Novel pharmaceutical formulation of golexanolone

Abstract

An oral pharmaceutical formulation comprising the compound golexanolone and a vehicle comprising (A) a mixture of mono-di-and triglycerides of caprylic acid (C8) and capric acid (C10); (B) a mixture of fatty acid esters with a melting point (m.p.) of 30-45°C; and optionally (C) a triglyceride comprising caprylic acid (C8) in amount of 50-80 % and capric acid (C10) in an amount of 20-50 %; wherein the amount of golexanolone in the pharmaceutical formulation is from 16 to 43 % by weight of the total weight of the pharmaceutical formulation.

Description

[0001] NOVEL PHARMACEUTICAL FORMULATION OF GOLEXANOLONE

[0002] FIELD OF THE INVENTION

[0003] The present invention is directed to a novel pharmaceutical formulation of golexanolone and the use thereof in therapy, such as for the treatment of a CNS disorder, a liver disorder or an autoimmune disorder.

[0004] BACKGROUND OF THE INVENTION

[0005] One of the largest challenges in pharmaceutical drug development is that drug compounds very often are insoluble, or poorly soluble, in aqeous media. Insufficient drug solubility in turn means insufficient bioavailability and poor plasma exposure of the drug when administered to subjects such as humans and animals.

[0006] It is estimated that between 40% and 70 % of all new chemical entities identified in drug discovery programs are insufficiently soluble in aqeous media (M. Lindenberg, S et al.: European Journal of Pharmaceutics and Biopharmaceuticals, vol. 58, no.2, pp. 265-278, 2004; D.J. Hauss: Drugs and Pharmaceutical Sciences, Vol. 170, pp. 1-339, Informa Healthcare NC, 2007 ; Gupta, 5 et a!.: International Scholarly Research Notices, vol. 2013, Article ID 848043, 16 pages, 2013, http: / / dx.doi.org / 10.1155 / 2013 / 848043

[0007] Scientists have investigated various ways of solving the problem with low drug solubility in order to enhance bioavailability of poorly absorbed drugs, aiming at increasing their clinical efficacy when administered orally. Technologies such as increase of the surface area and hence dissolution may sometimes solve solubility problems. Other techniques that may also solve bioavailability problems are addition of surfactants and polymers. However, each chemical compound has its own unique chemical and physical properties, and hence have its own different challenges when being formulated into a pharmaceutical drug that can exert its clinical efficacy.

[0008] Formulating a drug in different types of lipids are useful for particular drugs. Lipid formulations for oral administration generally consist of a drug dissolved in a blend of excipients with a wide variety of physicochemical properties ranging from pure triglyceride oils, mono-and diglycerides, and a substantial portion of lipophilic or hydrophilic surfactants and co-solvents. The main considerations in selecting appropriate excipients for any lipid-based formulation is identifying one or more excipients which have the ability to solubilise the complete dose and which at the same time provides a formulated unit dosage of the drug that can be taken orally and being of a size that can be swallowed by the patient. Usually, the drug load in combination with the size of a tablet or capsule is a limitating factor.

[0009] Lipid-based formulations may contain one lipid only, or a mixture of different types of lipids in combination. It is also common that in formulating a poorly soluble drug, it is required to also include one or more additional excipients to obtain a satisfactory solublity as well as drug stability.

[0010] Pharmaceutical formulations comprising several types of lipid systems in combination often tend to be complicated to produce and hence the cost of goods (COGS) increases.

[0011] Self-Emulsifying Drug Delivery Systems (SEDDS) may be useful to formulate poorly soluble drugs. However, very few lipid based formulations have reached the pharmaceutical market place. The edible oils which represent the logical and preferred lipid excipient choice for the development of SEDDS, are not frequently selected due to their poor ability to dissolve large amounts of lipophilic drugs. The self-emulsifiyng properties also require the incorporation of relatively large amounts of surfactant in the formulation in addition to the oily drug carrier vehicle.

[0012] A mixture of mono- and diglycerides of caprylic / capric acid (Akoline) is an emulsifyer of natural origin that is preferred since it is considered as more safe than synthetic commercially available surfactants. However, it is recognized among scientists in the pharmaceutical field that such excipients have limited self-emulsification efficiency (P.P. Constantinides; Pharmaceutical Research, vol. 12, no. 11. Pp. 1561-1572, 1995).

[0013] Usually, the surfactant concentration ranges between 30 and 60% of the total formulation in order to form SEDDS (C.W. Pouton; International Journal of Pharmaceutics, vol. 27, no. 2-3, pp. 335-348, 1985). Large amounts of surfactants may cause Gl irritations. The surfactants involved in the formulation of SEDDS should have a relatively high HLB and hydrophilicity to enable rapid and facile dispersion in the aqeous Gl fluid as a very fine oil-in-water emulsion, and hence good self-emulsifying performance can be achieved. Also, one or more co-solvents are often added to the formulation to assist in solubilising high concentrations of the drug. The compound golexanolone (3a-ethynyl-3p-hydroxyandrostan-17-one oxime) is a compound currently in clinical development for the treatment of Hepatic Encephalopathy (HE), Primary Biliary Cholangitis (PBC) and Parkinsons Disease (PD). One of the problems with this compound is that it has a poor solubility in aqeous media. Further, the high dose required for therapeutic efficacy means that the patient has to take many capsules each day. There is thus a need for a pharmaceutical formulation which can offer a drug load which is sufficient to provide a clinically and commercially feasible drug product, offering patient convenience with regard to the number of doses which a patient has to take each day while maintaining the therapeutic dose for a particular disease.

[0014] Golexanolone is disclosed in WO 2008 / 063128 for use in various CNS disorders. WO 2015 / 114308 discloses the use of golexanolone for the treatment of Hepatic Encephalopathy (HE).

[0015] US2017 / 0348323 discloses a method for the treatment of hypersomnolence by administering golexanolone. WO 2022 / 223526 discloses golexanolone for use in chronic liver diseases such as Primary Biliary Cholangitis (PBC) and symptoms related thereto. WO 2019 / 102040 discloses a pharmaceutical formulation of the compound golexanolone in form of a lipid solution.

[0016] WO 2024 / 133831 discloses golexanolone for use in the treatment of Parkinsons Disease.

[0017] BRIEF DESCRIPTION OF THE INVENTION

[0018] The present invention is directed to an oral pharmaceutical formulation, comprising:

[0019] (i) 3a-ethynyl-3p-hydroxyandrostan-17-one oxime (golexanolone)

[0020] (ii) a vehicle comprising

[0021] (A) a mixture of mono-di-and triglycerides of caprylic acid (C8) and capric acid (CIO); and

[0022] (B) a mixture of fatty acid esters with a melting point (m.p.) of 30-45°C; wherein: the amount of golexanolone in the pharmaceutical formulation is from 16 to 43 % by weight of the total weight of the pharmaceutical formulation. BRIEF DESCRIPTION OF DRAWINGS

[0023] Figure 1A is a graph showing that the plasma concentration of golexanolone in minipigs.

[0024] Figure IB is a graph showing the drug exposure of golexanolone (Area Under the Curve, AUC) in minipigs.

[0025] DESCRIPTION OF THE INVENTION

[0026] The steroid compound 3a-ethynyl-3p-hydroxyandrostan-17-one oxime (Compound I)

[0027] (golexanolone) has a poor solubility in aqueous media. Moreover the drug load in lipid solutions is low and it is therefore difficult to reach a clinically therapeutic dose without giving patients an excessive number of drug doses or drug units. In order to make it possible to formulate this compound into a pharmaceutical drug product providing a sufficient drug load, and hence enabling the drug product to exert a clinically sufficient therapeutic effect without having to give a high number of daily doses, a new pharmaceutical formulation has been developed.

[0028] An object with the present invention is a pharmaceutical formulation of golexanolone providing a sufficiently high drug load which in turn makes it possible to minimize the amount of dosages per day for a patient being treated with golexanolone.

[0029] One aspect of the present invention is an oral pharmaceutical formulation, comprising:

[0030] (i) the compound golexanolone; and

[0031] (ii) a vehicle comprising

[0032] (A) a mixture of mono-di-and triglycerides of caprylic acid (C8) and capric acid (CIO); and

[0033] (B) a mixture of fatty acid esters with a melting point (m.p.) of 30-45°C; wherein the amount of golexanolone in the pharmaceutical formulation is from 16 to 43 % by weight of the total weight of the pharmaceutical formulation. The melting point (m.p.) of the mixture of fatty acid esters as herein described is determined in accordance with the method of monograph 2.2.15 (Melting point - Open capillary method) of the European Pharmacopeia 6.0.

[0034] One aspect of the invention is a pharmaceutical formulation as herein described, wherein the total amount of the vehicle is from 57 to 84 % by weight of the total weight of the pharmaceutical formulation.

[0035] One aspect of the invention is a pharmaceutical formulation as herein described, comprising the mixture of fatty acid esters (B) as thickening agent.

[0036] One aspect of the present invention is an oral pharmaceutical formulation as herein described, wherein the mixture of fatty acid esters (B) is a hard fat (Adeps solidus).

[0037] One aspect of the present invention is an oral pharmaceutical formulation as herein described, wherein the mixture of fatty acid esters (B) is a hard fat (Adeps solidus), and the hard fat has a melting point (m.p.) of about 30 to 40 °C.

[0038] One aspect of the present invention is an oral pharmaceutical formulation as herein described, wherein the mixture of fatty acid esters (B) is a hard fat (Adeps solidus), wherein the hard fat comprises up to 100 % by weight triglycerides comprising caprylic acid (C8), capric acid (CIO), myristic acid (C14), and stearic acid (C18).

[0039] An example of the mixture of fatty acid esters which may be useful in accordance with the invention as thickening agent is Softisan 378® (IOI Oleochemical GmbH, Germany).

[0040] One aspect of the present invention is an oral pharmaceutical formulation as herein described, wherein the vehicle further comprises (C) a triglyceride comprising caprylic acid (C8) in amount of 50- 80 % and capric acid (CIO) in an amount of 20-50 %.

[0041] One aspect of the present invention is an oral pharmaceutical formulation as herein described, wherein the triglyceride (C) is a medium chain triglyceride (MCT). Medium-chain triglycerides (MCT) which may be useful as component (C) in a vehicle according to the invention are medium-chain triglycerides (MCT) comprising caprylic acid (C8) in amount of 50-80 %; capric acid (CIO) in an amount of 20-50 %; and optionally caproic acid (C6) in a maximum amount of 2%, and / or optionally lauric acid (C12) in a maximum amount of 3 %; and / or optionally myristic acid (C14) in a maximum amount of 1 %.

[0042] One aspect of the present invention is an oral pharmaceutical formulation, comprising:

[0043] (i) the compound golexanolone;

[0044] (ii) a vehicle comprising

[0045] (A) a mixture of mono-di-and triglycerides of caprylic acid (C8) and capric acid (CIO);

[0046] (B) a mixture of fatty acid esters with a melting point (m.p.) of 30-45°C; and

[0047] (C) a triglyceride comprising caprylic acid (C8) in amount of 50-80 % and capric acid (CIO) in an amount of 20-50 %; wherein: the amount of golexanolone in the pharmaceutical formulation is from 16 to 43 % by weight of the total weight of the pharmaceutical formulation.

[0048] One aspect of the present invention is an oral pharmaceutical formulation as herein described, wherein said formulation is a suspension. In said suspension, the compound golexanolone is suspended in the mixture formed by the mixture of the mono-di-and triglycerides of caprylic acid (C8) and capric acid (CIO) (A) and the mixture of fatty acid esters with a melting point (m.p.) of 30- 45°C (B) and, optionally, the triglyceride comprising caprylic acid (C8) in amount of 50-80 % and capric acid (CIO) in an amount of 20-50 % (C) used as vehicle. The suspension may be a solid, semisolid or waxy suspension. In one aspect of the invention, the suspension is a solid suspension or a waxy suspension.

[0049] One aspect of the present invention is an oral pharmaceutical formulation as herein described, wherein the vehicle comprises 30-95 % by weight of the mixture of mono-di-and triglycerides (A), and 5-30 % by weight of the mixture of fatty acid esters (B).

[0050] One aspect of the present invention is an oral pharmaceutical formulation as herein described, wherein the vehicle comprises 95 % by weight of the mixture of mono-di-and triglycerides (A) and 5 % by weight of the mixture of fatty acid esters (B). One aspect of the present invention is an oral pharmaceutical formulation as herein described, wherein the vehicle comprises 30-50 % by weight of the mixture of mono-di-and triglycerides (A), 5- 30 % by weight of the mixture of fatty acid esters (B), and 30-50 % by weight of the triglyceride (C).

[0051] One aspect of the present invention is an oral pharmaceutical formulation as herein described, wherein the vehicle comprises 35 % by weight of the mixture of mono-di-and triglycerides (A), 30 % by weight of the mixture of fatty acid esters (B), and 35 % by weight of the triglyceride (C).

[0052] One aspect of the present invention is an oral pharmaceutical formulation as herein described, wherein the vehicle comprises 47.5 % by weight of the mixture of mono-di-and triglycerides (A), 5 % by weight of the mixture of fatty acid esters (B), and 47.5 % by weight of the triglyceride (C).

[0053] In one aspect of the invention, the mixture of mono-di-and triglycerides (A) further comprises caproic acid (C6).

[0054] In one aspect of the invention, the mixture of mono-di-and triglycerides (A) further comprises lauric acid (C12).

[0055] In one aspect of the invention, the mixture of mono-di-and triglycerides (A) further comprises one or more of myristic acid (C14), palmitic acid (C16) and / or stearic acid (C18).

[0056] One aspect of the invention is an oral pharmaceutical formulation consisting of the compound golexanolone and the vehicle only.

[0057] One aspect of the invention is a pharmaceutical formulation as herein described, wherein the amount of the compound golexanolone in the pharmaceutical formulation is from 16 to 32 % by weight of the total weight of the pharmaceutical formulation.

[0058] One aspect of the invention is a pharmaceutical formulation as herein described, wherein the amount of the compound golexanolone is 16 % by weight of the total weight of the formulation.

[0059] One aspect of the invention is a pharmaceutical formulation as herein described, wherein the amount of vehicle is 84 % by weight of the total weight of the formulation. One aspect of the invention is a pharmaceutical formulation as herein described, wherein said pharmaceutical formulation is comprised in a capsule.

[0060] One aspect of the invention is a pharmaceutical formulation as herein described, wherein said pharmaceutical formulation is comprised in a hard capsule or a soft capsule.

[0061] One aspect of the invention is a pharmaceutical formulation as herein described, wherein said pharmaceutical formulation is comprised in a hard gelatin capsule or a soft gelatin capsule.

[0062] One aspect of the invention is a pharmaceutical formulation or a capsule as herein described, wherein said pharmaceutical formulation or capsule is administered once daily or twice daily.

[0063] The present invention is completely unexpected in that it is possible to obtain a pharmaceutical formulation of golexanolone with a drug load when formulated into a drug product, which in turn provides a drug product with higher bioavailability and drug exposure compared to the prior art. This may also provide the advantage that the number of daily doses or drug units which a patient needs to take in order to achieve a therapeutic efficacy may be reduced, which is beneficial from a patient compliance perspective. The cost of goods (COGS) may also be reduced due to the listed advantages.

[0064] DEFINITIONS

[0065] The compound 3a-ethynyl-3|3-hydroxyandrostan-17-one oxime has the INN (International Nonproprietary Name) golexanolone, having the chemical structure

[0066] The wording "poorly soluble" as used herein when discussing the solubility in aqueous media of the compound golexanolone, refers to a solubility in the pg / ml magnitude. The solubility of golexanolone was shown to be as low as 1.5 pg / ml in water, 0.2 pg / ml in SGF (Simulated Gastric Fluid), 7 pg / ml in FaSSIF (Fasted State Simulated Intestinal) and 19 pg / ml in FeSSIF (Fed State Simulated Intestinal Fluid). The wording "bioequivalent product" or "product showing bioequivalence" is herein defined as a product which comprises the compound golexanolone as therapeutic agent, in the same oral dosage form and the same dosage amount, or concentration, of said compound, and which has an identical AUC + 20 % and / or an identical Cmax + 20 %, and which shows the same or similar therapeutic effect.

[0067] The wording "Cmax" is herein defined as the maximum plasma concentration of the therapeutic compound golexanolone, which is reached at a specific time point from the time of administering the compound to an animal or human subject.

[0068] The wording "AUC" (Area Under the Curve) is used herein in accordance with its common meaning as a measure of drug absorption. A larger AUC means that the drug has a higher drug absorption in a subject, whereas a smaller AUC means that the drug has a lower drug absorption.

[0069] The wording "PK" as used throughout the specification relates to the pharmacokinetic properties for a compound being investigated.

[0070] The wording "once daily" as used herein, means that the compound golexanolone, is administered to a subject only once each day in a specified dose.

[0071] The wording "twice daily" or "BID" as used herein, means that the compound golexanolone, is administered twice each day in a specified dose.

[0072] The wording "vehicle" as used herein relates to a mixture of pharmaceutically acceptable excipients used for forming the pharmaceutical formulation of the invention and is defined as a mixture of

[0073] • the mixture of mono-di-and triglycerides of caprylic acid (C8) and capric acid (CIO) (A); and

[0074] • the mixture of fatty acid esters with a melting point (m.p.) of 30-45°C (B), and

[0075] • optionally, the triglyceride comprising caprylic acid (C8) in amount of 50-80 % and capric acid (CIO) in an amount of 20-50 % (C).

[0076] In one aspect of the invention as herein described, the "vehicle" is a mixture of mono-di-and triglycerides of caprylic acid (C8) and capric acid (CIO) (A) and a hard fat (Adeps solidus) (B). In yet an aspect of the invention as herein described, the "vehicle" is a mixture of mono-di-and triglycerides of caprylic acid (C8) and capric acid (CIO) (A), a hard fat (Adeps solidus) (B), and a medium chain triglyceride (MCT) (C).

[0077] The wording "medium-chain triglyceride (MCT)" as used herein, is a triester comprising caprylic acid (C8) in amount of 50-80 % and capric acid (CIO) in an amount of 20-50 %, and may optionally comprise caproic acid (C6) in a maximum amount of 2% and / or optionally acid lauric acid (C12) in a maximum amount of 3 %, and / or optionally myristic acid (C14) in a maximum amount of 1 %. Each of the three fatty acids in the medium-chain triglyceride (MCT) may be the same or different from each other.

[0078] The wording triglyceride (triacylglycerol or triacylglyceride) means an ester derived from glycerol and three fatty acids.

[0079] The wording thickening agent as used herein means a compound which has the function of rendering the vehicle as herein described solid, semisolid or waxy at room temperature.

[0080] The wording "hard fat (Adeps solidus)" is used herein in accordance with definition of the European Pharmacopoeia 6.0 and relates to a mixture of monoglycerides, diglycerides and triglycerides of higher saturated fatty acids such as CIO to C18. A hard fard as used in accordance with the invention may have a melting point of about 30°C to 45°C. Further, a hard fat as used in accordance with the invention may comprise up to 100 % by weight triglycerides of caprylic acid (C8), capric acid (CIO), myristic acid (C14), and stearic acid (C18).

[0081] Imwitor®742 (IOI Oleochemical GmbH, Germany) is a mixture of mono-di-and triglycerides of caprylic acid(C8) and capric acid (CIO), and may optionally also comprise up to 3 % of caproic acid (C6) and / or up to 3 % of lauric acid (C12) and / or up to 1 % of myristic acid (C14) and / or up to 0.1 % of palmitic acid (C16) and / or up to 0.1 % of stearic acid (C18).

[0082] Softisan® 378 (IOI Oleochemical GmbH, Germany) is classified as a hard fat according to the Pharmacopeia (EP / NF / JPE) and comprises triglycerides of the fatty acids caprylic acid (C8); capric acid (CIO); myristic acid (C14); and stearic acid (C18).

[0083] The wording "drug load” as used herein means the amount of golexanolone that can be incorporated (forming part of) in the oral pharmaceutical formulation of the invention. The wording "final drug product" means a capsule comprising a formulation of golexanolone as herein described and claimed.

[0084] The singular forms "a", "an", and "the" as used throughout this specification also include plural referents unless the context clearly states otherwise.

[0085] The wording "about" as used herein means a deviation of + / - 2%, or + / - 5%, or + / - 10 %, of a given numerical value.

[0086] PHARMACEUTICAL FORMULATIONS AND DOSING

[0087] An aspect of the invention is a pharmaceutical formulation as herein described, wherein said pharmaceutical formulation is administered once daily.

[0088] An aspect of the invention is a pharmaceutical formulation as herein described, wherein said pharmaceutical formulation is administered twice daily.

[0089] An aspect of the invention is a pharmaceutical formulation as herein described, wherein said formulation is filled into a capsule.

[0090] An aspect of the invention is a capsule comprising a pharmaceutical formulation as herein described, wherein said capsule is administered once daily.

[0091] An aspect of the invention is a capsule comprising a pharmaceutical formulation as herein described, wherein said capsule is administered twice daily.

[0092] One aspect of the invention is a capsule as herein described comprising from 20 to 320 mg of the compound golexanolone.

[0093] One aspect of the invention is a capsule as herein described, wherein the amount of the compound golexanolone in said capsule is from 80 to 160 mg.

[0094] One aspect of the invention is a capsule as herein described, wherein the amount of the compound golexanolone in said capsule is selected from any one of 40 to 320 mg; 60 to 320 mg; 80 to 320 mg; 100 to 320 mg; 120 to 320 mg; 140 to 320 mg; 160 to 320 mg; 180 to 320 mg; 200 to 320 mg; 220 to 320 mg; 240 to 320 mg; 260 to 320 mg; 280 to 320 mg; and 300 to 320 mg.

[0095] One aspect of the invention is a capsule as herein described, wherein the amount of the compound golexanolone in said capsule is selected from any one of 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 260 mg, 270 mg, 280 mg, 290 mg, 300 mg, 310 mg and 320 mg.

[0096] One aspect of the invention, is a capsule as herein described, comprising 20 mg of the compound golexanolone and wherein the capsule has a total fill weight of 125 mg, corresponding to a drug load of 16 % golexanolone.

[0097] One aspect of the invention is a capsule as herein described comprising 40 mg of the compound golexanolone and wherein the capsule has a total fill weight of 250 mg, corresponding to a drug load of 16 % golexanolone.

[0098] One aspect of the invention is a capsule as herein described, comprising 80 mg of the compound golexanolone and wherein the capsule has a total fill weight of 500 mg, corresponding to a drug load of 16 % golexanolone.

[0099] One aspect of the invention is a capsule as herein described comprising 160 mg of the compound golexanolone and wherein the capsule has a total fill weight of 500 mg, corresponding to a drug load of 32% golexanolone.

[0100] One aspect of the invention is a capsule as herein described comprising 160 mg of the compound golexanolone and wherein the capsule has a total fill weight of 1000 mg, corresponding to a drug load of 16 % golexanolone.

[0101] One aspect of the invention is a capsule as herein described comprising 215 mg of the compound golexanolone and wherein the capsule has a total fill weight of 500 mg, corresponding to a drug load of 43 % golexanolone.

[0102] Yet an aspect of the invention is a drug product which is bioequivalent to a pharmaceutical formulation or bioequivalent to a combination, as herein described and claimed. MEDICAL USES AND MEDICAL TREATMENT

[0103] One aspect of the invention, is a pharmaceutical formulation, or a capsule as herein described, in particular a capsule comprising a pharmaceutical formulation as herein described, for use in the treatment of a CNS disorder such as Parkinsons Disease (PD).

[0104] One aspect of the invention is a pharmaceutical formulation, or a capsule as herein described, in particular a capsule comprising a pharmaceutical formulation as herein described, for use in the treatment of a liver disorder such as Type A, Type B or Type C Hepatic Encephalopathy (HE).

[0105] One aspect of the invention is a pharmaceutical formulation, or a capsule as herein described, in particular a capsule comprising a pharmaceutical formulation as herein described, for use in the treatment of an an autoimmune disease in the bile duct such as Primary Biliary Cholangitis (PBC) including symptomatic PBC treatment such as cognititive symptoms, fatigue symptoms, motor symptoms and any other symptom related to Primary Biliary Cholangitis (PBC).

[0106] Also included in the present invention is combination therapy with a Standard of Care agent used in the treatment of Parkinsons Disease (PD), Hepatic Encephalopathy (HE), or Primary Biliary Cholangitis (PBC).

[0107] ADMINISTRATION ROUTES

[0108] The pharmaceutical formulation as herein described and claimed is suitable for oral administration. In particular, the pharmaceutical formulation as herein described and claimed is administered orally.

[0109] GENERAL PROCESS FOR THE PREPARATION OF FORMULATIONS

[0110] A pharmaceutical formulation according to the present invention may be manufactured by the process described below.

[0111] The compound golexanolone (3a-Ethynyl-3p-hydroxyandrostan-17-one oxime) may be prepared by following the synthetic procedure as decribed in the published patent application WO 2008 / 053128.

[0112] Step I - Manufacture of the vehicle

[0113] Each of the mixture of mono-di-and triglycerides of caprylic acid (C8) and capric acid (CIO) (A) and the mixture of fatty acid esters (B) and, optionally, the triglyceride (C) are weighed in in the respective amount and thereafter placed under magnetic stirring in a heat chamber or on a heating plate set to a temperature providing a homogeneous solution of each component (45°C).

[0114] Each component of A, B and C (where applicable) is weighed in the intended ratio and mixed at 37°C for 1 hour or until a clear solution (premix) is obtained.

[0115] If needed, any of components A, B and C (where applicable) are placed in a heating chamber at the melting temperature of said components for at least about 2 hours prior to use, and is maintained in the heat chamber until the time for mixing with the other component(s).

[0116] Step II - Manufacture of the pharmaceutical formulation

[0117] The API golexanolone is weighed and mixed with the homogenous premix (vehicle) under agitation at room temperature until a homogenous white opaque formulation is obtained. If the pharmaceutical formulation solidifies, the temperature should be increased to a temperature allowing agitation and capsule filling.

[0118] Step III - Capsule filling

[0119] A pre-weighted softgel capsule of the size suitable for a particular dose of golexanolone is filled with a pharmaceutical formulation as prepared according to step (II) above. The filling is performed by using an 18G needle and a 2 ml syringe. During the aspiration of the pharmaceutical formulation prepared in step II, bubbles shall be avoided.

[0120] The capsules are filled with the syringe content until the desired formulation weight is obtained. Thereafter the needle is removed from the capsule and the correct weight is verified, with any adjustment if needed.

[0121] The capsules are thereafter sealed by applying a sealing solution of melted capsules on the hole from the syringe. The capsules are then dried at room temperature for about 2 hours. EXAMPLES

[0122] Example 1

[0123] A pharmaceutical formulation comprising 20 mg / capsule of golexanolone was prepared by following the general process described above. The formulation consisted of the ingredients shown in Table 1 below.

[0124] Table 1 l1)A mixture of mono-di-and triglycerides of caprylic acid (C8) and capric acid (CIO)

[0125] (2)A hard fat lmwitor®742 was purchased from 101 Oleochemical GmbH, Germany. Softisan® 378 (hard fat) was purchased from 101 Oleochemical GmbH, Germany. The API golexanolone was provided in-house by Umecrine Cognition AB (manufactured as described above).

[0126] The hard fat Softisan®378 and lmwitor®742 were treated at 45°C for a half day. An aliquot of 0.84 grams of Softisan®378 was taken out and added to a beaker with 15.96 grams of lmwitor®742 corresponding to a weight ratio of 95:5 (95 % lmwitor®742 and 5 % Softisan® 378). The mixture was stirred at room temperature for 1 hour until a clear solution (premix) was obtained.

[0127] Golexanolone (3.2 grams) was weighed in and added to the premix at room temperature. The mixture was homogenized under stirring until a white opaque formulation was visually observed.

[0128] The obtained pharmaceutical formulation was filled in softgel capsules according to the general procedure described above:

[0129] Nitrogen filled 10 Oval capsules were tared and filled with the partial suspension prepared. The target fill weight was 125 mg resulting in a strength of 20 mg golexanolone / capsule (i.e. 20 mg of the capsule content was golexanolone and 105 mg of the capsule content was vehicle). During the filling, the suspension was kept under stirring to avoid resolidification of the formulation. Filling was performed by careful injection of the suspension using a 18G needle with a 2mL syringe. The weight was controlled and adjusted if needed. Once the correct weight was obtained the capsule was sealed. Sealing solution was prepared using 15-20 units of 10 Oval nitrogen-filled capsules that were melted at 70°C in approx. 7.5 mL of demineralized water. The melt was homogenized using a spatula to result in a viscous liquid. The surface of the filled capsule was cleaned with an absorbent paper moistened with ethanol. The sealing solution was applied to the whole in the capsule to cover it entirely. The capsules were dried at room temperature for approx. 2 hours. Tightness was controlled by visual observation.

[0130] Example 2

[0131] A pharmaceutical formulation comprising golexanolone was prepared by following the general process described above. The formulation consisted of the ingredients shown in Table 2 below.

[0132] Table 2

[0133] (1)A medium chain triglyceride (MCT)

[0134] (2)A mixture of mono-di-and triglycerides of caprylic acid (C8) and capric acid (CIO)

[0135] (3)A hard fat

[0136] Miglyol®812N, lmwitor®742 and Softisan®378 were purchased from 101 Oleochemical GmbH, Germany. The API golexanolone was provided in-house by Umecrine Cognition AB (manufactured as described above).

[0137] The hard fat Softisan®378 and Imwitor® 742 were treated at 45°C for a half day. An aliquot of 5.04 grams of Softisan®378 and 5.88 grams of Imwitor 742 were taken out and added to a beaker with 5.88 grams of Miglyol® corresponding to a weight ratio of 35:35:30 (35 % Miglyol®812N, 35 % lmwitor®742, and 30 % Softisan® 378). The mixture was stirred at 700 rpm at 37°C in a water bath for 1 hour until a clear solution (premix) was obtained. Golexanolone (3.2 grains) was weighed in and added to the premix at room temperature. The mixture was homogenized under stirring at 500 rpm at room temperature until a white opaque formulation was visually observed.

[0138] Example 3

[0139] A pharmaceutical formulation comprising golexanolone was prepared by following the general process described above. The formulation consisted of the ingredients shown in Table 3 below.

[0140] Table 3

[0141] (1)A medium chain triglyceride (MCT)

[0142] (2)A mixture of mono-di-and triglycerides of caprylic acid (C8) and capric acid (CIO)

[0143] (3)A hard fat

[0144] Miglyol®812N, lmwitor®742 and Softisan®378 were purchased from 101 Oleochemical GmbH, Germany. The API golexanolone was provided in-house by Umecrine Cognition AB (manufactured as described above).

[0145] The hard fat Softisan®378 and lmwitor®742 were treated at 45°C for a half day. An aliquot of 0.84 grams of Softisan®378 and 7.98 grams of lmwitor®742 were taken out and added to a beaker with 7.98 grams of Miglyol® corresponding to a weight ratio of 47.5:47.5:5 (47.5 % Miglyol®812N, 47.5 % lmwitor®742, and 5 % Softisan® 378). The mixture was stirred at 700 rpm at 37°C in a water bath for 1 hour until a clear solution (premix) was obtained.

[0146] Golexanolone (3.2 grams) was weighed in and added to the premix at room temperature. The mixture was homogenized under stirring at 500 rpm at room temperature until a white opaque formulation was visually observed. Comparative Example

[0147] A pharmaceutical formulation for use in the comparative biological study described below was prepared. The formulation comprising 10 mg golexanolone was prepared by following the general process described in WO 2019 / 102040. The formulation in the form of a solution consisted of the ingredients shown in Table 4 below.

[0148] Table 4

[0149] The obtained solution was filled in softgel capsules by using fully automated softgel capsule filling.

[0150] The size of the softgel capsules had an approximate length of 1.56 cm and an approximate width of 0.98 cm, and had an oval shape.

[0151] The total fill weight was 500 mg, with 10 mg golexanolone and 490 mg vehicle (Imwitor® 742) in the capsule. No other excipients were added to the capsule.

[0152] BIOLOGICAL STUDIES

[0153] / . Comparative Pharmacokinetic (PK) Study in minipigs

[0154] Four Male Naive Gottingen Minipigs, weighing about 8-10 kg and 4-5 months of age at dosing, were supplied for use in this study. The animals were supplied to Charles River Edinburgh by a recognised supplier of Laboratory Animals, Ellegaard Gottingen Minipigs. Following study completion, the animals were transferred to a holding colony at the Test Facility.

[0155] Animals were uniquely identified by ear tag. During the pre-trial holding and on-study periods, the animals were group housed in custom designed pens with an area of at least 2.25 m2. Animals had access to 150-250 g of Lab Certified Mini-pig Grower / Maintenance Diet 5K99 diet twice daily throughout the study. Mains quality tap water was available ad libitum. Animals were fed about 2 hrs post-dose and checked regularly throughout the duration of the study. Any clinical signs were closely monitored and recorded.

[0156] Four male minipigs received each formulation in a single oral dose of 20 mg (corresponding to one capsule of the formulation of Example 1 of the invention and two capsules of the Comparative Example) with a 7-day wash-out between doses in the following order: Comparative Example and thereafter Example 1 of the invention. Capsules were administered with fruit and / or juice to encourage swallowing. All capsules were successfully administered.

[0157] Plasma samples were collected up to 32 hours post dose and analysed for golexanolone levels with a previously established method.

[0158] II. Results

[0159] Pharmacokinetic parameters were calculated, and are shown in Table 5 below.

[0160] Table 5

[0161] As shown in Table 5, the one capsule of Example 1 of the invention provided an an exposure over time which was about 44 % higher than for the two capsules of the Comparative Example. The results are also shown in Figure 1A and Figure IB.

Claims

CLAIMS1. An oral pharmaceutical formulation, comprising:(i) the compound golexanolone; and(ii) a vehicle comprising(A) a mixture of mono-di-and triglycerides of caprylic acid (C8) and capric acid (CIO); and(B) a mixture of fatty acid esters with a melting point (m.p.) of 30-45°C; wherein: the amount of golexanolone in the pharmaceutical formulation is from 16 to 43 % by weight of the total weight of the pharmaceutical formulation.

2. The oral pharmaceutical formulation according to claim 1, wherein the total amount of the vehicle is from 57 to 84 % by weight of the total weight of the pharmaceutical formulation.

3. The oral pharmaceutical formulation according to any one of claims 1 to 2, wherein said formulation is a suspension.

4. The oral pharmaceutical formulation according to any one of claims 1 to 3, wherein the mixture of fatty acid esters (B) is a hard fat (Adeps solidus).

5. The oral pharmaceutical formulation according to claim 4, wherein the hard fat has a melting point (m.p.) of about 30 to 40 °C.

6. The oral pharmaceutical formulation according to claim 4 or 5, wherein the hard fat comprises up to 100 % by weight triglycerides comprising caprylic acid (C8), capric acid (CIO), myristic acid (C14), and stearic acid (C18).

7. The oral pharmaceutical formulation according to any one of claims 1 to 6, wherein the vehicle further comprises (C) a triglyceride comprising caprylic acid (C8) in amount of 50-80 % and capric acid (CIO) in an amount of 20-50 %.

8. The oral pharmaceutical formulation according to claim 7, wherein the triglyceride (C) is a medium-chain triglyceride (MCT).

9. The oral pharmaceutical formulation according to any one of claims 1 to 6, wherein the vehicle comprises 30-95 % by weight of the mixture of mono-di-and triglycerides (A), and 5-30 % by weight of the mixture of fatty acid esters (B).

10. The oral pharmaceutical formulation according to claim 9, wherein the vehicle comprises 95 % by weight of the mixture of mono-di-and triglycerides (A) and 5 % by weight of the mixture of fatty acid esters (B).

11. The oral pharmaceutical formulation according to claim 7, wherein the vehicle comprises 30-50 % by weight of the mixture of mono-di-and triglycerides (A), 5-30 % by weight of the mixture of fatty acid esters (B), and 30-50 % by weight of the triglyceride (C).

12. The oral pharmaceutical formulation according to claim 11, wherein the vehicle comprises 35 % by weight of the mixture of mono-di-and triglycerides (A), 30 % by weight of the mixture of fatty acid esters (B), and 35 % by weight of the triglyceride (C).

13. The oral pharmaceutical formulation according to claim 11, wherein the vehicle comprises 47.5 % by weight of the mixture of mono-di-and triglycerides (A), 5 % by weight of the mixture of fatty acid esters (B), and 47.5 % by weight of the triglyceride (C).

14. The oral pharmaceutical formulation according to any one of claims 1 to 13, wherein the mixture of mono-di-and triglycerides (A) further comprises caproic acid (C6).

15. The oral pharmaceutical formulation according to any one of claims 1 to 14, wherein the mixture of mono-di-and triglycerides (A) further comprises lauric acid (C12).

16. The oral pharmaceutical formulation according to any one of claims 1 to 15, wherein the mixture of mono-di-and triglycerides (A) further comprises one or more of myristic acid (C14), palmitic acid (C16) and stearic acid (C18).

17. The oral pharmaceutical formulation according to any one of claims 1 to 16, wherein the formulation consists of the compound golexanolone and the vehicle only.

18. The oral pharmaceutical formulation according to any one of claims 1 to 17, wherein the amount of the compound golexanolone is from 16 to 32 % by weight of the total weight of the pharmaceutical formulation.

19. The oral pharmaceutical formulation according to any one of claims 1 to 18, wherein the amount of the compound golexanolone is 16 % by weight of the total weight of the formulation.

20. The oral pharmaceutical formulation according to any one of claims 1 to 19, wherein the amount of vehicle is 84 % by weight of the total weight of the formulation.

21. A capsule comprising the oral pharmaceutical formulation according to any one of claims 1 to 20.

22. The capsule according to claim 21, comprising from 20 to 320 mg of the compound golexanolone.

23. The capsule according to claim 21 or 22, wherein the amount of the compound golexanolone in said capsule is selected from any one of 40 to 320 mg; 60 to 320 mg; 80 to 320 mg; 100 to 320 mg; 120 to 320 mg; 140 to 320 mg; 160 to 320 mg; 180 to 320 mg; 200 to 320 mg; 220 to 320 mg; 240 to 320 mg; 260 to 320 mg; 280 to 320 mg; and 300 to 320 mg.

24. The capsule according to claim 21 or 22, wherein the amount of the compound golexanolone in said capsule is from 80 to 160 mg.

25. The capsule according to claim 21 or 22, wherein the amount of the compound golexanolone in said capsule is selected from any one of 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 260 mg, 270 mg, 280 mg, 290 mg, 300 mg, 310 mg and 320 mg.

26. The capsule according to claim 25, comprising 20 mg of the compound golexanolone, wherein the capsule has a total fill weight of 125 mg.U. The capsule according to claim 25, comprising 40 mg of the compound golexanolone, wherein the capsule has a total fill weight of 250 mg.

28. The capsule according to claim 25, comprising from 80 mg of the compound golexanolone, wherein the capsule has a total fill weight of 500 mg.

29. The capsule according to claim 25, comprising 160 mg of the compound golexanolone, wherein the capsule has a total fill weight of 500 mg.

30. The capsule according to claim 25, comprising 160 mg of the compound golexanolone, wherein the capsule has a total fill weight of 1000 mg.

31. The pharmaceutical formulation or the capsule according to any one of claims 1 to 30 for use in the treatment of a CNS disorder.

32. The pharmaceutical formulation or the capsule according to any one of claims 1 to 30 for use in the treatment of a liver disorder.

33. The pharmaceutical formulation or the capsule according to any one of claims 1 to 30 for use in the treatment of an an autoimmune disease in the bile duct.

34. The pharmaceutical formulation or the capsule according to claim 33, wherein the autoimmune disease is Primary Biliary Cholangitis (PBC).

35. The pharmaceutical formulation or the capsule according to claim 31, wherein the CNS disorder is Parkinsons Disease (PD).

36. The pharmaceutical formulation or the capsule according to claim 32, wherein the liver disorder is Hepatic Encephalopathy (HE).

37. The pharmaceutical formulation or the capsule according to any one of claims 1 to 36, wherein said pharmaceutical formulation or capsule is administered once daily or twice daily.

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