incubation time and temperature. However, this remained below 0.5 % throughout. PEG 6000 showed two peaks which grew with incubation time and temperature: RRT 0.63 and RRT 1.65. However, these remained below 0.2 % throughout.

[0448] For the binary samples where the ratios of the two solvents were adjusted, the following could be noted:PEG1500 + Vitamin E TPGS:

[0449] Weak peaks (area NMT 0.3%), which grew with incubation time and temperature, were detected at RRT 0.85 and RRT 0.86 / 0.87, and were seen in all of these samples stored for T= 28 days at 25 °C and 40 °C . The areas of these peaks increased slightly with Vitamin E TPGS content suggesting they may be associated with the Vitamin E TPGS. A pair of peaks were also detected between RRT 1.61 and 1.65 (exact RRT of both peaks changed across the three sample families) whose area increased markedly with Vitamin E TPGS content reaching up to ~3% and 7% for the earlier and later eluting peak, respectively, in the case of 1:9 PEG 1500:TPGS after 28 days at 40 °C, suggesting they are associated with the Vitamin E TPGS. Samples made at 1:9 PEG1500:TPGS showed additional peaks (RRT0.56, RRT0.69, RRT0.71, RRT0.82, and RRT1.20), which did not increase with time or temperature). Because these peaks are not seen in PEG:TPGS = 9:1, they are likely associated with the TPGS and not the PEG 1500. PEG 400 + PEG1500

[0450] Numerous peaks were detected (at least after 28 days at 40 °C) which grew with incubation time and temperature, for example see peaks at RRT~0.62, RRT~0.63, RRT 0.77, RRT 0.89, RRT 1.06 and RRT 1.34 were seen. The area % of all of these peaks tended to increase as the ratio of PEG 400 increases in the binary mixture, for example, see RRT 0.63 and 0.77.

[0451] The drop in assay seen with sample PEG400:PEG1500 (9:1) and PEG400:PEG1500 (1:1) for the samples stored at 40 °C for 28 day appears to be associated with the growth of the related substance peaks in these samples.PEG 1500 + PEG 6000

[0452] Peaks with low area (< 0.2% of the total) grew with incubation time and temperature in both families but at different RRTs: At 1:9 PEG 1500:PEG 6000, the peaks detected were RRT 0.83 and RRT 0.85 At 9:1 PEG 1500:PEG 6000, the peaks detected were RRT 0.61, RRT 0.62 and RRT0.77. Overall conclusions:

[0453] There was no evidence of excipient:API incompatibilities with incubation time and temperature for Polysorbate 20, Gelucire 50 / 13, Gelucire 48 / 16, Capmul 808G, and propylene glycol dilaurate. Consistent assays were determined with incubation time / temperature for PEG 4000, PEG 6000, Cremophor RH40, Kolliphor HS15, Polysorbate 80, octanoic acid, diethylene glycol monoethyl ether, PEG400:PEG1500 (1:9), PEG1500:PEG6000 (9:1), glyceryl monooleate, PEG1500:PEG6000 (1:9), PEG1500:TPGS (1:1), PEG1500:TPGS (9:1), and PEG1500:TPGS (1:9). The grade of PEG 400 used (alone or in combination with PEG1500 in a 9:1 and 1:1 PEG400:PEG1500) was incompatible with the API as assay decreased and related substances peaks increased with incubation time / temperature. It is postulated that the grade of PEG400 used may in part be contributing to the API incompatibility and that a super refined grade of PEG400 may be compatible with the API considering other PEG solvents have been demonstrated to be compatible with the API (see this Example and Example 4). Using a super-refined PEG may be advantageous for other PEGs (e.g. PEG1500, PEG4000, PEG6000), for example, extend the shelf life of the product. Table 34 - Assay (as % of nominal) stability data Assay as % of Nominal 14 days (-20°C) 14 days (25°C) 14 days (40°C) 28 days (25°C) 28 days (40°C) Excipient Rep 1 Rep 2 Mean Rep 1 Rep 2 Mean Rep 1 Rep 2 Mean Rep 1 Rep 2 Mean Rep 1 Rep 2 Mean PEG 40095.890.993.392.293.092.690.494.192.392.991.592.284.981.483.1PEG 400082.384.683.489.789.989.890.690.790.785.390.487.991.495.493.4PEG 600049.553.351.465.658.261.969.259.964.55868.763.359.867.563.7Cremophor RH407175.273.170.171.170.669.274.671.971.273.072.174.278.176.1Kolliphor HS1583.990.687.287.990.289.188.889.389.190.294.192.186.395.490.9Gelucire 50 / 1343.342.743.046.837.842.342.437.940.151.649.550.548.942.745.8Polysorbate 2043.4*65.054.258.561.460.060.461.160.760.459.660.059.362.460.9Gelucire 48 / 1672.0n / a*72.078.678.678.680.680.880.783.782.483.082.381.281.7Polysorbate 8054.258.256.259.853.856.866.165.866.057.059.858.461.172.466.8Capmul 808G86.789.588.188.186.687.393.785.189.484.188.286.184.486.085.2Octanoic acid69.369.169.269.067.868.467.667.967.859.961.860.967.858.763.2Propylene Glycol monocaprylate26.923.725.32427.625.825.527.326.423.824.424.123.924.224.1Propylene Glycol dilaurate87.188.187.685.182.883.986.283.985.086.277.181.746.8 #< 80.963.9Diethylene glycol monoethyl ether87.788.187.987.184.285.786.547.2 #< 66.98.4 #< 88.848.683.483.183.2Glyceryl monooleate87.287.987.594.092.693.389.593.491.594.295.895.088.780.884.8PEG400:PEG1500 (9:1)92.993.893.491.685.788.691.092.191.692.086.989.578.684.181.4PEG400:PEG1500 (1:1)90.272.4*81.394.293.994.092.793.192.994.394.294.285.680.883.2PEG400:PEG1500 (1:9)102.097.399.799.995.997.996.594.995.799.793.896.793.899.096.4PEG1500:PEG6000 (9:1)93.693.493.589.491.090.288.790.889.891.690.991.289.192.891.0PEG1500:PEG6000 (1:9)77.075.776.376.175.375.774.975.074.977.075.276.177.174.375.7PEG1500:TPGS (1:1)91.792.191.995.195.695.493.499.296.398.496.797.599.7100.299.9PEG1500:TPGS (9:1)87.486.687.090.091.090.590.687.288.988.488.288.392.787.390.0PEG1500:TPGS (1:9)74.477.475.973.774.974.370.875.373.173.675.774.770.668.769.7 * Low assay value seen for one of the replicates. # A low assay result was observed - all peaks for this sample in the chromatogram were reduced which suggests a lower volume of solution was injected into the UPLC. Table 35 - Related substances stability data for PEG 400 Excipient Storage Time point Area of Peak (as % of Total peak area) RRT ± 0.01 RRT 0.63 RRT 0.64 RRT 0.70 RRT 0.77 RRT 0.87 RRT 0.96 RRT 1.01 RRT 1.04 RRT 1.07 RRT 1.08 Total PEG 400-20°C14 daysNDND<0.10ND0.120.200.790.531.64PEG 40025°C14 daysNDND0.180.27<0.100.190.750.471.86PEG 40040°C14 days0.150.270.160.35<0.100.170.850.462.41PEG 40025°C28 daysNDND<0.10ND0.180.20NDNDND0.37PEG 40040°C28 days0.611.292.10.20.150.160.170.180.265.11 Table 36- Related substances stability data for PEG 4000 Excipient Storage Time point Area of Peak (as % of Total peak area) RRT ± 0.01 RRT 0.15 RRT 0.39 RRT 0.41 RRT 0.65 RRT 0.89 RRT 0.96 RRT 0.97 RRT 1.02 RRT 1.07 RRT 1.18 RRT 1.20 RRT 1.36 Total PEG 4000-20°C14 days0.29NDNDNDND0.20< 0.100.31ND0.37ND1.18PEG 400025°C14 days1.840.24*1.21*0.12*0.20*0.170.100.280.170.340.104.77PEG 400040°C14 daysNDNDNDNDND0.19< 0.100.29ND0.39ND0.87PEG 400025°C28 days0.240.110.340.381.07PEG 400040°C28 days0.240.110.340.401.09 * peaks only seen for one on the two replicates - indicates likely inadvertent contamination for that replicate Table 37- Related substances stability data for PEG 6000 Excipient Storage Time point Area of Peak (as % of Total peak area) RRT ± 0.01 RRT 0.57 RRT 0.63 RRT 0.81 RRT 0.89 RRT 0.96 RRT 1.01 RRT 1.21 RRT 1.65 Total PEG 6000-20°C14 daysNDND<0.100.201.040.35ND1.6PEG 600025°C14 daysNDND< 0.100.190.790.34ND1.31PEG 600040°C14 days0.130.320.160.200.720.370.132.03PEG 600025°C28 days0.12ND0.160.190.36ND0.83PEG 600040°C28 daysND0.110.170.200.380.191.05 Table 38- Related substances stability data for Cremophor RH40 Excipient Storage Time point Area of Peak (as % of Total peak area) RRT ± 0.01 RRT 0.53 RRT 0.88 RRT 0.96 RRT 0.97 RRT 1.01 RRT 1.03 RRT 1.17 RRT 1.33 RRT 1.36 Total Cremophor RH40-20°C14 daysNDND0.13< 0.100.13Cremophor RH4025°C14 daysND0.160.14<0.100.31Cremophor RH4040°C14 days0.110.130.220.130.59Cremophor RH4025°C28 days0.230.120.330.18NDNDND0.85Cremophor RH4040°C28 days0.230.170.47ND0.250.560.171.85 Note: peak shifting from placebo injection to the active sample occurred, as a result the related substance data for T = 28 days (mainly 40°C) is not as accurate as for the other samples. Table 39 - Related substances stability data for Kolliphor HS15 Excipient Storage Time point Area of Peak (as % of Total peak area) RRT ± 0.01 RRT 0.96 RRT 0.97 RRT 1.01 RRT 1.04 RRT 1.22 RRT 1.44 RRT 1.63 RRT 1.64 RRT 1.97 Total Kolliphor HS15-20°C14 days0.210.670.460.10< 0.100.330.282.05Kolliphor HS1525°C14 days0.210.680.53< 0.100.110.390.262.17Kolliphor HS1540°C14 days0.210.560.45< 0.100.100.380.281.97Kolliphor HS1525°C28 days0.220.100.38ND0.70Kolliphor HS1540°C28 days0.22< 0.100.370.250.84 Difference in RRT 1.01 and RRT 1.04 peaks between T = initial and T=14 days compared to T=28 days is likely due to variation of API peak integration between the two sequences. Table 40 - Related substances stability data for Gelucire 50 / 13 Excipient Storage Time point Area of Peak (as % of Total peak area) RRT ± 0.01 RRT 0.55 RRT 0.87 RRT 0.96 RRT 0.97 RRT 1.01 RRT 1.10 RRT 1.32 RRT 1.54 RRT 1.71 Total Gelucire 50 / 13-20°C14 days<0.100.140.230.110.290.120.460.131.47Gelucire 50 / 1325°C14 days< 0.100.140.200.100.290.110.47ND1.31Gelucire 50 / 1340°C14 days0.100.140.190.100.310.110.38ND1.31Gelucire 50 / 1325°C28 days0.220.190.420.83Gelucire 50 / 1340°C28 days0.190.20ND0.40 Table 41 - Related substances stability data for Polysorbate 20 Excipient Storage Time point Area of Peak (as % of Total peak area) RRT ± 0.01 RRT 0.15 RRT 0.84 RRT 0.85 RRT 0.87 RRT 0.89 RRT 0.90 RRT 0.96 RRT 1.01 Total Polysorbate 20-20°C14 days2.900.110.291.18ND1.600.160.116.36Polysorbate 2025°C14 days1.96< 0.100.210.74ND1.310.18< 0.104.42Polysorbate 2040°C14 daysNDNDNDND0.460.100.11< 0.100.67Polysorbate 2025°C28 days0.200.20Polysorbate 2040°C28 daysND0.00 Table 42 - Related substances stability data for Gelucire 48 / 16 Excipient Storage Time point Area of Peak (as % of Total peak area) RRT ± 0.01 RRT 0.40 RRT 0.96 RRT 0.97 RRT 1.02 RRT 1.11 RRT 1.53 Total Gelucire 48 / 16-20°C14 days0.20< 0.10NDND0.20Gelucire 48 / 1625°C14 days0.200.10NDND0.30Gelucire 48 / 1640°C14 days0.21< 0.100.150.851.21Gelucire 48 / 1625°C28 days0.10.220.110.360.79Gelucire 48 / 1640°C28 daysND0.210.110.370.69 Table 43 - Related substances stability data for Polysorbate 80 Excipient Storage Time point Area of Peak (as % of Total peak area) RRT ± 0.01 RRT 0.41 RRT 0.43 RRT 0.53 RRT 0.55 RRT 0.56 RRT 0.58 RRT 0.62 RRT 0.66 RRT 0.71 RRT 0.72 RRT 0.74 RRT 0.81 RRT 0.82 RRT 0.83 RRT 0.84 Polysorbate 80-20°C14 daysPolysorbate 8025°C14 daysPolysorbate 8040°C14 days0.670.520.490.380.370.490.560.320.260.140.290.200.15Polysorbate 8025°C28 daysNDNDPolysorbate 8040°C28 days0.550.22 The related substances data for both replicates at 40°C at 14 days were consistent. However, significant placebo degradation is seen at T=28 days 40°C compared to T=28 days 25°C and T=initial. The additional peaks at 40°C 14 days are likely from placebo degradation, but the peaks could not be discounted at the time of the analysis as there was not a representative degraded placebo for T=14 days at 40°C. Table 44 - Related substances stability data for Polysorbate 80 (continued) Area of Peak (as % of Total peak area) RRT ± 0.01 Excipient Storage Time point RRT 0.85 RRT 0.86 RRT 0.90 RRT 1.06 RRT 1.09 RRT 1.11 RRT 1.13 RRT 1.16 RRT 1.18 RRT 1.22 RRT 1.32 RRT 1.35 RRT 1.76 RRT 1.78 Total 0.00Polysorbate 80-20°C14 days0.00Polysorbate 8025°C14 days0.00Polysorbate 8040°C14 days0.150.243.122.111.691.771.000.980.550.342.141.873.2316.0640.06Polysorbate 8025°C28 days0.00Polysorbate 8040°C28 days0.00 The related substances data for both replicates at 40°C at 14 days were consistent. However, significant placebo degradation is seen at T=28 days 40°C compared to T=28 days 25°C and T=initial. The additional peaks at 40°C 14 days are likely from placebo degradation, but the peaks could not be discounted at the time of the analysis as there was not a representative degraded placebo for T=14 days at 40°C. Table 45 - Related substances stability data for Capmul 808G Excipient Storage Time point Area of Peak (as % of Total peak area) RRT ± 0.01 RRT 0.30 RRT 0.31 RRT 0.73 RRT 0.79 RRT 0.82 RRT 0.86 RRT 1.02 RRT 1.10 RRT 1.51 Total Capmul 808G-20°C14 daysNDND0.820.140.230.331.08< 0.102.59Capmul 808G25°C14 daysNDND0.840.150.350.381.04< 0.102.76Capmul 808G40°C14 days0.850.280.810.130.510.360.830.113.86Capmul 808G25°C28 days0.330.340.100.77Capmul 808G40°C28 days0.330.37< 0.100.69 Table 46 - Related substances stability data for Octanoic Acid Excipient Storage Time point Area of Peak (as % of Total peak area) RRT ± 0.01 RRT 0.34 RRT 0.55 RRT 0.96 Total Octanoic Acid-20°C14 days0.26<0.100.26Octanoic Acid25°C14 days0.27<0.100.27Octanoic Acid40°C14 days0.28<0.100.28Octanoic Acid25°C28 daysND0.190.19Octanoic Acid40°C28 days0.190.210.40 Table 47 - Related substances stability data for propylene glycol monocaprylate Excipient Storage Time point Area of Peak (as % of Total peak area) RRT ± 0.01 RRT 0.92 RRT 0.93 Total Propylene Glycol monocaprylate-20°C14 days69.369.3Propylene Glycol monocaprylate25°C14 days72.272.2Propylene Glycol monocaprylate40°C14 days70.570.5Propylene Glycol monocaprylate25°C28 days0.3470.971.3Propylene Glycol monocaprylate40°C28 days67.767.7 Table 48 - Related substances stability data for propylene glycol dilaurate Excipient Storage Time point Area of Peak (as % of Total peak area) RRT ± 0.01 RRT 0.96 RRT 1.02 RRT 1.22 Total Propylene glycol dilaurate-20°C14 days0.120.160.28Propylene glycol dilaurate25°C14 days0.130.140.27Propylene glycol dilaurate40°C14 days0.140.100.24Propylene glycol dilaurate25°C28 days0.230.500.74Propylene glycol dilaurate40°C28 days0.340.480.83 Table 49 - Related substances stability data for diethylene glycol monoethyl ether Excipient Storage Time point Area of Peak (as % of Total peak area) RRT ± 0.01 RRT 0.37 RRT 0.41 RRT 0.45 RRT 0.47 RRT 0.48 RRT 0.53 RRT 0.54 RRT 0.55 RRT 0.62 RRT 0.63 RRT 0.73 RRT 0.75 RRT 0.79 RRT 0.85 RRT 0.89 Diethylene glycol monoethyl ether-20°C14 days1.432.310.360.190.100.300.110.110.830.531.21ND0.120.24Diethylene glycol monoethyl ether25°C14 days1.232.02NDNDND0.310.120.13ND0.170.91ND< 0.10< 0.10Diethylene glycol monoethyl ether40°C14 days0.190.35NDNDND0.330.310.13ND0.450.570.10< 0.10< 0.10Diethylene glycol monoethyl ether25°C28 days1.031.78NDNDNDDiethylene glycol monoethyl ether40°C28 daysNDND0.210.530.43 Table 50 - Related substances stability data for diethylene glycol monoethyl ether (continued) Excipient Storage Time point Area of Peak (as % of Total peak area) RRT ± 0.01 RRT 0.91 RRT 0.94 RRT 0.96 RRT 0.97 RRT 1.02 RRT 1.06 RRT 1.37 RRT 1.50 RRT 1.53 RRT 1.94 Total Diethylene glycol monoethyl ether-20°C14 days0.520.110.132.940.130.120.1811.95Diethylene glycol monoethyl ether25°C14 days0.35< 0.100.183.12ND< 0.10< 0.10ND8.54Diethylene glycol monoethyl ether40°C14 days0.34< 0.100.192.860.14< 0.10< 0.10ND5.98Diethylene glycol monoethyl ether25°C28 days0.190.110.33ND< 0.103.44Diethylene glycol monoethyl ether40°C28 days0.16< 0.100.301.030.102.76 Table 51 - Related substances stability data for glyceryl monooleate Excipient Storage Time point Area of Peak (as % of Total peak area) RRT ± 0.01 RRT 0.96 RRT 1.17 RRT 1.43 Total Glyceryl monooleate-20°C14 days3.77*3.77Glyceryl monooleate25°C14 days4.39*4.39Glyceryl monooleate40°C14 days6.43*6.43Glyceryl monooleate25°C28 daysND0.950.95Glyceryl monooleate40°C28 days0.481.311.79 *likely to be an excipient related peak Table 52 - Related substances stability data for PEG400:PEG1500 (9:1) Excipient Storage Time point Area of Peak (as % of Total peak area) RRT ± 0.01 RRT 0.62 RRT 0.63 RRT 0.77 RRT 0.80 RRT 0.87 RRT 0.89 RRT 0.96 RRT 0.97 RRT 1.01 RRT 1.03 RRT 1.04 RRT 1.06 RRT 1.34 Total PEG 400:PEG 1500 (9:1)-20°C14 daysNDND< 0.100.100.200.100.280.67PEG 400:PEG 1500 (9:1)25°C14 daysNDND< 0.100.130.20< 0.100.270.60PEG 400:PEG 1500 (9:1)40°C14 days0.160.300.230.100.200.100.271.36PEG 400:PEG 1500 (9:1)25°C28 daysNDND< 0.10NDND0.220.100.360.10NDNDND0.77PEG 400:PEG 1500 (9:1)40°C28 days0.922.063.830.190.210.160.130.20< 0.100.140.600.218.64 Table 53 - Related substances stability data for PEG400:PEG1500 (1:1) Excipient Storage Time point Area of Peak (as % of Total peak area) RRT ± 0.01 RRT 0.53 RRT 0.54 RRT 0.61 RRT 0.63 RRT 0.77 RRT 0.87 RRT 0.89 RRT 0.96 RRT 0.97 RRT 1.01 RRT 1.03 RRT 1.06 RRT 1.34 Total PEG 400:PEG 1500 (1:1)-20°C14 daysND< 0.100.130.210.10.350.79PEG 400:PEG 1500 (1:1)25°C14 daysND< 0.100.110.20< 0.100.330.64PEG 400:PEG 1500 (1:1)40°C14 days0.240.17< 0.100.19< 0.100.330.94PEG 400:PEG 1500 (1:1)25°C28 days0.180.46NDND< 0.10ND0.230.110.340.100.22ND1.63PEG 400:PEG 1500 (1:1)40°C28 daysNDND0.321.191.540.180.200.120.22< 0.100.570.134.45 Table 54 - Related substances stability data for PEG400:PEG1500 (1:9) Excipient Storage Time point Area of Peak (as % of Total peak area) RRT ± 0.01 RRT 0.15 RRT 0.41 RRT 0.48 RRT 0.55 RRT 0.60 RRT 0.61 RRT 0.66 RRT 0.69 RRT 0.77 RRT 0.86 RRT 0.96 RRT 0.97 RRT 1.01 RRT 1.06 RRT 1.34 RRT 1.58 Total PEG 400:PEG 1500 (1:9)-20°C14 daysNDNDND0.10NDNDNDND0.20<0.100.36ND0.66PEG 400:PEG 1500 (1:9)25°C14 days0.57*0.20*0.13*0.860.13*0.30*ND0.14*0.18<0.100.310.12*2.94PEG 400:PEG 1500 (1:9)40°C14 daysNDNDND0.17NDND0.12ND0.210.100.35ND0.95PEG 400:PEG 1500 (1:9)25°C28 daysNDND<0.100.220.100.36<0.10ND0.68PEG 400:PEG 1500 (1:9)40°C28 days0.230.290.460.210.100.320.290.132.03 * peaks only seen for one on the two replicates - indicates likely inadvertent contamination for that replicate Table 55 - Related substances stability data for PEG1500:PEG6000 (9:1) Excipient Storage Time point Area of Peak (as % of Total peak area) RRT ± 0.01 RRT 0.55 RRT 0.61 RRT 0.62 RRT 0.77 RRT 0.96 RRT 0.97 RRT 1.01 Total PEG 1500:PEG 6000 (9:1)-20°C14 days0.120.210.100.360.80PEG 1500:PEG 6000 (9:1)25°C14 days0.140.20<0.100.370.71PEG 1500:PEG 6000 (9:1)40°C14 days0.180.20<0.100.360.74PEG 1500:PEG 6000 (9:1)25°C28 daysNDNDND0.200.240.44PEG 1500:PEG 6000 (9:1)40°C28 days0.120.140.150.190.230.84 Table 56 - Related substances stability data for PEG1500:PEG6000 (1:9) Excipient Storage Time point Area of Peak (as % of Total peak area) RRT ± 0.01 RRT 0.83 RRT 0.85 RRT 0.96 RRT 1.02 RRT 1.66 Total PEG1500:PEG6000 (1:9)-20°C14 days0.180.320.51PEG1500:PEG6000 (1:9)25°C14 days0.180.320.49PEG1500:PEG6000 (1:9)40°C14 days0.170.310.48PEG1500:PEG6000 (1:9)25°C28 days0.140.120.170.200.200.83PEG1500:PEG6000 (1:9)40°C28 days0.170.150.140.20ND0.66 Table 57 - Related substances stability data for PEG1500:TPGS (1:1) Excipient Storage Time point Area of Peak (as % of Total peak area) RRT ± 0.01 RRT 0.56 RRT 0.85 RRT 0.86 RRT 0.96 RRT 0.97 RRT 1.01 RRT 1.62 RRT 1.64 Total PEG1500:TPGS (1:1)-20°C14 days0.300.200.290.791.843.40PEG1500:TPGS (1:1)25°C14 days0.220.200.310.911.773.40PEG1500:TPGS (1:1)40°C14 days0.420.200.291.511.764.18PEG1500:TPGS (1:1)25°C28 days0.140.170.100.190.100.221.821.834.57PEG1500:TPGS (1:1)40°C28 days0.300.200.120.200.110.212.301.695.14 Table 58 - Related substances stability data for PEG1500:TPGS (9:1) Excipient Storage Time point Area of Peak (as % of Total peak area) RRT ± 0.01 RRT 0.40 RRT 0.54 RRT 0.85 RRT 0.86 RRT 0.96 RRT 1.01 RRT 1.61 RRT 1.63 Total PEG1500:TPGS (9:1)-20°C14 daysND0.180.340.110.401.03PEG1500:TPGS (9:1)25°C14 days3.310.190.330.130.394.34PEG1500:TPGS (9:1)40°C14 daysND0.180.330.190.371.06PEG1500:TPGS (9:1)25°C28 days0.38*0.170.140.200.220.170.361.64PEG1500:TPGS (9:1)40°C28 daysND0.150.120.230.200.280.321.30 * peak only seen for one on the two replicates - indicates likely inadvertent contamination for that replicate Table 59 - Related substances stability data for PEG1500:TPGS (1:9) Excipient Storage Area of Peak (as % of Total peak area) RRT ± 0.01 Time point RRT 0.56 RRT 0.69 RRT 0.71 RRT 0.82 RRT 0.85 RRT 0.87 RRT 0.96 RRT 0.97 RRT 1.01 RRT 1.20 RRT 1.63 RRT 1.65 Total PEG1500:TPGS (1:9)-20°C14 days1.330.230.150.330.191.510.392.266.39PEG1500:TPGS (1:9)25°C14 days1.040.200.170.310.190.390.452.975.72PEG1500:TPGS (1:9)40°C14 days1.320.230.130.290.201.960.563.368.05PEG1500:TPGS (1:9)25°C28 days2.620.200.230.260.170.170.120.181.477.5012.94PEG1500:TPGS (1:9)40°C28 days1.310.230.280.300.180.170.120.283.376.8113.05 1 st< replicate of 25°C 28 days displayed more peaks than 2 nd< replicate but no more than replicates for 40°C 28 days Example 7 - Dissolution testing of capsules

[0454] A number of capsules were prepared using a selection of solvents and dissolution testing was performed.Part 1: Methodology:Materials

[0455] The materials used during this study are summarised in Table 60. Table 60 - Materials list Material Function Manufacturer Compound IAPIOnyxPEG 1500SolventsMerckPEG 6000MerckVitamin E TPGS 1000IsochemSize 2 Quali-G PEG capsulesCapsulesQualicaps Preparation of Blends

[0456] The following blends were prepared: Blend A: 0.4% w / w API in Vitamin E TPGS Blend B: 0.4% w / w API in PEG1500 Blend C: 0.4% w / w API in PEG6000 Blend Ww: 0.4% w / w API in PEG1500:TPGS (1:1) Blend Yy: 0.4% w / w API in PEG1500:TPGS (9:1) Blend Zz: 0.4% w / w API in PEG1500:TPGS (1:9)

[0457] The composition and preparation process of the blends are summarised in Table 61. Table 61 - Summary compositions of semisolid blends Blend Composition Material Blend A Blend B Blend C Compound I 0.0440.0430.042Vitamin E TPGS 9.97PEG1500 9.95PEG6000 9.95Total 10.0110.009.99Preparation Process Total mixing time (hr:min) 02:4001:2001:20Mixing temperature (°C) 66.162.479.2API solutions Yy, Ww and Zz were prepared as described in Example 5.

[0458] The API solutions used for encapsulation were manufactured as described below: I. The semi solids were dispensed as follows: a. The required amount of PEG 1500 and PEG 6000 were dispensed and then molten at ~ 60 °C (PEG 1500) or at ~80 °C (PEG 6000) b. Vitamin E TPGS was molten at ~ 60 °C, prior to dispensing the required amount II. The API was added to the molten semi-solid and mixed until fully dissolved (at ~ 60°C for PEG1500 and Vitamin E TPGS or 80 °C for PEG 6000) Encapsulation

[0459] The API solutions prepared as described above or in Example 5 were left to melt for 30 - 60 minutes at 70 - 80 °C (for the semi-solids containing PEG 6000) or 60°C - 70 °C (for the remaining semi-solids). Liquid solutions were encapsulated at room temperature. The solution were encapsulated as follows: 1. A Size 2 Profiller was loaded with 10 x size 2 Quali-G PEG capsules 2. A pipette (set to dispense 0.49 - 0.51 g of the blend) was used to systemically fill the capsule with one aliquot of the molten blend 3. The capsules were than locked Analytical testing

[0460] The dissolution was carried out in two different dissolution media (n=2 per media), 0.1 M HCl and pH 6.8 phosphate buffer. For both dissolution media the dissolution parameters were as follows: Paddles (USP apparatus II) 500 mL media volume 50 rpm paddle speed and 200 rpm infinity spin. Temperature of 37 ± 0.5 °C Band sinker - O-ring internal diameter between 6 mm to 7 mm ResultsBlend preparation and encapsulation

[0461] The three API solutions (in Vitamin E TPGS, PEG 6000 and PEG 1500 and the mixtures of Vitamin E TPGS and PEG 1500) containing 0.4 %w / w API were successfully produced. The API fully dissolved in the semi-solids in < 2 hours for PEG 1500 and PEG 6000 and < 3 hours in Vitamin E TPGS. All solutions appeared clear and free from particles.

[0462] All six solutions were successfully filled into Size 2 Quali-G - PEG capsules.Dissolution:

[0463] The dissolution data is presented in Figures 16 and 17. Figure 16 shows the dissolution profiles Raw Data (mean API dissolved from the 2 capsules, expressed as % of the nominal dose). This is replotted as Normalised Data in Figure 17 where the Raw Data result at each sample point is expressed as a % of the mean result at the final (60 min) sample point.

[0464] With two exceptions, the dissolution Raw Data result at the final timepoint (60 min) was within ±10% of nominal API content of the capsules: PEG 1500 capsules in both media were ~12 - 14 % above the nominal API content. The capsule weights were very close of the target weight, so there is no clear explanation for the high %API released. PEG 6000 in both media were ~30 % below the nominal API content. Below are the investigated potential causes of the incomplete API release, followed by the investigation conclusion (in brackets) and the underlying rationale for the status: ∘ Incorrect Drug loading of the blend (discounted) - When the composition was checked the quantities were found to be correct ∘ Capsule fill weight (discounted) - Capsule weights were checked and the fill weight deduced to be within ±10% of target ∘ API degradation (considered very unlikely) - PEG 1500 (chemically similar to PEG 6000) was known to be compatible with the API (see Example 4). ∘ Incomplete disintegration of the PEG 6000 matrix (only likely explanation) - PEG 6000 is likely to be translucent in the dissolution media which could be difficult to notice any small undissolved residues in an amber dissolution vessel- its high molecular weight plausibly slows the disintegration of the matrix, i.e., reducing the ultimate drug release with the 60 minutes of the test.

[0465] All the capsules plateaued to within ±2% ultimate (60 min) value at or before 45 minutes with the exception of PEG1500:TPGS 1:9 in the pH6.8 medium where the API released increased by about 8% from 45 to 60 min, consistent with it being the slowest releasing capsule formulation.

[0466] (From the Normalised Data) Capsules made from all the API solutions showed slower dissolution rate in pH 6.8 phosphate buffer than in 0.1 M HCl.

[0467] (Excluding the anomaly of PEG 6000, discussed above) PEG1500:TPGS 1:9 capsules, showed the slowest Normalised drug release in pH 6.8 phosphate buffer, followed by TPGS capsules. This implies that (excluding the PEG 6000 anomaly) the API solvent with the slowest erosion in the medium is Vitamin E TPGS.Part 2:

[0468] A number of different solvents were used to prepare capsules, either at 0.1% w / v or 0.4% w / v depending on the solubility of the API in the solvent. These capsules were analysed by dissolution (n = 2) in 0.1 M HCl and pH 6.8 phosphate buffer media.Methodology:

[0469] Encapsulate 13 sets of ~200 µg capsules prepared with either 0.1 % or 0.4 % API (dissolved), one set per solvent. The composition of the blends are summarised in Table 62. Table 62 - Summary of blend compositions Blend Composition (%w / w) Blend detail Blend Code API Diethylene glycol monoethyl ether PEG 400 PEG 4000 Capmul PG-2L PEG 1500 Cremo phor RH40 Kolli phor HS15 Gelu cire 48 / 16 PEG 6000 TPGS Diethylene glycol monoethyl ether O 0.499.6PEG 400 A 0.199.9PEG 4000 Aa 0.499.6Cremophor RH40 Dd 0.499.6Kolliphor HS15 Ee 0.499.9Gelucire 48 / 16 Gg 0.199.6PEG400: PEG1500 @ 9:1 Mm 0.489.69.96PEG400: PEG1500 @ 1:1 Nn 0.449.849.8PEG400: PEG1500 @ 1:9 Qq 0.49.9689.6PEG1500: PEG6000 @ 9:1 Rr 0.489.69.96PEG1500: PEG6000 @ 1:1 ¥< Tt 0.449.849.8PEG1500: PEG6000 @ 1:9 Uu 0.49.9689.6 Materials

[0470] Most of the materials needed to make the capsules are already listed in Example 5. The additional materials are listed in Table 63. Table 63 - List of Materials to make the capsules Compound I API Onyx Size 2 Quali-G PEG capsules Capsules Qualicaps Preparation of Blends

[0471] API solutions were prepared as described in Example 5 the API solutions used for encapsulation were manufactured as described below: I. In case of semi-solid excipients, the API was added to the molten semi-solid and mixed until fully dissolved. II. In case of excipients that were liquid at room temperature, the API was added at room temperature and mixed until fully dissolved Encapsulation

[0472] The API solutions prepared as described above and in Example 5. Whereas the liquid solutions were encapsulated at room temperature, the semi-solid API solutions were left to melt for 30 - 60 minutes at 70 - 80 °C (for the semi-solids containing PEG 6000) or 60°C - 70 °C (for the remaining semi-solids).. All the solutions were encapsulated as follows: a) A Size 2 Profiller was loaded with 10 x size 2 Quali-G PEG capsules b) A pipette was used to systemically fill the capsule with one aliquot of the molten blend (set to dispense i) 0.245 - 0.255 g - For 0.4 % drug loading blends ii) 0.98 - 1.02 g - For 0.1 % drug loading blends c) The capsules were then locked Analytical testing

[0473] As per Part 1.Results and DiscussionBlend preparation and encapsulation:

[0474] All solutions appeared clear and free from particles. All solutions were successfully filled into Size 2 Quali-G - PEG capsules Dissolution:

[0475] The dissolution profiles are separated into two groups of solvents to make them easy to compare: Single excipients Binary mixtures of excipients

[0476] The results are plotted as the mean results for the two capsules tested for each solvent studied - there was very good agreement between the results from the two individual capsules in all cases. Two representations of the same data are shown: The Raw Data where the dissolution is calculated as the API dissolved as % of the nominal dose. The Normalised Data where the result for each timepoint is expressed as % of the result at the end of the test (60 minutes ).

[0477] The single excipient dissolution profiles are summarised in Figure 18 (Raw Data) and Figure 19 (Normalized), and the binary mixture dissolution profiles in Figure 20 (Raw Data) and Figure 21 (Normalized).

[0478] The dissolution plots are broadly similar with the following trends and differences: All capsule batches plateau plateaued to within ±3% of their ultimate (60 min or 45 min) value at or before 20 minutes. All capsules fully disintegrated within the first 15 minutes of the dissolution test. Gelucire 48 / 16 gave the slowest dissolution - it was the only capsule batch to not reach its ultimate release value at 45 min in both medium. Slow disintegration of the capsule was not reported. All the Capsules batches showed slower dissolution rate in pH 6.8 phosphate buffer than in 0.1 M HCl. It might have been anticipated that the dissolution rate (and potentially also the disintegration rate) of the API from PEG-based capsules might increase with decreasing molecular weight of the PEG i.e., increase in the order PEG 6000 < PEG 4000 < PEG 1500 < PEG 400. However, across the normalised dissolution data in this study, no clear trend was seen between the dissolution rate and either: ∘ The molecular weight of the PEG in the single-solvent systems. ∘ The proportions of the higher molecular weight PEG in the mixed solvent systems (PEG 400 + PEG 1500 or PEG 1500 + PEG 6000). Overall Conclusions:

[0479] All capsules prepared released at least 75% of API (normalised data) within 45 minutes of the dissolution test.Example 7: Stability study of PEG1500 in gelatine capsules comprising 50 µg and 200 µg of N-(2-(tert-butyl)-1-((4,4-difluorocyclohexyl)methyl)-1H-benzimidazol-5-yl)ethanesulfonamide

[0480] Capsules were prepared containing either 50 µg or 200 µg N-(2-(tert-butyl)-1-((4,4-difluorocyclohexyl)methyl)-1H-benzimidazol-5-yl)ethanesulfonamide in PEG1500. Gelatine capsule shells were used (Compositions of capsules and preparation as per Example 4). The capsules were put down on stability at 25°C / 60%RH for 12 months and 45°C / 75%RH for 6 months. Capsules were stored in 50 mL HDPE DUMA bottle with PP DUMA twist off cap.

[0481] The results show that the capsules comply with the specifications when stored for at least 12 months at 25°C / 60%RH.

[0482] The results also show that the capsules comply with specification when stored for 3 months at 40°C / 75%RH. Some results at 6 months for the 50 µg capsule are outside of specification (assay and dissolution) but this is considered to be due to residue been observed on capsules at this time point.Results: Appearance:50 µg dose capsules;

[0483] Storage Condition Specification Time Point (Months) Results N / AOpaque green / grey size 4 capsules with no physical defectsInitialComplies with specification25°C / 60%RH1Complies with specification3Complies with specification6Complies with specification9Complies with specification12Complies with specification40°C / 75%RH1Complies with specification3Complies with specification6Complies with specification 200 µg dose capsules;

[0484] Storage Condition Specification Time Point (Months) Results N / AOpaque size 2 white capsules with no physical defectsInitialComplies with specification25°C / 60%RH1Complies with specification3Complies with specification6Complies with specification9Complies with specification128 / 10 capsules complied with the specification. Physical defects for 2 / 10 capsules; 1 capsule has a small blue line on the surface and 1 capsule has a small red dot on the surface40°C / 75%RH1Complies with specification3Complies with specification6Complies with specification Assay:50 µg dose capsules;

[0485] Storage Condition Specification Time Point (Months) Result (%) Result (%) Weight corrected Non-weight corrected N / A90.0-110.0% of label claimInitialRep 1 = 96.2%Rep 1 = 97.5%Rep 2 = 100.4%Rep 2 = 102.0%Mean = 98.3%Mean =99.8%25°C / 60%RH1Rep 1 = 99.0%Rep 1 = 100.8%Rep 2 = 100.0%Rep 2 = 100.7%Mean = 99.5%Mean = 100.8%3Rep 1 = 100.8%Rep 1 = 103.7%Rep 2 = 99.2%Rep 2 = 99.5%Mean = 100.0%Mean = 101.6%6Rep 1 = 98.7%Rep 1 = 100.4%Rep 2 = 97.7%Rep 2 = 100.4%Mean = 98.2%Mean = 100.4%9Rep 1 = 96.6%Rep 1 = 100.0%Rep 2 = 97.3%Rep 2 = 100.0%Mean = 96.9%Mean = 100.0%12Rep 1 = 98.7%Rep 1 = 102.5%Rep 2 = 98.7%Rep 2 = 101.4%Mean =98.7%Mean = 102.0%40°C / 75%RH1Rep 1 = 98.0%Rep 1 = 100.5%Rep 2 = 97.9%Rep 2 = 99.3%Mean =98.0%Mean = 99.9%3Rep 1 = 95.2%Rep 1 = 98.7%Rep 2 = 97.0%Rep 2 = 100.9%Mean = 96.1%Mean = 99.8%6 1< Rep 1 = 81.8%Rep 1 = 85.7%Rep 2 = 95.4%Rep 2 = 100.1%Mean = 88.6%Mean =92.9% 1< Out of specification investigation performed. Result considered valid due to residue seen on capsules during inspection 200 µg dose capsules;

[0486] Storage Condition Specification Time Point (Months) Result (%) Weight corrected Result (%) Non-weight corrected N / A90.0-110.0% of label claimInitialRep 1 = 101.1%Rep 1 = 102.6%Rep 2 = 101.2%Rep 2 = 103.1%Mean = 101.1%Mean =102.9%25°C / 60%RH1Rep 1 = 99.9%Rep 1 = 102.1%Rep 2 = 99.3%Rep 2 = 101.1%Mean = 99.6%Mean = 101.6%3Rep 1 = 100.1%Rep 1 = 101.7%Rep 2 = 99.4%Rep 2 = 101.8%Mean = 99.8%Mean = 101.8%6Rep 1 = 100.6%Rep 1 = 102.3%Rep 2 = 102.3%Rep 2 = 103.2%Mean = 101.5%Mean = 102.7%9Rep 1 = 99.5%Rep 1 = 100.6%Rep 2 = 100.0%Rep 2 = 103.0%Mean = 99.8%Mean = 101.8%12Rep 1 = 99.7%Rep 1 = 102.5%Rep 2 = 98.5%Rep 2 = 100.9%Mean =99.1%Mean = 101.7%40°C / 75%RH1Rep 1 = 98.9%Rep 1 = 101.1%Rep 2 = 100.5%Rep 2 = 102.2%Mean =99.7%Mean = 101.6%3Rep 1 = 96.7%Rep 1 = 99.7%Rep 2 = 97.5%Rep 2 = 100.7%Mean = 97.1%Mean = 100.2%6Rep 1 = 94.3%Rep 1 = 99.4%Rep 2 = 95.6%Rep 2 = 99.8%Mean = 94.9%Mean =99.6% Related Substances:50 µg dose capsules;

[0487] Storage Condition Specification Time Point (Months) Result (%) Result (%) Rep 1 Rep 2 N / AIndividual impurities NMT 1.00%InitialRRT0.94: 0.12RRT0.94: 0.13RRT0.96: 0.10RRT0.96: 0.14RRT1.05-1.06: 0.24RRT1.05-1.06: 0.27RRT1.40: 0.19RRT1.40: 0.21RRT1.65: 0.12Total: 0.75Total: 0.7625°C / 60%RHTotal Impurities NMT 3.00%1RRT0.80: <0.10RRT0.94: 0.16RRT0.94: 0.14RRT0.96: 0.16RRT0.96: 0.15RRT1.05: 0.20RRT1.05: 0.26RRT1.41: 0.21RRT1.41: 0.22Total: 0.72Total: 0.773RRT0.96: 0.10RRT0.96: 0.10RRT0.97: 0.12RRT0.97: 0.12RRT1.03: 0.11RRT1.03: <0.10RRT1.05: 0.11RRT1.04: 0.26RRT1.06:<0.10RRT1.05: <0.10RRT1.07:<0.10RRT1.07:<0.10RRT1.23: 0.27RRT1.23: 0.26Total: 0.72Total: 0.746RRT0.97: 0.14RRT0.71:<0.10RRT1.01: 0.41RRT0.97: 0.13RRT1.04: 0.16RRT1.01: 0.36Total: 0.71RRT1.04: 0.11Total: 0.619RRT0.96: 0.13RRT0.96: 0.14RRT0.97: 0.16RRT0.97: 0.16RRT1.04: 0.22RRT1.04: 0.21Total: 0.51Total: 0.5112RRT0.96: <0.10RRT0.96: 0.10RRT0.97: <0.10RRT0.97: <0.10RRT1.03: <0.10RRT1.03: 0.13RRT1.22: 0.18RRT1.23: 0.17Total: 0.18Total: 0.4040°C / 75%RH1RRT0.69: <0.10RRT0.69: <0.10RRT0.94: 0.16RRT0.94: 0.18RRT0.96: 0.16RRT0.96: 0.18RRT0.97: <0.10RRT0.97: <0.10RRT1.06: 0.17RRT1.06: 0.18RRT1.14: 0.24RRT1.14: 0.23RRT1.36: <0.10RRT1.36: <0.10RRT1.41: 0.22RRT1.41: 0.32Total: 0.94Total: 1.003RRT0.77: 0.29RRT0.77: <0.1RRT0.96: 0.10RRT0.96: 0.10RRT0.97: 0.12RRT0.97: 0.10RRT1.03: 0.11RRT1.04: <0.10RRT1.04: 0.25RRT1.05: 0.21RRT1.05: <0.10RRT1.06: <0.10RRT1.09: <0.10RRT1.09: <0.10RRT1.11: 0.19RRT1.11: 0.16RRT1.12: <0.10RRT1.49: 0.47Total: 1.05Total: 1.046RRT0.76: 0.17RRT0.76: 0.21RRT0.97: 0.12RRT0.85: 0.49RRT1.01: 0.67RRT0.97: 0.10RRT1.08: <0.10RRT1.01: 0.56RRT1.09: 0.14RRT1.09: 0.16RRT1.12: 0.16RRT1.12: 0.15RRT1.13: 0.10RRT1.13: 0.12Total: 1.34Total: 1.79 200 µg dose capsules;

[0488] Storage Condition Specification Time Point (Months) Result (%) Result (%) Rep 1 Rep 2 N / AIndividual impurities NMT 1.00%InitialRRT0.66: 0.25RRT0.66: <0.10RRT0.94: 0.13RRT0.94: 0.13RRT0.96: 0.12RRT0.96: 0.13RRT1.05-1.06: 0.23RRT1.05-1.06: 0.37RRT1.26: <0.10RRT1.40: 0.22RRT1.30: 0.12Total: 0.86RRT1.40: 0.20RRT1.92: <0.10Total: 1.0625°C / 60%RHTotal Impurities NMT 3.00%1RRT0.66: <0.10RRT0.66: <0.10RRT0.94: 0.13RRT0.94: 0.14RRT0.96: 0.14RRT0.96: 0.15RRT1.06: 0.28RRT1.05: 0.34RRT1.40: 0.21RRT1.41: 0.22Total: 0.77Total: 0.863RRT0.96: 0.10RRT0.96: 0.11RRT0.97: <0.10RRT0.97: 0.13RRT1.03: 0.13RRT1.04: <0.10RRT1.05: 0.11RRT1.05: 0.11RRT1.06: <0.10RRT1.06: <0.10Total: 0.34RRT1.09: <0.10Total: 0.356RRT0.75: <0.10RRT0.96: 0.12RRT0.96: 0.10RRT0.97: 0.13RRT0.97: 0.12RRT1.01: 0.38RRT1.01: 0.37RRT1.04: 0.20RRT1.04: 0.14RRT1.70: <0.10Total: 0.73Total: 0.839RRT0.96: 0.14RRT0.96: 0.15RRT0.97: 0.15RRT0.97: 0.16RRT1.04: 0.21RRT1.04: 0.21Total: 0.49Total: 0.5212RRT0.96: 0.15RRT0.96: <0.10RRT0.97: 0.10RRT0.97: 0.10RRT1.03: <0.10RRT1.03: <0.10RRT1.22: 0.12RRT1.22: 0.16Total: 0.37Total: 0.2640°C / 75%RH1RRT0.66: <0.10RRT0.66: <0.10RRT0.93: 0.15RRT0.94: 0.14RRT0.96: 0.15RRT0.96: 0.15RRT1.05: 0.31RRT1.05: 0.25RRT1.40: 0.23RRT1.40: 0.23Total: 0.84Total: 0.773RRT0.96: 0.11RRT0.77: 0.42RRT0.97: 0.13RRT0.96: 0.11RRT1.04: <0.10RRT0.97: 0.13RRT1.05: 0.13RRT1.04: <0.10RRT1.06: <0.10RRT1.05: <0.10RRT1.09: 0.15RRT1.09: 0.16RRT1.11: 0.20RRT1.11: 0.18RRT1.24: 0.30RRT1.24: 0.28Total: 1.02Total: 1.296RRT0.75: <0.10RRT0.77: 0.19RRT0.77: 0.15RRT0.96: 0.13RRT0.96: 0.14RRT0.97: 0.13RRT0.97: 0.15RRT1.04: 0.18RRT1.04: 0.15RRT1.09: 0.14RRT1.09: 0.15RRT1.11: 0.25RRT1.12: 0.26Total: 1.02Total: 1.00 Dissolution:

[0489] For dissolution plots for the 50 µg and 200 µg see Figures 22-29Dissolution 0.1M HCl50 µg dose capsules;

[0490] Storage Condition Specification Time Point (Months) Result N / AInitial45 minutes Mean = 102.4%Min = 99.7%Max = 105.2%25°C / 60%RH145 minutes Mean = 104.3%Min = 102.0%Max = 107.5%NLT Q+5345 minutes Mean = 102.4%Min = 100.6%(Q = 75%) release at 45 minutes in HCl mediumMax = 104.7%645 minutes Mean = 100.8%Min = 98.2%Max = 102.6%945 minutes Mean = 101.4%Min = 99.3%Max = 104.8%1245 minutes Mean = 99.8%Min = 91.9%Max = 103.7%40°C / 75%RH145 minutes Mean = 101.4%Min = 100.7%Max = 101.7%345 minutes Mean = 100.2%Min = 96.8 %Max = 103.6%6 1< 45 minutes Mean = 96.2%Min = 77.6%Max = 105.4% 1< Low results are seen on the 40°C / 75%RH samples for assay. 200 µg dose capsules;

[0491] Storage Condition Specification Time Point (Months) Result N / AInitial45 minutes Mean = 99.9%Min = 92.7%Max = 104.5%25°C / 60%RH145 minutes Mean = 103.2%Min = 102.4%Max = 103.8%345 minutes Mean = 100.8%NLT Q+5Min = 97.2%Max = 102.2%(Q = 75%) release at 45 minutes in HCl medium645 minutes Mean = 101.2%Min = 99.9%Max = 102.6%945 minutes Mean = 102.9%Min = 101.4%Max = 104.9%1245 minutes Mean = 103.0%Min = 101.2%Max = 104.6%40°C / 75%RH145 minutes Mean = 101.4%Min = 96.6%Max = 103.5%345 minutes Mean = 100.6%Min = 100.4%Max = 100.9%645 minutes Mean = 98.6%Min = 96.9%Max = 101.4% Dissolution Phosphate Buffer pH 6.850 µg dose capsules;

[0492] Storage Condition Specification Time Point (Months) Result N / AInitial45 minutes Mean = 102.5%Min = 100.8%Max = 105.4%25°C / 60%RH145 minutes Mean = 100.4%Min = 99.8%Max = 100.9%345 minutes Mean = 105.8%Min = 103.9%NLT Q+5Max = 107.7%645 minutes Mean = 102.3%(Q = 75%) release at 45 minutes in HCl mediumMin = 99.3%Max = 107.2%945 minutes Mean = 106.8%Min = 102.9%Max = 109.5%1245 minutes Mean = 98.5%Min = 97.7%Max = 99.0%40°C / 75%RH145 minutes Mean = 96.4%Min = 95.5%Max = 97.3%345 minutes Mean = 98.7%Min = 98.2%Max = 99.4%6 1< 45 minutes Mean = 69.7%Min = 56.5%Max =77.3% 1< Low results are seen on the 40°C / 75%RH samples for assay. 200 µg dose capsules;

[0493] Storage Condition Specification Time Point (Months) Result N / AInitial45 minutes Mean = 100.3%Min = 99.6%Max = 101.0%25°C / 60%RH145 minutes Mean = 102.4%Min = 99.3%Max = 104.0%345 minutes Mean = 101.4%Min = 96.7%Max = 104.0%NLT Q+5645 minutes Mean = 97.8%Min = 96.0%(Q = 75%) release at 45 minutes in HCl mediumMax = 99.2%945 minutes Mean = 102.9%Min = 101.9%Max = 104.9%1245 minutes Mean = 89.9%Min = 88.9%Max = 91.1%40°C / 75%RH145 minutes Mean = 102.2%Min = 99.2%Max = 104.2%345 minutes Mean = 95.2%Min = 94.7%Max = 96.1%645 minutes Mean = 98.1%Min = 96.3%Max =99.5% Uniformity of dosage units:50 µg dose capsules;

[0494] Storage Condition Specification Time (months) Point Results N / AComplies with Ph. Eur 2.9.40InitialAV = 13.0 200 µg dose capsules;

[0495] Storage Condition Specification Time (months) Point Results N / AComplies with Ph. Eur 2.9.40InitialAV = 3.4 Identity:50 µg and 200 µg dose capsules;

[0496] Storage Condition Specification Time (months) Point Results N / ART of samples is ± 0.5 mins of the RT of reference standardInitialRT of samples is ± 0.5 mins of the RT of reference standardUV spectra matches that of the reference standardUV spectra matches that of the reference standard Micro:50 µg dose capsules;

[0497] Storage Condition Specification Method Time point (Months) Result N / ATAMC NMT 10 3< CFU / gPh. Eur. 2.6.12Initial135 cfu / gPh. Eur. 2.6.13<10 cfu / gRSSL method reference: P20-08080Absent in 1g25°C / 60%RHPh. Eur. 2.6.1212 months10 cfu / gTYMC NMT 10 2< CFU / gPh. Eur. 2.6.13<10 cfu / gRSSL method reference: P20-08080Absent in 1gAbsence of E. Coli40°C / 75%RHPh. Eur. 2.6.126 months<10 cfu / gPh. Eur. 2.6.13<10 cfu / gRSSL method reference: P20-08080Absent in 1g 200 µg dose capsules;

[0498] Storage Condition Specification Method Time point (Months) Result N / ATAMC NMT 10 3< CFU / gPh. Eur. 2.6.12Initial45 cfu / gPh. Eur. 2.6.1318 cfu / gRSSL method reference: P20-08080Absent in 1g25°C / 60%RHPh. Eur. 2.6.1212 months100 cfu / gTYMC NMT 10 2< CFU / gPh. Eur. 2.6.13<100 cfu / gRSSL method reference: P20-08080Absent in 1gAbsence of E. Coli40°C / 75%RHPh. Eur. 2.6.126 months<10 cfu / gPh. Eur. 2.6.13<10 cfu / gRSSL method reference: P20-08080Absent in 1g Example 8: Clinical trial Protocol: A Phase 1 / 2 Trial of Formulations comprising (N-(2-(tert-butyl)-1-((4,4-difluorocyclohexyl)methyl)-1H-benzimidazol-5-yl)ethanesulfonamide (50 µg and 200 µg) in Patients with Cancer Anorexia and Weight Loss Objectives: Stage 1 (Phase 1)Primary Objectives:

[0499] Determine the safety profile of the product in patients with cancer anorexia at different doses. Determine dose-limiting toxicity, if any, within the range of doses used during the 4 weeks after the first dose of the product. Determine the most effective, safe dose (recommended Phase 2 dose, or RP2D) to be used in Stage 2. Secondary Objectives:

[0500] Assess the activity of the product in the patient population in terms of increase in lean body mass, weight gain, and improvement of anorexia. Assess quality of life (QoL) of patients. Determine the pharmacokinetic profile of the product in the patient population. Assess any change in Karnofsky Performance Status (KPS) Exploratory Objectives:

[0501] Assess the anti-inflammatory and hormonal effects of the product. Assess any effect on mood of patients while on the trial. Assess the abuse potential of the product. Assess the opioid-sparing effects of the product. Stage 2 (Phase 2)Primary Objectives:

[0502] Determine point estimates of activity of the product in terms of weight gain, lean body mass, KPS, and improvement of anorexia at the RP2D at 12 weeks. Secondary Objectives:

[0503] Continue to assess the safety profile of the product in patients with cancer anorexia. Assess QoL of patients. Exploratory Objectives:

[0504] Assess the anti-inflammatory and hormonal effects of the product. Assess the mood of patients while on the trial. Assess the abuse potential of the product. Assess the physical activity of patients while on the trial based on activity reported by a wearable, physical activity monitor. Assess the opioid sparing effects of the product. Study Design:

[0505] Phase 1 dose escalation in Stage 1 to determine the dose of a randomized, doubleblind, placebo-controlled, Phase 2 trial in Stage 2Study Treatments:

[0506] In Stage 1, the product alone; in Stage 2, the product and placebo (4:1 randomization)Dose-Limiting Toxicity:

[0507] Dose-limiting toxicities are those that occur during the first 4 weeks of dosing with the product and that cannot be explained by the underlying malignancy, its treatment, comorbidities, or their treatment and are: Grade 3 or 4 myelotoxicity that does not reduce to ≤ Grade 2 within two weeks of onset despite adequate supportive therapy. Grade 3 or 4 non-haematological toxicity lasting for more than 4 days despite adequate supportive therapy or preventing the next scheduled dose from being administered within 4 days of scheduled day; for Grade 3 fatigue to be considered a Dose Limiting Toxicity (DLT), it must be present for more than 7 days. Any Grade 2 single adverse event or constellation of adverse events that, in the opinion of the patient, is intolerable. Stage 1 Dose-Escalation:

[0508] Dose levels are 150, 250, and 400 µg / dose / day. If in the 400 µg / dose / day dose group, no dose-limiting toxicities have been observed through 4 weeks and average weight gain of at least 2% body weight has not been achieved, a higher dose group up to 650 µg / dose / day may be explored in another 6 patients.Stage 2 Dose and design:

[0509] RP2D determined in Stage 1. Stage 2 is randomized, double-blind, placebo-controlled at the most active dose found in Stage 1. If the most active dose is not deemed safe, then the next lowest dose will be used. In the case the initial dose level is above the MTD, the participating Investigators and Medical Monitor with the consent of the Sponsor, may allow a lower dose level to be evaluated. Given that smallest capsule size is limited to 50 µg, the possible dose levels are 50 or 100 µg. Twenty-five patients will be randomized 4:1 (drug to placebo) in Stage 2.Number of Patients:

[0510] Assuming a screen failure rate of 15%, approximately 60 patients will be consented to enter the study, and up to 49 evaluable patients (up to 24 patients in Stage 1 and 25 in Stage 2) will receive study treatment.Study Population:

[0511] Patients with certain cancers who are on no anticancer therapy or stable daily doses of certain treatments and have documented weight loss of >5% body weight in the prior 6 months from signing the informed consent document (enrolment).Inclusion criteria:

[0512] 1. Have cancer (except those excluded by the exclusion criteria) documented by histopathology or cytology. 2. Have anorexia as determined by self-reported decrease or lack of appetite or aversion to food. 3. Have documented, unintentional weight loss of >5% of body weight in the past 6 months dating back from the date of enrolment. 4. Patients are on either: a. no anti-cancer therapy for the 2 weeks before enrolment and are not expected to have anti-cancer therapy for the first 12 weeks after the first dose of the product (Stage 1) or if in Stage 2, after the start of the product / placebo; or b. stable daily dosing from 2 weeks before enrolment and expected to be on such therapy for another 12 weeks of anti-cancer monotherapy therapy with hormonal therapy for breast, prostate, or uterine cancer or capecitabine for breast or colon cancer. 5. Estimated life expectancy of at least 12 weeks as judged by the Investigator based on clinical impression. 6. Have a KPS of >50. 7. At least 18 years of age at the time of enrolment. 8. Adequate haematological, renal, and hepatic function based on laboratory values obtained within 14 days of randomization: Absolute neutrophil count ≥ 1.0 X 109 / L Platelets ≥ 75 X 109 / L Serum creatinine ≤ 1.5 times upper limit of laboratory normal (ULN) Total serum bilirubin ≤ 1.5 times ULN ( ≤ 3.0 times ULN if patient has been diagnosed with Gilbert's syndrome) Aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (AP) ≤ 2.5 times ULN 9. For women of child-bearing potential and for men with partners of child-bearing potential, patient must agree to take contraceptive measures for duration of treatments and for 6 months after last study treatment. 10. Understand and voluntarily sign and date an Informed Consent Document ICD prior to any study related assessments / procedures. 11. Willing and able to adhere to the study visit schedule and other protocol requirements. 12. Willing to avoid sun exposure by using protective measures such as sunscreen, clothing, and sunglasses during therapy because the phototoxicity of the product has not been studied in animals. 13. Agree to not driving or operating heavy machinery for the first 4 weeks of treatment or longer if adverse events warrant as known adverse events of the product include dizziness and somnolence. Exclusion criteria:

[0513] 1. Primary brain tumours or symptomatic brain metastases. 2. Unable to swallow food or medication capsules. 3. Patients with oral mucositis or oral fungal infection causing anorexia or impairing taste. 4. Have a disorder that causes obstruction of the gastrointestinal tract or limits the absorption of calories such as bowel obstruction or celiac disease. 5. Receiving tube feedings or parenteral nutrition. 6. Be on, been on within 4 weeks prior to enrolment, or expected to be on medications that have the potential to affect anorexia or caloric intake. Examples of such medications include any synthetic or natural cannabinoid (inhaled or administered by any other route) and megestrol. 7. Corticosteroids are allowed if on a stable or tapering dose for 2 weeks prior to enrolment. Patients taking inhaled corticosteroids are permitted. 8. History of any recreational or illicit drug use, alcohol misuse, or other drug misuse. Current illicit drug use or recreational or medicinal use of cannabinoids is also excluded. 9. Known hypersensitivity to API or any of its excipients. A list of ingredients of the product will be provided to sites prior to the start of Stage 1 of the protocol. Prior to the start of Stage 2, the list of ingredients will be provided for placebo. 10. Pregnant or breast feeding. 11. Clinically significant depression requiring current use of antidepressant medications. 12. Condition other than cancer that could cause anorexia and / or weight loss such as AIDS, chronic obstructive pulmonary disease, chronic kidney disease, heart failure, or pathological eating disorder. 13. Uncontrolled, intercurrent illness including, but not limited to, ongoing or active infection requiring intravenous (IV) antibiotics & psychiatric illness / social situations that would limit compliance with study requirements. 14. Major surgery within 2 weeks prior to enrolment. 15. Any comorbid condition that confounds the ability to interpret data from the study as judged by the Investigator or Medical Monitor. 16. Known human immunodeficiency virus infection, acute or chronic hepatitis B, or acute hepatitis C infection. 17. Clinically significant ascites requiring or expected to require paracentesis. 18. Corrected QT intervals (QTc) intervals calculated according to Fridericia's formula (QTcF) >480 ms. 19. Anticipated need for anti-cancer therapy from 2 weeks prior to enrolment and 12 weeks after the first dose of the product or in Stage 2 the product / placebo. (Continued use of current daily-dose anti-cancer therapy is allowed.) 20. Investigational agent within 4 weeks prior to enrolment or expected need for an investigational agent for 12 weeks after the first dose of the product or in Stage 2 placebo. 21. Receiving radiotherapy within 2 weeks dating back from enrolment or anticipated to need radiotherapy within 12 weeks of enrolment. Short term palliative radiation treatment involving a local lesion is allowed. Formulations: As per Example 4 for 50 and 200 µg dosesOverview of Assessments:

[0514] Safety will be based on physical examinations, assessments of adverse events, vital signs, and electrocardiograms, and the results of haematology and chemistry tests and urinalysis. Pharmacokinetic parameters will be assessed. Activity will be assessed by changes in lean body mass, weight, body mass index, and degree of anorexia. In Stage 2, physical activity will be monitored by a wearable, physical activity monitor. The potential for drug abuse and opioid sparing effects will also be assessed.Statistical Analyses:

[0515] Descriptive statistics will be used to describe the multiple dose groups and in Stage 2 placebo for demographics and measures of safety and efficacy. Non-compartmental models will be used to describe pharmacokinetics. Any comparative analytical tests conducted after the trial data has been collected and unblinded will be considered hypothesis generating.Study Endpoints:Primary EndpointsSafety:

[0516] Analysis of the type of, frequency, and severity of adverse drug effects as determined by reported AEs and evaluation of routine chemistry and hematologic values, urinalyses, vital signs, and electrocardiograms. Assessment of type and incidence of dose-limiting toxicity (DLT). Most effective, safe dose (RP2D) to be used in Stage 2. Effectiveness is based primarily on the endpoint of lean body mass and weight gain at 4 weeks. Secondary Endpoints:Activity:

[0517] Change in lean body mass as determined by weight and DEXA scans. Change in anorexia as determined by a visual analog scale (VAS). Assess QoL using the Functional Assessment of Anorexia Cachexia Therapy (FAACT), the patient-generated subjective global assessment (PG-SGA), the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C15-PAL, and revised Edmonton Symptom Assessment Scale (ESAS-r) questionnaires. Change in KPS. Pharmacokinetics:

[0518] Determine the pharmacokinetics of API in patients with cancer anorexia by analysing the blood concentrations of API and metabolites over time. Exploratory Endpoints:Anti-inflammatory:

[0519] Change in sedimentation rate, C-reactive protein, and IL-6 levels. Hormonal:

[0520] Change in thyroid stimulating hormone (TSH), thyroxine (T4), luteinizing hormone (LH), and testosterone levels. Mood:

[0521] Change in mood as measured by the Beck's Depression Inventory-II (BDI-II). Abuse Potential:

[0522] Assess the abuse potential by the assessment of AEs that might suggest abuse and 4 VAS for drug liking, high, take drug again, and overall drug liking. Opioid-Sparing Effect

[0523] Decrease in opioid use for patients taking opioids medications as determined from patient diaries. Stage 2Primary EndpointsActivity:

[0524] Change in lean body mass as determined by weight and DEXA scans at 12 weeks. Change in anorexia as determined by a visual analog scale (VAS) and (FAACT) questionnaire. Change in KPS. Secondary EndpointsSafety:

[0525] Assessment of the safety profile of the product by analysing the type of, frequency, and severity of adverse drug effects as determined by reporting AEs and evaluation of routine chemistry and hematologic values, urinalyses, vital signs, and electrocardiograms. Quality of Life:

[0526] Assess QoL using the Functional Assessment of Anorexia Cachexia Therapy (FAACT), the patient-generated subjective global assessment (PG-SGA), the EORTC QLQ-C15-PAL, and revised Edmonton Symptom Assessment Scale (ESAS-r) questionnaires Exploratory EndpointsAnti-inflammatory:

[0527] Change in sedimentation rate, C-reactive protein, and IL-6 levels. Hormonal:

[0528] Change in TSH, T4, LH, and testosterone levels. Mood:

[0529] Change in mood as measured by the BDI-II. Abuse Potential

[0530] Assess the abuse potential by the assessment of AEs that might suggest abuse and 4 VAS for drug liking, high, take drug again, and overall drug liking. Physical Activity

[0531] Change in physical activity as determined by a wearable, physical activity monitor. Opioid-Sparing Effect Decrease in opioid use for patients taking opioids medications as determined from patient diaries. Duration of study participation

[0532] The expected duration of patient participation is 18 weeks, which includes 2 weeks of screening, 12 weeks of treatment, and 4 weeks for follow-up. Participation may be shorter if the patient is prematurely withdrawn. During Stage 2, participation may be up to 34 weeks if patients are randomized to receive placebo and go on to receive the product (see below). The study duration will be divided into pre-treatment, treatment, and follow-up periods. Cycle length is 28 days.

Claims

1. A pharmaceutical composition for oral use comprising as an active substance N-(2-(tert-butyl)-1-((4,4-difluorocyclohexyl)methyl)-1H-benzimidazol-5-yl)ethanesulfonamide, or a pharmaceutically acceptable salt thereof, and a non-aqueous solvent for the active substance wherein: (i) the pharmaceutical composition comprises 0.001% (+ / - 10%) to 0.8% (+ / - 10%) w / w of the active substance by weight of the total pharmaceutical composition; (ii) the pharmaceutical composition comprises at least 20% w / w of the non-aqueous solvent by weight of the total pharmaceutical composition and the non-aqueous solvent comprises polyethylene glycol having an average molecular weight of between 400 and 10000 g / mol.

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

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

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

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

6. The pharmaceutical composition according to the preceding claims wherein the pharmaceutical composition comprises 0.1 to 0.4% w / w of the active substance by weight of the total pharmaceutical composition.

7. The pharmaceutical composition according to any preceding claim wherein the active substance is stable in the pharmaceutical composition for at least 2 weeks, 1, 2, 3, 6, 12, or 24 months.

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

9. The pharmaceutical composition according to any preceding claim wherein the active substance is homogenously distributed throughout the non-aqueous solvent and optionally wherein the active substance is homogenously distributed throughout the non-aqueous solvent for at least 2 weeks, 1, 2, 3, 6, 12, or 24 months.

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

11. An immediate release pharmaceutical formulation for oral use comprising the pharmaceutical composition according to the preceding claims.

12. The immediate release pharmaceutical formulation according to claim 11 wherein when the immediate release pharmaceutical formulation is subjected to a content uniformity test as described in the European Pharmacopeia the acceptance value is less than 15 and / or the immediate release pharmaceutical formulation is an immediate release capsule formulation.

13. The pharmaceutical composition according to claims 1 to 10 or the immediate release pharmaceutical formulation according to claims 11 and 12 for use as a medicament.

14. The pharmaceutical composition or the immediate release pharmaceutical formulation according to claim 13 for use in a disease state or disorder in which dysfunction of CB1 and / or CB2 receptors are present or implicated.

15. The pharmaceutical composition or the immediate release pharmaceutical formulation according to claims 13 or 14 for use in the treatment of an anorexia associated condition; a cachexia associated condition; or anorexia nervosa.