Novel pharmaceutical formulation of golexanolone

Abstract

The present invention is directed to a novel oral pharmaceutical formulation comprising a vehicle comprising (A) a triglyceride comprising caprylic acid (C8) in amount of 50-80 % and capric acid (C10) in an amount of 20-50 %; and (B) a fatty acid ester or a mixture of fatty acid esters with a melting point (m.p.) of 30-65°C; wherein: the weight ratio between the triglyceride (A) and the fatty acid ester or a mixture of fatty acid esters (B) is in the range of 60:40 to 80:20; and the amount of golexanolone in the pharmaceutical formulation is from 3 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, S et al.: 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 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 triglyceride comprising caprylic acid (C8) in amount of 50-80 % and capric acid (CIO) in an amount of 20-50 %; and

[0022] (B) a fatty acid ester or a mixture of fatty acid esters with a melting point (m.p.) of 30- 65°C; wherein: the weight ratio between the triglyceride (A) and the fatty acid ester or the mixture of fatty acid esters (B) is in the range of 60:40 to 80:20; and the amount of golexanolone in the pharmaceutical formulation is from 3 to 43 % by weight of the total weight of the pharmaceutical formulation.

[0023] BRIEF DESCRIPTION OF DRAWINGS

[0024] Figure 1A is a graph showing that the plasma concentration of golexanolone in minipigs.

[0025] Figure IB is a graph showing the drug exposure of golexanolone (Area Under the Curve, AUC) in minipigs.

[0026] DESCRIPTION OF THE INVENTION

[0027] The steroid compound 3a-ethynyl-3P-hydroxyandrostan-17-one oxime (Compound I)

[0028] (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.

[0029] 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.

[0030] One aspect of the present invention is an oral pharmaceutical formulation comprising:

[0031] (i) the compound golexanolone; and

[0032] (ii) a vehicle comprising (A) a triglyceride comprising caprylic acid (C8) in amount of 50-80 % and capric acid (CIO) in an amount of 20-50 %; and

[0033] (B) a fatty acid ester or a mixture of fatty acid esters with a melting point (m.p.) of 30-65°C; wherein: the weight ratio between the triglyceride (A) and the fatty acid ester or the mixture of fatty acid esters (B) is in the range of 60:40 to 80:20; and the amount of golexanolone in the pharmaceutical formulation is from 3 to 43 % by weight of the total weight of the pharmaceutical formulation.

[0034] 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.

[0035] One aspect of the invention is a pharmaceutical formulation as herein described, wherein the total amount of the vehicle is from 57 to 97 % by weight of the total weight of the pharmaceutical formulation.

[0036] One aspect of the invention is a pharmaceutical formulation as herein described, wherein the weight ratio between the triglyceride (A) and the fatty acid ester or the mixture of fatty acid esters (B) is in the range of 60:40 to 75:25.

[0037] One aspect of the invention is a pharmaceutical formulation as herein described, wherein the weight ratio between the triglyceride (A) and the fatty acid ester or the mixture of fatty acid esters (B) is is 70:30.

[0038] One aspect of the invention is a pharmaceutical formulation as herein described comprising the fatty acid ester or the mixture of fatty acid esters (B) as thickening agent.

[0039] One aspect of the invention is a pharmaceutical formulation as herein described, wherein said pharmaceutical formulation is a suspension. In said suspension, the compound golexanolone is suspended in the mixture formed by the triglyceride and the fatty acid ester or the mixture of fatty acid esters 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. One aspect of the invention is a pharmaceutical formulation as herein described, wherein the triglyceride comprises caprylic acid (C8) in amount of 50-80 % and capric acid (CIO) in an amount of 20-50 %.

[0040] One aspect of the invention is a pharmaceutical formulation as herein described, wherein the triglyceride comprises caprylic acid (C8) in amount of 50-80 %, capric acid (CIO) in an amount of 20- 50 %, and the fatty acid caproic acid (C6) in a maximum amount of 2%.

[0041] One aspect of the invention is a pharmaceutical formulation as herein described, wherein the triglyceride comprises caprylic acid (C8) in amount of 50-80 %, capric acid (CIO) in an amount of 20- 50 %, caproic acid (C6) in a maximum amount of 2%, and lauric acid (C12) in a maximum amount of 3 %.

[0042] One aspect of the invention is a pharmaceutical formulation as herein described, wherein the triglyceride comprises caprylic acid (C8) in amount of 50-80 %, capric acid (CIO) in an amount of 20- 50 %, caproic acid (C6) in a maximum amount of 2%, lauric acid (C12) in a maximum amount of 3 %, and myristic acid (C14) in a maximum amount of 1 %.

[0043] One preferred aspect of the invention is a pharmaceutical formulation as herein described, wherein the triglyceride is a medium-chain triglyceride (MCT) comprising caprylic acid (C8) in amount of 50-80 % and capric acid (CIO) in an amount of 20-50 %.

[0044] One aspect of the invention is a pharmaceutical formulation as herein described, wherein the fatty acid ester or the mixture of fatty acid esters is a hard fat (Adeps solidus).

[0045] One aspect of the invention is a pharmaceutical formulation as herein described, wherein the hard fat has a melting point of about 30 to 45 °C.

[0046] One aspect of the invention is a pharmaceutical formulation as herein described, wherein the fatty acid ester or the mixture of fatty acid esters 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). One aspect of the invention is a pharmaceutical formulation as herein described, wherein the fatty acid ester or the mixture of fatty acid esters is a mixture of triglycerides comprising caprylic acid (C8), capric acid (CIO), myristic acid (C14), and stearic acid (C18).

[0047] One aspect of the invention is a pharmaceutical formulation as herein described, wherein the fatty acid ester or the mixture of fatty acid esters is a mixture of mono-, di- and triesters of palmitic (C16) and stearic (C18) acid.

[0048] One aspect of the invention is a pharmaceutical formulation as herein described, wherein the fatty acid ester or the mixture of fatty acid esters is a mixture of mono- and diesters of palmitic (C16) and / or stearic (C18) acid.

[0049] One aspect of the invention is a pharmaceutical formulation as herein described, wherein the fatty acid ester or the mixture of fatty acid esters is a mixture of mono- and diesters of stearic (C18) acid.

[0050] One aspect of the invention is a pharmaceutical formulation as herein described, wherein the fatty acid ester or the mixture of fatty acid esters is a monoester of palmitic (C16) or stearic (C18) acid.

[0051] One aspect of the invention is a pharmaceutical formulation as herein described, wherein the fatty acid ester or the mixture of fatty acid esters is a monoester of stearic (C18) acid.

[0052] One aspect of the invention is a pharmaceutical formulation as herein described, wherein the fatty acid ester or the mixture of fatty acid esters has a melting point of 54 to 65 °C.

[0053] Examples of fatty acid esters or mixtures of fatty acid esters which may be useful in accordance with the invention as thickening agent are Geleol™ (Gattefosse) and Softisan 378® (101 Oleochemical GmbH, Germany).

[0054] One aspect of the invention is a pharmaceutical formulation as herein described, wherein the formulation consists of the compound golexanolone and the vehicle only.

[0055] 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 43 % by weight of the total weight of the pharmaceutical formulation. 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.

[0056] 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.

[0057] One aspect of the invention is a pharmaceutical formulation as herein described, wherein the amount of vehicle in said pharmaceutical formulation is 84 % by weight of the total weight of the formulation.

[0058] One aspect of the invention is a pharmaceutical formulation as herein described, wherein said pharmaceutical formulation is comprised in a capsule.

[0059] 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.

[0060] 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.

[0061] 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.

[0062] The present invention is completely unexpected in that it is possible to obtain a pharmaceutical formulation of golexanolone with a high 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.

[0063] One aspect of the invention, is a pharmaceutical formulation as herein described consisting of the compound golexanolone and the vehicle only. A further aspect of the invention is a vehicle comprising (A) a medium-chain triglyceride (MCT) comprising caprylic acid (C8) in amount of 50-80 % and capric acid (CIO) in an amount of 20-50 %; and (B) a a fatty acid ester or mixture of fatty acid esters with a melting point (m.p.) of 30-65°C; wherein the weight ratio between the medium-chain triglyceride (MCT) (A) and the fatty acid ester or the mixture of fatty acid esters (B) is in the range of 60:40 to 80:20, such as 60:40 to 75:25.

[0064] Medium-chain triglycerides (MCT) which may be useful as component (A) 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 %.

[0065] DEFINITIONS

[0066] The compound 3a-ethynyl-3P-hydroxyandrostan-17-one oxime has the INN (International Nonproprietary Name) golexanolone, having the chemical structure

[0067] 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).

[0068] 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. 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.

[0069] 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.

[0070] The wording "PK” as used throughout the specification relates to the pharmacokinetic properties for a compound being investigated.

[0071] 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.

[0072] The wording "twice daily" or "BID” as used herein means that the compound golexanolone is administered twice each day in a specified dose.

[0073] 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 a triglyceride comprising caprylic acid (C8) in amount of 50-80 % and capric acid (CIO) in an amount of 20-50 % and a fatty acid ester or a mixture of fatty acid esters with a melting point (m.p.) of 30-65°C.

[0074] 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 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.

[0075] The wording triglyceride (triacylglycerol or triacylglyceride) means an ester derived from glycerol and three fatty acids.

[0076] 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. The wording "hard fat (Adeps solidus)" is used herein in accordance with the 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 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).

[0077] Miglyol®812N (101 Oleochemical GmbH, Germany) is a medium-chain triglyceride (MCT) comprising the fatty acid caprylic acid (C8) in amount of 50-80 % and capric acid (CIO) in an amount of 20-50 %. This excipient may also comprise caproic acid (C6) in a maximum amount of 2%, lauric acid (C12) in a maximum amount of 3 %; and myristic acid (C14) in a maximum amount of 1 %.

[0078] Softisan® 378 (101 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).

[0079] Geleol™ (Gattefosse) is a mixture of mono-, di- and triesters of palmitic (Cis) and stearic (Cig) acids with a melting point of about 54 - 65 °C.

[0080] 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.

[0081] The wording "final drug product" means a capsule comprising a formulation of golexanolone as herein described and claimed.

[0082] The singular forms "a", "an", and "the" as used throughout this specification also include plural referents unless the context clearly states otherwise.

[0083] The wording "about" as used herein means a deviation of + / - 2%, or + / - 5%, or + / - 10 %, of a given numerical value. PHARMACEUTICAL FORMULATIONS AND DOSING

[0084] An aspect of the invention is a pharmaceutical formulation as herein described, wherein said pharmaceutical formulation is administered once daily.

[0085] An aspect of the invention is a pharmaceutical formulation as herein described, wherein said pharmaceutical formulation is administered twice daily.

[0086] An aspect of the invention is a pharmaceutical formulation as herein described, wherein said formulation is filled into a capsule.

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

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

[0089] One aspect of the invention is a capsule as herein described comprising from 20 to 320 mg of the compound golexanolone.

[0090] 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.

[0091] 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.

[0092] 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. 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.

[0093] 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.

[0094] 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.

[0095] 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.

[0096] 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.

[0097] 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.

[0098] 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.

[0099] MEDICAL USES AND MEDICAL TREATMENT

[0100] 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).

[0101] 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). 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).

[0102] Also included in the present invention is a combination therapy with a Standard of Care agent used in the treatment of Parkinsons Disease (PD), Hepatic Encephalopathy (HE), or Primary Biliary Cholangitis (PBC).

[0103] ADMINISTRATION ROUTES

[0104] 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.

[0105] GENERAL PROCESS FOR THE PREPARATION OF FORMULATIONS

[0106] A pharmaceutical formulation according to the present invention may be manufactured by the process described below.

[0107] 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 / 063128.

[0108] Step I - Manufacture of the vehicle

[0109] Each of the triglyceride and the fatty acid ester or the mixture of fatty acid esters are weighed in the intended weight ratio, and thereafter placed under magnetic stirring at room temperature in a heat chamber or on a heating plate set to a temperature providing a homogeneous premix (vehicle) in the liquid state.

[0110] If needed, the fatty acid ester or the mixture of fatty acid esters is placed in a heating chamber at the melting temperature of said fatty acid ester or the mixture of fatty acid esters for at least about 2 hours prior to use, and is maintained in the heat chamber until the time for mixing with the triglyceride. Step II - Manufacture of the pharmaceutical formulation

[0111] 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.

[0112] Step III - Capsule filling

[0113] 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 ll7bubbles shall be avoided.

[0114] 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.

[0115] 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.

[0116] EXAMPLES

[0117] Example 1

[0118] A pharmaceutical formulation comprising 16 % by weight of golexanolone (20 mg / capsule) was prepared by following the general process described above. The formulation consisted of the ingredients shown in Table 1 below.

[0119] Table 1 (1)A medium chain triglyceride (MCT);(2)A hard fat used as thickening agent

[0120] Miglyol® was purchased from 101 Oleochemical GmbH, Germany. Softisan® 378 was purchased from

[0121] 101 Oleochemical GmbH, Germany. The API golexanolone was provided in-house by Umecrine Cognition AB (manufactured as described above).

[0122] The hard fat Softisan®378 was treated at 45°C for a half day. An aliquot of 5.04 grams was taken out and added to a beaker with 11.76 grams of Miglyol® corresponding to a weight ratio of 70:30 (70 % Miglyol®812N and 30 % Softisan® 378). The mixture was stirred at room temperature for 1 hour until a clear solution was obtained (i.e. the vehicle).

[0123] Golexanolone (3.2 grams) was weighed in and added to the vehicle at room temperature. The mixture was homogenized under stirring until a white opaque formulation was visually observed.

[0124] The obtained pharmaceutical formulation was filled in softgel capsules according to the general procedure described above:

[0125] 10 nitrogen-filled Oval capsules were tared and filled with the full suspension prepared. The target fill weight was 125 mg resulting in a dose 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.

[0126] Example 2

[0127] A pharmaceutical formulation comprising 16 % by weight of golexanolone was prepared as described in Example 1 above with the mixture of the MCT Miglyol®812N and Geleol® heated at above 55°C and stirred with a magnetic stirrer at 250rpm for one hour until a homogeneous mix was obtained, and with golexanolone added under magnetic stirring at 250rpm at 45°C until a white opaque formulation was obtained. The formulation consisted of the ingredients shown in Table 2 below.

[0128] Table 2 'A medium chain triglyceride (MCT); •■'•'A a mixture of mono-, di- and triesters used as thickening agent

[0129] Example 3

[0130] A pharmaceutical formulation comprising 32 % by weight of golexanolone was prepared as described in Example 1 above. The formulation consisted of the ingredients shown in Table 3 below. A white opaque formulation was obtained.

[0131] Table 3

[0132] (1)A medium chain triglyceride (MCT);(2)A hard fat used as thickening agent

[0133] Example 4

[0134] A pharmaceutical formulation comprising 43 % by weight of golexanolone was prepared as described in Example 1 above. The formulation consisted of the ingredients shown in Table 4 below. A white opaque formulation was obtained. Table 4

[0135] (1)A medium chain triglyceride (MCT);(2)A hard fat used as thickening agent

[0136] Example 5 A pharmaceutical formulation comprising 16 % by weight of golexanolone was prepared as described in Example 2 above, but with a different weight ratio between the MCT Miglyol®812N and Geleol®. The formulation consisted of the ingredients shown in Table 5 below. A white opaque formulation was obtained. Table s

[0137] (1)A medium chain triglyceride (MCT);(2)A a mixture of mono-, di- and triesters used as thickening agent

[0138] Example 6 A pharmaceutical formulation comprising 16 % by weight of golexanolone was prepared as described in Example 2 above, but with a different weight ratio between the MCT Miglyol®812N and Geleol®. The formulation consisted of the ingredients shown in Table 6 below. A white opaque formulation was obtained. Table 6

[0139] 'A medium chain triglyceride (MCT);(2)A a mixture of mono-, di- and triesters used as thickening agent

[0140] Comparative Example

[0141] A pharmaceutical formulation for use in the comparative biological study described below was prepared. The formulation comprising 10 mg of 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 7 below.

[0142] Table 7

[0143] The obtained solution was filled in softgel capsules by using fully automated softgel capsule filling.

[0144] 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.

[0145] 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.

[0146] BIOLOGICAL STUDIES

[0147] I. Comparative Pharmacokinetic (PK) Study in minipigs

[0148] 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.

[0149] 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.

[0150] 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.

[0151] Plasma samples were collected up to 32 hours post dose and analysed for golexanolone levels with a previously established method.

[0152] II. Results

[0153] Pharmacokinetic parameters were calculated, and are shown in Table 8 below.

[0154] Table 8

[0155] As shown in Table 8, the one capsule of Example 1 of the invention provided a maximum plasma concentration (Cmax) which was 83 % higher than for the two capsules of the Comparative Example, and an exposure over time which was over 100 % higher (a factor of two). 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 triglyceride comprising caprylic acid (C8) in amount of 50-80 % and capric acid (CIO) in an amount of 20-50 %; and(B) a fatty acid ester or a mixture of fatty acid esters with a melting point (m.p.) of 30-65°C; wherein: the weight ratio between the triglyceride (A) and the fatty acid ester or the mixture of fatty acid esters (B) is in the range of 60:40 to 80:20; and the amount of golexanolone in the pharmaceutical formulation is from 3 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 97 % by weight of the total weight of the pharmaceutical formulation.

3. The oral pharmaceutical formulation according to claim 1 or 2, wherein said formulation is a suspension.

4. The oral pharmaceutical formulation according to any one of claims 1 to 3, wherein the weight ratio between the triglyceride (A) and the fatty acid ester or the mixture of fatty acid esters (B) is in the range of 60:40 to 75:25.

5. The oral pharmaceutical formulation according to any one of claims 1 to 4, wherein the weight ratio between the triglyceride (A) and the fatty acid ester or the mixture of fatty acid esters (B) is 70:30.

6. The oral pharmaceutical formulation according to any one of claims 1 to 5, wherein the triglyceride (A) is a medium-chain triglyceride (MCT).

7. The oral pharmaceutical formulation according to any one of claims 1 to 6, wherein the fatty acid ester or the mixture of fatty acid esters (B) is a hard fat (Adeps solidus).

8. The oral pharmaceutical formulation according to claim 7 , wherein the hard fat has a melting point of about 30 to 45 °C.

9. The oral pharmaceutical formulation according to claim 7 or 8, 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).

10. The oral pharmaceutical formulation according to any one of claims 1 to 6, wherein the fatty acid ester or the mixture of fatty acid esters (B) is a mixture of mono-, di- and triesters of palmitic (C16) and stearic (C18) acid.

11. The oral pharmaceutical formulation according to claim 10, wherein the mixture of mono-, di- and triesters of palmitic (C16) and stearic (C18) acid has a melting point of 54 to 65 °C.

12. The oral pharmaceutical formulation according to any one of claims 1 to 11, wherein the triglyceride (A) further comprises the fatty acid caproic acid (C6) in a maximum amount of 2%.

13. The oral pharmaceutical formulation according to any one of claims 1 to 12, wherein the triglyceride (A) further comprises the fatty acid lauric acid (C12) in a maximum amount of 3 %.

14. The oral pharmaceutical formulation according to any one of claims 1 to 13, wherein the triglyceride (A) further comprises the fatty acid myristic acid (C14) in a maximum amount of 1 %.

15. The oral pharmaceutical formulation according to any one of claims 1 to 14, wherein the formulation consists of the compound golexanolone and the vehicle only.

16. The oral pharmaceutical formulation according to any one of claims 1 to 15, wherein the amount of the compound golexanolone in the pharmaceutical formulation is from 16 to 43 % by weight of the total weight of the pharmaceutical formulation.

17. The oral pharmaceutical formulation according to any one of claims 1 to 16, 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.

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

19. The oral pharmaceutical formulation according to any one of claims 1 to 18, wherein the amount of vehicle in said pharmaceutical formulation is 84 % by weight of the total weight of the formulation.

20. A capsule comprising the oral pharmaceutical formulation according to any one of claims 1 to 19.

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

22. The capsule according to claim 20 or 21, 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.

23. The capsule according to claim 20 or 21, wherein the amount of the compound golexanolone in said capsule is from 80 to 160 mg.

24. The capsule according to any one of claims 20 or 21, 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.

25. The capsule according to claim 24, comprising 20 mg of the compound golexanolone, wherein the capsule has a total fill weight of 125 mg.

26. The capsule according to claim 24, comprising 40 mg of the compound golexanolone, wherein the capsule has a total fill weight of 250 mg.

27. The capsule according to claim 24, comprising from 80 mg of the compound golexanolone, wherein the capsule has a total fill weight of 500 mg.

28. The capsule according to claim 24, comprising 160 mg of the compound golexanolone, wherein the capsule has a total fill weight of 500 mg.

29. The capsule according to claim 24, comprising 160 mg of the compound golexanolone, wherein the capsule has a total fill weight of 1000 mg.

30. The oral pharmaceutical formulation or the capsule according to any one of claims 1 to 29 for use in the treatment of a CNS disorder.

31. The oral pharmaceutical formulation or the capsule according to any one of claims 1 to 29 for use in the treatment of a liver disorder.

32. The oral pharmaceutical formulation or the capsule according to any one of claims 1 to 29 for use in the treatment of an an autoimmune disease in the bile duct.

33. The oral pharmaceutical formulation or the capsule according to claim 32, wherein the autoimmune disease is Primary Biliary Cholangitis (PBC).

34. The oral pharmaceutical formulation or the capsule according to claim 30, wherein the CNS disorder is Parkinsons Disease (PD).

35. The oral pharmaceutical formulation or the capsule according to claim 31, wherein the liver disorder is Hepatic Encephalopathy (HE).

36. The oral pharmaceutical formulation or the capsule according to any one of claims 1 to 35, wherein said pharmaceutical formulation or capsule is administered once daily or twice daily.

37. A vehicle comprising (A) a triglyceride comprising caprylic acid (C8) in amount of 50-80 % and capric acid (CIO) in an amount of 20-50 %; and (B) a fatty acid ester or a mixture of fatty acid esters with a melting point (m.p.) of 30-65°C; wherein the weight ratio between the triglyceride (A) and the fatty acid ester or a mixture of fatty acid esters (B) is in the range of 60:40 to 80:20.

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