WO2022155507A1

WO2022155507A1 - Transmucosal dosage forms of brexanolone

Info

Publication number: WO2022155507A1
Application number: PCT/US2022/012582
Authority: WO
Inventors: Indranil Nandi; Tusharmouli Mukherjee; Dinesh Kumar; Rakesh Kumar Singh
Original assignee: Jubilant Pharma Holdings Inc.
Priority date: 2021-01-15
Filing date: 2022-01-14
Publication date: 2022-07-21

Abstract

The present invention relates to sublingual pharmaceutical compositions comprising brexanolone and the process for preparing such compositions. Compositions prepared as per the present invention increase bioavailability by avoiding first-pass metabolism. The compositions of brexanolone proposed as per the present invention are useful in the treatment of depression including postpartum depression (PPD), COVID-19 infection, and other diseases.

Description

TRANSMUCOSAL DOSAGE FORMS OF BREXANOLONE

FIELD OF THE INVENTION

[0001] The present invention relates to sublingual pharmaceutical compositions of brexanolone. In particular, but without restriction to the particular embodiments hereinafter described in accordance with the best mode of practice, the present invention provides sublingual pharmaceutical compositions comprising brexanolone and processes for preparing these compositions to increase bioavailability by avoiding first-pass metabolism and reducing the variation in bioavailability. The present invention provides application of sublingual pharmaceutical compositions of brexanolone for treating and/or preventing depression including postpartum depression, COVID-19 infection, and other diseases.

BACKGROUND OF THE INVENTION

[0002] Allopregnanolone, also known as brexanolone, an endogenous metabolite of progesterone, occurs naturally in the body when the female sex hormone progesterone is metabolized. Brexanolone is a neuroactive steroid gamma-aminobutyric acid (GABA) A receptor positive modulator, that is chemically identical to endogenous allopregnanolone.

[0003] Brexanolone is chemically known as l-[(lS,3aS,3bR,5aS,7R,9aS,9bS, 11 aS)-7-hydroxy-9a, 11 a-dimethyl-hexadecahydro- lH-cyclopenta[a]phenanthren- 1 -yl] ethan-l-one. Brexanolone is a white to off-white crystalline powder. It is insoluble in water and is represented by the following formula:

[0004] Brexanolone is presently approved in the USA as Zulresso® injectable dosage form in the strength of 100 mg/20 ml by Sage Therapeutics for the treatment of postpartum depression (PPD) in adults. Each mL of Zulresso® solution contains 5 mg of brexanolone, 250 mg of betadex sulfobutyl ether sodium, 0.265 mg of citric acid monohydrate, 2.57 mg of sodium citrate dihydrate, and water for injection. Zulresso® is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) because of the risk of serious harm resulting from excessive sedation or sudden loss of consciousness.

[0005] Brexanolone is reported to be poorly water-soluble, which leads to poor dissolution and poor bioavailability. Moreover, the terminal half-life of brexanolone is approximately 9 hours. Brexanolone also shows poor hepatic stability, which results in its complete first-pass clearance. These characteristics of brexanolone pose technical challenges to formulation scientists in the development of suitable oral and transmucosal formulations with desired technical attributes.

[0006] Further, the dosage regimen of approved intravenous (IV) infusion product is administered as a continuous intravenous infusion over a total of 60 hours (2.5 days). The 60-hours infusion regimen begins with a starting dose of 30 mcg/kg/h for 4 hours, which is increased to 60 mcg/kg/h for 4 to 24 hours, and further increased to 90 mcg/kg/h for 24 to 52 hours. The dose is then ramped down to 60 mcg/kg/h for 52 to 56 hours, and finally to 30 mcg/kg/h for the last 4 hours (56 to 60 hours). This undesirable long time of about 2.5 days injectable therapy is painful and not patient compliant.

[0007] US Patent No. 10,322,139 assigned to Sage Therapeutics discloses a parenteral composition comprising allopregnanolone. This patent further discloses a parenteral composition comprising allopregnanolone at a concentration of about 5 mg/mL, sulfobutyl ether P-cyclodextrin at a concentration of about 250 mg/mL, and a citrate buffer. [0008] US Patent No. 10,251,894 assigned to The Regents of the University of California discloses a method of treating post-partum depression by intravenously administering to the subject a composition comprising allopregnanolone and sulfobutylether-beta-cyclodextrin salt. The said patent fails to disclose any sublingual dosage form or its development.

[0009] US Patent Publication Nos. 2014/0057885, 2019/0038639, and 2019/0269699 assigned to Sage Therapeutics disclose methods of treating epilepsy, seizure-related disorder, or status epilepticus by administering to the subject a neuroactive steroid such as allopregnanolone. These publications also provide a listing of numerous dosage forms and excipients that may be included in the dosage form along with the numerous compounds disclosed. The patent publication fails to highlight technical problems associated with solid dosage form development particularly transmucosal dosage forms development.

[0010] US Patent Publication Nos. 2015/0313915, 2018/0133229, and 2019/0142845 assigned to The Regents of the University of California disclose injection compositions of allopregnanolone and cyclodextrin and use in the treatment of traumatic brain injury, Alzheimer's disease, epilepsy, anxiety, fragile X syndrome, post-traumatic stress disorder, lysosomal storage disorders, depression (including post-partum depression), premenstrual dysphoric disorder, alcohol craving, and smoking cessation.

[0011] US Patent Publication No. 2020/0171049 assigned to Sage Therapeutics discloses a method for treating post-partum depression in a human by administering allopregnanolone at a dosing regimen over a time period of about 60 hours. US Patent Publication No. 2020/0306265 assigned to Sage Therapeutics discloses a method for treating depression or an anxiety disorder by administering allopregnanolone.

[0012] These publications provide a listing of numerous dosage forms and excipients that may be included in the dosage form along with the numerous compounds disclosed. However, these patent publications do not appear to recognize the problem associated with solid dosage form development. For example, the specification states that the pH of the formulations may range from about 3 to about 9. As such, it is not clear how one of the skill in the art can make a soluble and stable solid oral dosage form of brexanolone based on the publications with desired technical attributes. Further, the amount of cyclodextrin used in the injection formulations is very high (ratio of drug to cyclodextrin is 1 :50). This high amount and ratio is not desirable and may cause accumulation in the patient body.

[0013] As per the above-mentioned literature, the development of oral dosage forms of brexanolone is not feasible or challenging due to its adverse physicochemical properties such as poor solubility and complete first-pass metabolism. Many alternative routes of drug administration are available to by-pass first-pass metabolism such as ophthalmic, injectable, nasal, transdermal, topical, buccal, and sublingual routes. In the sublingual administration, the patient needs to keep the pharmaceutical composition under the tongue while the drug diffuses into the mouth, through the mucosa lining, and from there into the bloodstream. As an alternative to solid oral dosage form or gastrointestinal delivery of the drug, sublingual administration might conceivably increase the bioavailability of brexanolone by avoiding first-pass hepatic metabolism.

[0014] In view of the foregoing, there is an unmet need of improvement in the methods of administering brexanolone to increase the bioavailability of the drug and reduce variability in dosing.

[0015] The present inventors have developed pharmaceutical compositions of brexanolone suitable for sublingual administration to provide consistent absorption. The prepared dosage forms are suitable for the treatment of depression including postpartum depression and COVID-19 infection and/or COVID-19 related acute respiratory distress syndrome (ARDS).

SUMMARY OF THE INVENTION

[0016] The present invention relates to a sublingual pharmaceutical composition comprising brexanolone and the process for preparing such composition.

[0017] The present invention also relates to a sublingual pharmaceutical composition comprising brexanolone and at least one or more pharmaceutically acceptable excipients and processes for preparing such composition.

[0018] The present invention also relates to a sublingual pharmaceutical composition comprising brexanolone and at least one or more pharmaceutically acceptable excipients selected from the group comprising diluent, binder, disintegrant, lubricant, glidant, adsorbent, surfactant, pH regulating agent, effervescent agent, salivating agent, solubilizing agent, stabilizer, sweetener, taste masking agent, preservative, flavoring, and coloring agent, film-forming agent, and solvent or mixtures thereof.

[0019] The present invention further relates to a sublingual pharmaceutical composition comprising brexanolone and at least one or more pharmaceutically acceptable excipients, which exhibit desired pharmaceutical technical attributes such as wetting time, pH, disintegration, dissolution, thickness, diameter, hardness, friability, compressibility index, assay, related substance, content uniformity, stability, patient compliance and commercially viable and other requirements also.

[0020] The present invention also relates to the use of a sublingual pharmaceutical composition comprising brexanolone in the manufacture of a medicament for treating, preventing, ameliorating, and/or delaying the onset of one or more symptoms associated with or resulting from depression and/or post-partum depression.

[0021] The present invention also relates to the use of a sublingual pharmaceutical composition comprising brexanolone in the manufacture of a medicament for treating, preventing, ameliorating, and/or delaying the onset of one or more symptoms associated with or resulting from COVID-19 infection and/or COVID-19 related acute respiratory distress syndrome (ARDS).

[0022] The sublingual pharmaceutical composition is not a rapidly disintegrating tablet that releases small fragments of the composition for swallowing and drug release in the gastrointestinal tract. As such, in one aspect the present invention does not release the brexanolone in a manner that would result in first-pass metabolism of the drug and therefore undesirably reduced bioavailability.

DETAILED DESCRIPTION

[0023] The present invention can be more readily understood by reading the following detailed description of the invention and study of the included examples.

[0024] As used herein, the term “composition”, or “dosage form” or “drug delivery system”, as in pharmaceutical composition, is intended to encompass a drug product comprising brexanolone and other inert ingredient(s) (pharmaceutically acceptable excipients). Such pharmaceutical compositions are synonymous with “formulation” and “dosage form” and “composition of the present invention,”. It can be administered in any pharmaceutical dosage form that can be held in the mouth for a suitable period of time and permits diffusion or erosion of the drug into the mouth cavity where it can be absorbed through the mucosa lining of the mouth. Such dosage forms include transmucosal dosage forms, tablets, lozenges, sublingual tablets, sublingual capsule, sublingual film, sublingual aerosol, sublingual solution, sublingual spray, buccal tablets, mucoadhesive tablets, bioadhesive tablets, troches, pastilles, pills, viscous liquids, pastes, drops, gels, patches and the like. "Sublingual administration" may be defined herein as the therapeutic administration of a pharmaceutical composition under the tongue. Preferably, the pharmaceutical composition refers to sublingual tablets. The tablet dosage form as per the present invention can be used for both sublingual or buccal administration or any of them. In another embodiment, the composition can be film-coated or uncoated. In another embodiment, the composition can be scored or unscored tablet. Preferably, the sublingual tablet is unscored. Preferably, the pharmaceutical compositions as per the present invention are intended for immediate or quick release. Preferably, the sublingual tablet compositions as per the present invention dissolve or disperse or disintegrate in the mouth of the subject from about 1 second to 300 seconds, in particular about 30 seconds to about 300 seconds, in particular about 50 seconds to about 300 seconds, in particular about 60 second to about 300 seconds. In further embodiment, the composition as per the present invention is not an injectable composition and not intended for parenteral administration. In a further embodiment, the composition as per the present invention does not exert its action via the gastrointestinal route. In a further embodiment, brexanolone is present as the sole active ingredient in the composition as per the present invention.

[0025] As used herein, the term " brexanolone” is used in the broad sense to include not only “brexanolone” per se (free base) but also its pharmaceutically acceptable salts, solvates, esters, hydrates, isomers, enantiomers, stereoisomers, diastereoisomers, derivatives, metabolites, polymorphs, and prodrugs thereof. Polymorph may refer to various crystalline and amorphous forms, which can be characterized by methods such as melting point, X-ray diffraction pattern, Raman spectra, IR spectra, or any other method known in the art. As used herein, the pharmaceutically acceptable salt(s) include, but are not limited to, such as hydrochloric, hydrobromic, sulfuric, nitric, phosphoric, acetic, hexanoic, glycolic, lactic, malonic, succinic, malic, maleic, fumaric, tartaric, citric, benzoic, cinnamic, mandelic, methanesulfonic, ethanesulfonic, benzenesulfonic, tosylate, mesylate, carboxylic, stearic, sodium, potassium, magnesium, calcium, ammonium, diethanolamine triethanolamine or like.

[0026] The pharmaceutical compositions of the present invention comprise about

0.01 mg to about 800 mg of brexanolone, preferably about 0.01 mg to about 750 mg, preferably about 0.01 mg to about 700 mg, preferably about 0.01 mg to about 650 mg, preferably about 0.01 mg to about 600 mg, preferably about 0.01 mg to about 550 mg, preferably about 0.01 mg to about 500 mg, preferably about 0.01 mg to about 450 mg, preferably about 0.01 mg to about 400 mg, preferably about 0.01 mg to about 350 mg, preferably about 0.01 mg to about 200 mg, preferably about 0.01 mg to about 100 mg, preferably about 0.01 mg to about 80 mg, preferably about 0.01 mg to about 70 mg, more preferably about 0.01 mg to about 60 mg and more preferably about 0.01 mg to about 50 mg brexanolone as described herein. In a further embodiment, compositions of the present invention comprise about 0.01 mg to about 30 mg of brexanolone. In a further embodiment, compositions of the present invention comprise about 0.01 mg to about 25 mg of brexanolone. In a preferable embodiment, compositions of the present invention comprise about 0.01 mg to about 20 mg of brexanolone. In a further embodiment, compositions of the present invention comprise about 0.01 mg to about 15 mg of brexanolone. In a further embodiment, compositions of the present invention comprise about 5 mg to about 10 mg of brexanolone. The dose may be administered one or more times a day (such as from one to ten times per day).

[0027] The term "excipient" means a pharmacologically inactive component such as diluents, binders, disintegrants, lubricants, glidants, surfactants, wetting agents, pH regulating or adjusting agents, buffers, taste-masking agents, water-soluble and/or water- dispersible carrier materials, effervescent agents, salivating agents, antioxidants, permeation/penetration enhancers, solubilizing agents, plasticizers, acidulants, polymers, mucoadhesive agents, bioadhesive polymers, stabilizers, emulsifying agents, suspending agents, adsorbents, sweeteners, taste-masking agents, preservatives, flavoring, and coloring agents, film-forming agents, mouth feel improvers and solvents and the like. Coprocessed excipients are also covered under the scope of the present invention. The excipient may be in the form of powder or the form of a dispersion. A combination of excipients performing the same function may also be used to achieve desired formulation characteristics. Excipients may be present in any part (intra and/or extra granular) of the composition in any proportion.

[0028] Unless the context requires otherwise, throughout the present specification and claims, the word “comprise” and variations thereof, such as, “comprises” and “comprising” are to be construed in an open, inclusive sense, that is as “including, but not limited to”.

[0029] As used in this specification, the singular forms “a”, “an”, and “the” include plural references unless the context clearly dictates otherwise. Thus, for example, a reference to “a process” includes one or more processes, and/or steps of the type described herein and/ or which will become apparent to those persons skilled in the art upon reading this disclosure and so forth. Unless otherwise stated the weight percentages expressed herein are based on the final weight of the composition. As used herein, the term "about" means ± approximately 20% of the indicated value, such that "about 10 percent" indicates approximately 08 to 12 percent.

[0030] The term “patient” and/or “subject” are used interchangeably herein. In some embodiments, the patient or subject is a human. In further embodiments, the patient or subject is an animal. In some embodiments, the human can be of any age such as adult, adolescent, pediatric, or geriatric. In some embodiments, a patient is a man or woman.

[0031] The term “stable” refers to the compositions of the present invention, wherein the amount of the active ingredient of a formulation does not deviate from the initial amount by more than the values given in the specification or the guidelines of the common Pharmacopoeias or loss in the active ingredient is less than 50% (less than 40%, 30%, 20%, 10%, 5%) of the initial content after being stored for at least 1 month, preferably for at least 2 months, preferably for at least 3 months, more preferably for at least 6 months, more preferably for at least 12 months or more preferably for at least 24 months. The stability of the composition may be evaluated at “long term” conditions 25°C/60% RH, at intermediate condition 30°C/65% RH, at “accelerated conditions” 40°C/75% RH, in the final container either measured as the loss in the content of active ingredient. Stability testing may be conducted according to the current guidelines by ICH and FDA. In another embodiment of the invention, there is provided a sublingual tablet composition, wherein the total impurity is less than 5%, less than 3%, less than 2.5%, less than 2%, less than 1.5%, less than 1%, less than 0.9%, less than 0.8%, less than 0.7%, less than 0.6%, or less than 0.5%. In a preferred embodiment of the invention, the total impurity is less than 1% or preferably less than 0.5%. In another embodiment, the composition comprises less than 2% of total impurities.

[0032] The present invention relates to transmucosal compositions of brexanolone or its pharmaceutically acceptable salts or solvates thereof.

[0033] In one embodiment of the invention, there is provided a sublingual pharmaceutical composition comprising brexanolone and at least one or more pharmaceutically acceptable excipients and processes for preparing such compositions. [0034] The present invention also relates to a pharmaceutical composition comprising brexanolone and at least one or more pharmaceutically acceptable excipients, wherein the composition is formulated for rapid disintegration in sublingual administration.

[0035] In another embodiment of the invention, there is provided a sublingual pharmaceutical composition comprising brexanolone and at least one or more pharmaceutically acceptable excipients, which exhibit desired pharmaceutical technical attributes such as wetting time, pH, disintegration, dissolution, thickness, diameter, hardness, friability, compressibility index, assay, related substance, content uniformity, stability, patient compliance and commercially viable and other requirements also.

[0036] In another embodiment of the invention, there is provided a sublingual pharmaceutical composition comprising brexanolone and at least one or more pharmaceutically acceptable excipients comprising diluent, binder, disintegrant, surfactant, pH regulating agent, glidant, adsorbent, lubricant, solubilizing agent, sweetener, tastemasking agent, and flavoring agent.

[0037] In another embodiment of the invention, the pharmaceutical composition as per the present invention is a sublingual tablet.

[0038] In another embodiment, the sublingual tablet composition comprises: a) about 0.01% to about 90% of brexanolone, and b) about 0.01% to about 90% of at least one or more pharmaceutically acceptable excipients.

[0039] In another embodiment, the sublingual tablet composition comprises brexanolone in an amount from about 0.1 mg to about 60 mg and at least one or more pharmaceutically acceptable excipients. In another embodiment, the sublingual tablet composition comprises brexanolone in an amount from about 0.1 mg to about 20 mg and at least one or more pharmaceutically acceptable excipients. In another embodiment, the sublingual tablet composition comprises brexanolone in an amount from about 0.1 mg to about 10 mg and at least one or more pharmaceutically acceptable excipients.

[0040] In another embodiment of the invention, the sublingual composition comprising: a) from about 0.1% to about 90% by weight of brexanolone, b) from about 0 to about 95% by weight of one or more diluents, c) from about 0 to about 40% by weight of one or more binders, d) from about 0 to about 30% by weight of one or more disintegrants, e) from about 0 to about 50% by weight of one or more carriers, f) from about 0 to about 8% by weight of one or more surfactants, g) from about 0 to about 5% by weight of one or more glidant, h) from about 0 to about 20% by weight of one or more pH regulating agents, i) from about 0 to about 50% by weight of one or more solubilizing agents, j) from about 0.01% to about 5% by weight of one or more lubricants, k) from about 0 to about 10% by weight of one or more preservatives, 1) from about 0% to about 10% by weight of one or more sweeteners, m) from about 0% to about 10% by weight of one or more flavouring agent, n) from about 0% to about 20% by weight of one or more tastemasking agent, o) from about 0 to about 20% by weight of one or more bio/mucoadhesive agent, and optionally p) one or more other pharmaceutically acceptable excipients.

[0041] In another embodiment of the invention, the sublingual composition comprising: a) from about 0.1% to about 60% by weight of brexanolone, b) from about 15% to about 80% by weight of one or more diluents, c) from about 0.01% to about 10% by weight of one or more binders, d) from about 0.01 to about 15% by weight of one or more disintegrants, e) from about 0.01% to about 2% by weight of one or more glidants, f) from about 0.01% to about 10% by weight of one or more pH regulating agents, g) from about 0.01% to about 35% by weight of one or more solubilizing agents, h) from about 0.01% to about 3% by weight of one or more lubricants, i) from about 0.01% to about 3% by weight of one or more sweeteners, and optionally]) one or more other pharmaceutically acceptable excipients.

[0042] In another embodiment of the invention, the sublingual composition comprising: a) from about 0.1% to about 60% by weight of brexanolone, b) from about 15% to about 80% by weight of one or more diluents, c) from about 0.01% to about 10% by weight of one or more binders, d) from about 0.01 to about 15% by weight of one or more disintegrants, e) from about 0.01% to about 2% by weight of one or more glidants, f) from about 0.01% to about 35% by weight of one or more solubilizing agents, g) from about 0.01% to about 3% by weight of one or more lubricants, h) from about 0.01% to about 3% by weight of one or more sweeteners, and optionally i) one or more other pharmaceutically acceptable excipients.

[0043] In another embodiment of the invention, the sublingual tablet composition comprising: a) from about 0.1% to about 35% by weight of brexanolone, b) from about 20% to about 70% by weight of one or more diluents, c) from about 0.1% to about 8% by weight of one or more binders, d) from about 0.1% to about 10% by weight of one or more disintegrants, e) from about 0.01% to about 3% by weight of one or more glidants, f) from about 0.01% to about 35% by weight of one or more solubilizing agents, g) from about 0.01% to about 3% by weight of one or more lubricants, h) from about 0.01% to about 5% by weight of one or more sweeteners, and optionally i) one or more other pharmaceutically acceptable excipients.

[0044] In another embodiment of the invention, the sublingual tablet composition comprising: a) from about 0.1% to about 35% by weight of brexanolone, b) from about 20% to about 70% by weight of one or more diluents, c) from about 0.1% to about 8% by weight of one or more binders, d) from about 0.1% to about 10% by weight of one or more disintegrants, e) from about 0.01% to about 3% by weight of one or more glidants, f) from about 0.01% to about 35% by weight of one or more solubilizing agents, g) from about 0.01% to about 5% by weight of one or more pH regulating agents, h) from about 0.01% to about 3% by weight of one or more lubricants, i) from about 0.01% to about 5% by weight of one or more sweeteners, and optionally ]) one or more other pharmaceutically acceptable excipients.

[0045] In another embodiment of the invention, the sublingual tablet composition comprising: a) from about 0.1% to about 35% by weight of brexanolone, b) from about 5% to about 95% by weight of one or more diluents, c) from about 0.01% to about 70% by weight of one or more solubilizing agents, d) from 0 to about 20% by weight of one or more disintegrants, e) from 0 to about 20% by weight of one or more binders, f) from 0 to about 30% by weight of one or more adsorbents or glidants, g) from 0 to about 5% by weight of one or more pH regulating agents, h) from about 0.01% to about 5% by weight of one or more lubricants, i) from 0 to about 20% by weight of one or more sweeteners, j) from 0 to about 20% by weight of one or more flavouring agents and optionally k) one or more other pharmaceutically acceptable excipients.

[0046] In another embodiment of the invention, there is provided a sublingual pharmaceutical composition comprising: a) brexanolone or its pharmaceutically acceptable salts thereof in an amount of about 0.01% to about 30% by weight; b) one or more solubilizing agents selected from the group consisting of cyclodextrin, sodium lauryl sulfate, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, or mixtures thereof in an amount from about 0.01% to about 60% by weight; c) one or more diluents selected from the group consisting of mannitol, lactose, microcrystalline cellulose, sucrose, starch, pregelatinized starch, maize starch, guar gum, xylitol, sorbitol, maltodextrin, mixture of mannitol and maize starch, mixture of microcrystalline cellulose and guar gum, polydextrose, isomalt, or mixtures thereof in an amount from about 5% to about 80% by weight; d) one or more disintegrants selected from the group consisting of croscarmellose sodium, crospovidone, sodium starch glycolate, and low substituted hydroxypropyl cellulose, or mixtures thereof in an amount from about 0.5% to about 20% by weight; and e) at least one or more other pharmaceutically acceptable excipients; wherein the weight ratio of brexanolone to the solubilizing agent is from about 0.1 :24 to about 24:0.1.

[0047] In another embodiment of the invention, the sublingual pharmaceutical composition is a sublingual tablet and is not an orally disintegrating tablet.

[0048] In another embodiment of the invention, there is provided a sublingual tablet pharmaceutical composition comprising: a) brexanolone in an amount of about 0.01% to about 10% by weight; b) one or more solubilizing agents selected from the group consisting of beta-cyclodextrin, sodium lauryl sulfate, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, or mixtures thereof in an amount from about 0.01% to about 40% by weight; c) one or more diluents selected from the group consisting of mannitol, lactose, microcrystalline cellulose, sucrose, starch, pregelatinized starch, maize starch, guar gum, xylitol, sorbitol, maltodextrin, mixture of mannitol and maize starch, mixture of microcrystalline cellulose and guar gum, polydextrose, isomalt, or mixtures thereof in an amount from about 5% to about 80% by weight; d) one or more disintegrants selected from the group consisting of croscarmellose sodium, crospovidone, sodium starch glycolate, and low substituted hydroxypropyl cellulose, or mixtures thereof in an amount from about 0.5% to about 15% by weight; and e) at least one or more other pharmaceutically acceptable excipients; wherein the weight ratio of brexanolone to the solubilizing agent is from about 0.1 : 15 to 15:0.1 and the composition exhibits an in-vitro dissolution rate of not less than 75% of drug release within 30 minutes when measured in 900 ml of 6.8 phosphate buffer and 0.5% sodium lauryl sulfate using a USP II apparatus (Paddle) at a temperature of 37±0.5°C and a rotation speed of 50 revolutions. [0049] In another embodiment of the invention, there is provided a sublingual tablet pharmaceutical composition comprising: a) brexanolone in an amount of about 0.01% to about 10% by weight; b) beta-cyclodextrin in an amount from about 0.01% to about 40% by weight; c) one or more diluents selected from the group consisting of mannitol, microcrystalline cellulose, maize starch, guar gum, or mixtures thereof in an amount from about 5% to about 80% by weight; d) one or more disintegrants selected from croscarmellose sodium, crospovidone and low substituted hydroxypropyl cellulose, or mixtures thereof in an amount from about 0.5% to about 15% by weight; and e) at least one or more other pharmaceutically acceptable excipients; wherein the composition has a disintegration time of about 300 seconds or less and the composition exhibits an in-vitro dissolution rate of not less than 75% of drug release within 30 minutes when measured in 900 ml of 6.8 phosphate buffer and 0.5% sodium lauryl sulfate using a USP II apparatus (Paddle) at a temperature of 37±0.5°C and a rotation speed of 50 revolutions.

[0050] In another embodiment of the invention, the diluent comprises one or more of mannitol, lactose, microcrystalline cellulose, silicified microcrystalline cellulose, sucrose, starch, pregelatinized starch, maize starch, guar gum, xylitol, sorbitol, maltodextrin, polydextrose, isomalt, mixture of mannitol and maize starch, mixture of microcrystalline cellulose and guar gum or any mixtures or co-processed excipients thereof.

[0051] In another embodiment of the invention, the pH regulating agent comprises one or more organic acids (such as citric acid), inorganic acids (such as hydrochloric acid, sulphuric acid, phosphoric acid, or hydrobromic acid), basic amino acids, base (sodium hydroxide, potassium hydroxide, ammonium hydroxide, calcium hydroxide, trimethylamine or mixtures thereof. In a preferred embodiment, the pH regulating agent comprises one or more of citric acid, tartaric acid, oxalic acid, hydrochloric acid, sodium hydroxide, or mixtures thereof.

[0052] In another embodiment of the invention, one or more solubilizing agents are selected from the group comprising cyclodextrin (cyclodextrin analogs, such as but not limited to, alpha-, beta- and gamma-cyclodextrin analogs and their derivatives), sodium lauryl sulfate, hydroxypropylmethylcellulose, hydroxypropyl cellulose, sodium carboxymethylcellulose, povidone, or any combination or mixtures thereof. [0053] In another embodiment of the invention, one or more disintegrants are selected from the group comprising croscarmellose sodium, crospovidone, sodium starch glycolate, and low substituted hydroxypropyl cellulose.

[0054] In another embodiment of the invention, the sublingual pharmaceutical composition further comprises one or more sweetening and flavoring agents in an amount of about 0.1% to about 10% of the composition.

[0055] In another embodiment of the invention, the sublingual pharmaceutical composition is prepared by wet granulation (rapid mixture granulation, fluid bed granulation, spray drying), dry granulation, dry blending, dry mixing, and direct compression. Other formulation techniques are also contemplated within the scope of the present invention such as extrusion-spheronization, hot-melt extrusion, melt-granulation, freeze-drying, spray drying, mass extrusion and molding, solid dispersion (solvent evaporation, melting method, kneading method, co-grinding method, co-precipitation method, freeze-drying, spray-drying, coating, or adsorbing the drug onto carrier particles), multi-particulate based technology-palletization and drug-ion exchange resin complexation.

[0056] In another embodiment of the invention, the solvent used in the preparation of the composition is selected from the group comprising an aqueous solvent, alcoholic solvent, hydro-alcoholic solvent, acidic solvent, an ether solvent, or any mixtures thereof. In a preferred embodiment, one or more solvents used in the preparation of composition are selected from the group comprising ethanol, water, methanol, tetrahydrofuran, hydrochloric acid, sodium hydroxide, or any mixtures thereof in any volume ratio.

[0057] In another embodiment of the invention, there is provided a process of preparing sublingual tablet composition, includes the steps of: a) sifting the accurately weighed quantities of one or more pharmaceutically acceptable excipient(s) such as diluent and pH regulating agent through a suitable sieve, b) preparing a solution or dispersion of drug in suitable solvent, c) dissolving a suitable surfactant in suitable solvent (preferably water) and then adding suitable binder in that solution, d) granulating the mixture of step a) with a solution or dispersion of step b) followed by granulation with solution or dispersion of step c), e) drying the granulated mass, optionally milling of the dried granules, f) blending of dried granules with one or more pharmaceutically acceptable excipient(s) such as suitable disintegrant, glidant, sweetener, and optional flavor, and passing through a suitable size sieve, g) lubricating the sifted blend of step and passing through a suitable sieve, h) compressing the lubricated granules into tablets.

[0058] In another embodiment of the invention, there is provided a process of preparing sublingual tablet composition, includes the steps of: a) sifting the accurately weighed quantities of one or more pharmaceutically acceptable excipient(s) such as one or more of diluent and disintegrant through a suitable sieve, b) preparing a solution of solubilizing agent in suitable solvent (water and ethanol), c) dissolving the drug in solution as prepared in step b), followed by pH adjustment with IN hydrochloric acid at suitable pH and sodium hydroxide at suitable pH (such as between pH 2 to pH 4), d) granulating the mixture of step a) with a solution of step c), e) sifting the wet mass through a suitable sieve, f) drying the wet granules, and sifting through a suitable sieve, g) blending of dried granules with suitable diluent, disintegrant, glidant, sweetener, and optional flavor, tastemasking agent and sifting through a suitable sieve, h) lubricating the sifted blend of step g) and passing through a suitable sieve, i) compressing the lubricated granules into tablets. [0059] In another embodiment of the invention, there is provided a sublingual pharmaceutical composition comprising brexanolone and at least one or more pharmaceutically acceptable excipients, wherein the composition is stable. In another embodiment of the invention, the composition is stable at a stress condition of 80°C for at least 3 days.

[0060] In another embodiment, the present invention includes a sublingual pharmaceutical composition comprising brexanolone and at least one or more pharmaceutically acceptable excipients, wherein the composition is free of other polymorphic forms or any polymorphic form conversion.

[0061] In one embodiment, the composition has a pH from about 2.0 and about 7.5.

[0062] In another embodiment of the invention, the pH regulating agent is selected such that the degradation of the active ingredient or other components of the composition is slowed or reduced, as compared to a composition in which the pH raising agent is not present. For example, the pH regulating agent may at least help in preventing significant degradation of the composition after a certain period of shelf life. The sublingual composition is stable in pH range from about 2 to about 7 without an increase in impurities in composition due to instability of active ingredient.

[0063] In one embodiment, the sublingual pharmaceutical compositions as per present invention provide a method of increasing the bioavailability of brexanolone. More particularly, sublingual pharmaceutical compositions allow the active agent to by-pass undesirable first-pass metabolism, thereby enhancing the bioavailability of the active agent. Such sublingual compositions can offer several advantages over other modes of drug delivery, including, but not limited to, increased chemical stability of the active ingredient, sufficient shelf-life, good pharmacotechnical properties, stable drug release, increasing the onset of action, lowering the required dosage, enhancing the efficacy and improving the safety profile of the active agent.

[0064] Bioavailability refers to the proportion of the drug administered that reaches the physiological site where the drug exerts its therapeutic effect, which is generally regarded as the bloodstream for many drugs. The bioavailability of a drug is most readily expressed as the concentration of the drug or its active metabolites in the blood plasma integrated over time. This quantity is commonly referred to as the “area under the curve” or “AUC”. Sublingual administration of brexanolone according to this invention preferably increases the drug’s bioavailability at least 2% or more, at least 5% or more, 10% or more, 20% or more, 30% or more, 40% or more, or 50% or more as compared to oral administration. In a further embodiment, relative bioavailability studies can be performed to compare the bioavailability of the sublingual tablet formulation with injection (intravenous) dosage form.

[0065] In another embodiment of the invention, there is provided a sublingual pharmaceutical composition comprising brexanolone and at least one or more pharmaceutically acceptable excipients, wherein brexanolone has a particle size distribution of Doo less than about 250 pm, Dso less than about 150 pm and Dio less than about 60 pm. More particularly, brexanolone has a particle size distribution of D90 less than about 100 pm, Dso less than about 50 pm, and Dio less than about 30 pm. The terms Dio, D50, and D90 used herein as per the present invention indicate that 10%, 50%, and 90%, respectively, of the distribution is below this value. The particle size can be achieved by any well-known particle size reduction processes, such as sifting, milling, micronization, fluid energy milling, media milling, ball milling, milled through the high-pressure homogenizer, air-jet milling, and the like. The particle size can be measured by suitable techniques such as Laser light scattering (e.g. Malvern Light Scattering), Coulter counter, microscopy, and any other technique known in the art.

[0066] In one embodiment, pharmaceutical compositions of the present invention are the solid pharmaceutical compositions that rapidly disintegrate in the mouth of a subject, upon insertion into the buccal cavity or when placed under the tongue. In another embodiment of the invention, there is provided a sublingual tablet composition, wherein the sublingual tablet is intended to disintegrate in a time range of about 1 second to 300 seconds, preferably in about 1 second to 240 seconds, preferably in about 1 second to 120 seconds or in about 1 second to 60 seconds or within about 30 seconds. Rapid disintegration may include where the pharmaceutical composition is disintegrated in about 1 second to 300 seconds, preferably in about 1 second to 240 seconds, preferably in about 1 second to 120 seconds or in about 1 second to 60 seconds or within about 30 seconds. Disintegration time testing for tablets can be performed in a United States Pharmacopoeia 43 (USP), tablet disintegration tester wherein a tablet is placed in a basket, which moves upward and downward in a 1 -liter beaker of water at 37±2° C.

[0067] In another embodiment of the invention, the disintegration or dissolution time can also be measured in-vivo by placing the tablet in the sublingual cavity and measuring, using a stopwatch, the time that elapses between beginning of the measurement and the moment when the tablet completely disintegrated under the action of saliva and without chewing, so as to form only a viscous pulp, the patient not having to use, during all this time, any action of the jaws.

[0068] In another embodiment of the invention, there is provided a sublingual tablet composition, wherein the sublingual tablet dissolves in about 1 second to about 300 seconds in the mouth of a subject upon placement under the tongue.

[0069] In another embodiment of the invention, there is provided a pharmaceutical composition for sublingual administration comprising brexanolone in an amount from about 0.1 mg to about 60 mg and at least one pH regulating agent, wherein the pH regulating agent is capable to maintain the pH from about 2.0 and about 7.5 to facilitate dissolution of the brexanolone in sublingual mucosa. In another embodiment, the pH regulating agent is capable to maintain the pH from about 2.0 and about 4.5 to facilitate the dissolution of the brexanolone in sublingual mucosa. The pH can be measured by the following method as 1 tablet was disintegrated in 100 mL of purified water and pH was noted down using a calibrated pH meter. In another embodiment, the pH was measured by the following method: 1 tablet was taken and was added to 250mL of various media (0.01 N Hydrochloric acid, Acetate buffer, and Phosphate buffer). The solution was shaken for a suitable time (about 2 hrs.) and pH was measured using a calibrated pH meter. In an embodiment, the pH of the composition was found in the range of about 2 to 7.5.

[0070] In another embodiment of the invention, there is provided a sublingual pharmaceutical composition comprising brexanolone and pH regulating agent, wherein the ratio of the weight of brexanolone to the weight of the pH regulating agent is from 10: 1 to 1 : 10. In another preferred embodiment, the ratio of brexanolone to pH regulating agent is 2: 1 to 10: 1. In another preferred embodiment, the ratio of brexanolone to pH regulating agent is 4: 1.

[0071] The present invention further relates to sublingual pharmaceutical tablet composition comprising brexanolone, wherein brexanolone is associated with cyclodextrin in the composition to improve the solubility profile of brexanolone.

[0072] Brexanolone is presently approved in the USA as Zulresso® Injection (100mg/20ml), wherein each mL contains 5 mg of brexanolone, and 250 mg of betadex sulfobutyl ether sodium. The amount of cyclodextrin is very high in the marketed injection product (ratio of drug to cyclodextrin is 1 :50). This high amount and ratio of drug to cyclodextrin (1 :50) is not desirable as a) Cyclodextrin is not metabolized in-vivo in the human body, and b) After administration cyclodextrin is cleared exclusively by renal filtration. As such, the cyclodextrin gets accumulated in the patient’s body particularly those having decreased renal function. Thus, it is not desirable to use cyclodextrin in the pharmaceutical composition in such a high amount. The present inventors based on their hard work in the form of a series of experiments have determined and successfully developed sublingual pharmaceutical composition of brexanolone with a lesser amount of cyclodextrin. The developed sublingual compositions were able to achieve all desired formulation technical attributes such as assay, pH, disintegration time, and dissolution profile. In an embodiment, the ratio of the weight of brexanolone to the weight of the solubilizing agent is from about 0.01 :25 to about 25:0.01. Preferably, from about 0.1 :24 to about 24:0.1. More preferably, from about 0.1 :15 to 15:0.1. In another preferred embodiment, the weight ratio of brexanolone to the solubilizing agent is less than 1 :25. Preferably, about 1 : 15 or less. A most preferred ratio range is about 1 : 10 to 1 :24 or even about 1 : 10 to 1 :20. The inventors observed that not all developed sublingual formulations were able to achieve desired technical attributes such as pH, disintegration and dissolution profile. The sublingual formulations having the weight ratio of drug and solubilizing agents 1 :25 or more were not able to achieve the desired disintegration and dissolution profile and accordingly found not suitable for sublingual administration.

[0073] In another embodiment of the invention, there is provided a sublingual pharmaceutical composition comprising brexanolone and one or more solubilizing agents, wherein the ratio of the weight of brexanolone to the weight of the solubilizing agent is from 10:0.5 to 1 : 10. In another preferred embodiment, the ratio of brexanolone to the solubilizing agent is 1 :4 to 10: 1. In another preferred embodiment, the ratio of the brexanolone and solubilizing agent have a weight ratio from about 0.5: 10 to 10:0.5.

[0074] In one embodiment, brexanolone is released 80% or more within 30 minutes or 20 minutes after administration of the composition. More preferably the composition releases at least 80% drug in 15 minutes or less. More preferably the composition releases not less than 85% drug in 5 minutes. More preferably the composition releases not less than 75% drug in 30 minutes. The sublingual tablet compositions prepared by the process as per present invention can be subjected to in-vitro dissolution evaluation according to Test 711 "Dissolution" in the United States Pharmacopoeia 37, United States Pharmacopoeial Convention, Inc., Rockville, Md., 2014 ("USP") to determine the rate at which the active substance is released from the dosage form, and the content of the active substance can be determined in solution by high-performance liquid chromatography.

[0075] In another embodiment of the invention, there is provided a sublingual pharmaceutical tablet composition comprising brexanolone in an amount from about 0.1 mg to about 60 mg, a pH regulating agent capable of maintaining the pH from 2.0 to 7.0 to facilitate dissolution of the brexanolone in sublingual mucosa, a solubilizing agent present in an amount such that the ratio of brexanolone to the solubilizing agent is from 1 :4 to 10: 1 and one or more pharmaceutically acceptable excipients, wherein the composition dissolve in about 1 second to about 300 seconds in the mouth of a subject upon placement under the tongue.

[0076] In an embodiment, the release can be measured in 900 ml of 0.1N Hydrochloric acid using a USP II apparatus (Paddle) at a temperature of 37+0.5°C and a rotation speed of 50 revolutions per minute or by any other method known in the art.

[0077] In another embodiment of the invention, the compositions prepared by the process as per the present invention have a hardness from about 1 to about 70 Newtons (N), and a friability of less than 2% when measured by USP (United States Pharmacopoeia) method. Preferably, the hardness of the tablet according to the present invention is between about 15 N to 30 N. Preferably, the friability of the tablet according to the present invention is not more than 1%. Several devices can be used to test tablet hardness such as a Monsanto tester, a Strong-Cobb tester, a Pfizer tester, an Erweka tester, a Schleuniger tester, etc. Friability can be determined using a Roche friabilator for 100 revolutions at 25 rpm (revolutions per minute). In another embodiment of the invention, there is provided a sublingual tablet composition, which has a thickness of about 2 to about 10 mm. In another embodiment of the invention, there is provided a sublingual tablet composition, which has a diameter of about 2 to about 12 mm, preferably, 3 to 8 mm. In another embodiment of the invention, there is provided a sublingual tablet composition, which has a Carr's index in the range of about 1-30%, preferably about 20% value, more preferably about 5% to 15% value, which indicates good flowability.

[0078] In another embodiment of the invention, there is provided a sublingual tablet composition of brexanolone, wherein the composition has the assay in the range from 90% to 110% as measured by HPLC (High-Performance Liquid Chromatography) method using suitable column (such as Zorbax SB-C18).

[0079] In another embodiment of the invention, content uniformity of sublingual composition is within acceptable limits and met the requirements for dosage uniformity, in the acceptance value less than or equal to 15% as measured by a suitable technique such as HPLC (High-Performance Liquid Chromatography) method.

[0080] In one embodiment, the present invention relates to use of sublingual pharmaceutical composition comprising brexanolone in the manufacture of medicament for treating, preventing, ameliorating, and/or delaying the onset of one or more symptoms associated with or resulting from seizures, epilepsy, partial-onset seizures, absence seizures, infantile spasms, PCDH19 epilepsy, tremor, depression, bipolar disorder, major depressive disorder, post-partum depression, treatment-resistant depression, seasonal affective disorder, stress, anxiety, generalized anxiety disorder, panic disorder with or without agoraphobia, schizophrenia, post-traumatic stress disorder, autistic disorder, Alzheimer's disease, Parkinson’s disease, insomnia, dementia, dementia-related psychosis, frontotemporal degeneration, Lewy body dementia, vascular dementia, disinhibition syndrome, alcohol craving, smoking cessation, traumatic brain injury, lysosomal storage disorders, premenstrual dysphoric disorder, status epilepticus such as generalized status epilepticus, early status epilepticus, established status epilepticus, refractory status epilepticus, super-refractory status epilepticus, non-convulsive status epilepticus, e.g., complex partial status epilepticus, pain associated with diabetic peripheral neuropathy, chronic musculoskeletal pain, genitourinary system diseases, Dravet syndrome, Lennox- Gastaut syndrome, tuberous sclerosis complex, and Rett syndrome.

[0081] In one embodiment, the present invention relates to the use of a sublingual pharmaceutical composition comprising brexanolone in the manufacture of a medicament for treating, preventing, ameliorating, and/or delaying the onset of one or more symptoms associated with or resulting from a viral infection, preferably a respiratory viral infection in a subject, caused by members of the filoviridae, flaviviridae paramyxoviridae, orthomyxoviridae, coronaviridae, arenaviridae or adenoviridae families. In an embodiment, the viral infection is a coronavirus infection. In another embodiment, the present invention provides the use of sublingual pharmaceutical compositions of the present invention in the treatment of COVID-19 infection. In another embodiment, the present invention provides the use of sublingual pharmaceutical compositions of the present invention in the treatment of CO VID-19 related acute respiratory distress syndrome (ARDS).

[0082] In one embodiment, the composition can be administered at least once daily or divided into multiple daily doses from once per day to once in six months such as twice daily, three times daily, four times daily, once a week, twice in a week, thrice in a week, once in two weeks, once in three weeks, once in four weeks or like. In one embodiment, the composition is intended for at least once daily administration. [0083] In one embodiment, the administration comprises administering one or more cycles of treatment with brexanolone. In one embodiment, the composition is administered in one or more cycles of treatment such that first administering the first dose followed by one or more other doses. The subsequent doses can be the same as, or reduced from, the first administered dose.

[0084] In a preferred embodiment, the sublingual tablets in a sufficient amount to provide 1 to 200 mg per day of brexanolone can be administered as needed. In another embodiment, the sublingual pharmaceutical compositions are for self-administration by patients. In another embodiment, the sublingual pharmaceutical compositions eliminate the hospitalization requirements. In another embodiment, sublingual pharmaceutical compositions avoid requirements of specialized infrastructure set-up, hospital settings, trained professional personnel, and any special storage conditions, and accordingly are cost-efficient.

[0085] In another embodiment, sublingual pharmaceutical compositions of the present invention may be packaged in HDPE bottles or glass bottles, or blister packs. Packaging material may optionally contain desiccants. Further, the composition of the present invention is packaged into a suitable pack together with instructions to place the dosage form under a patient's tongue or in the buccal cavity.

[0086] Any pharmaceutically acceptable granulating agent can be used for wet granulation. Preferable granulating solvents include, but are not limited to, aqueous, nonaqueous, alcoholic, hydro-alcoholic, ether, acidic solvents as a granulating liquid such as water, esters such as ethyl acetate, ketones such as acetone, alcohols such as methanol, ethanol (including ethanol 95%), isopropanol, butanol, di chloromethane, chloroform, dimethylacetamide, dimethyl sulfoxide, ether (such as tetrahydrofuran, methyl tert-butyl ether, 1,4-di oxane and combinations thereof), 2-methyl-tetrahydrofuran, diethyl ether, hydrochloric acid (such as IN hydrochloric acid), sodium hydroxide, mixtures of one or more alcohols and water and any combinations or mixtures thereof. In a further embodiment, solvents used are mixtures of one or more alcohol and water, in various volume ratios. In some embodiment, suitable organic or inorganic acids or bases selected from the group comprising citric acid, malic acid, fumaric acid, tartaric acid, hydrochloric acid, sodium hydroxide can also be added in the granulation process or granulation solution.

[0087] Various useful fillers or diluents or carriers include, but are not limited to, microcrystalline cellulose ("MCC"), sodium alginate, silicified MCC, microfine cellulose, lactitol, cellulose acetate, kaolin, glucose, lactose, maltose, fructose, sucrose, trehalose, starch, pregelatinized starch (PGS), maize starch, guar gum, sugar alcohols such as mannitol, D-mannitol, xylitol, maltitol, sorbitol, dextrates, dextrin, maltodextrin, compressible sugar, confectioner’s sugar, dextrose, poly dextrose, simethicone, calcium carbonate, calcium sulfate, calcium phosphate, dibasic calcium phosphate, tribasic calcium phosphate, magnesium carbonate, magnesium oxide, isomalt, a mixture of microcrystalline cellulose and mannitol, a mixture of mannitol and maize starch, a mixture of microcrystalline cellulose and guar gum such as Avicel® CE15 (combination of 85% microcrystalline cellulose and 15% guar gum) or any mixtures or combinations thereof. The amount of diluent ranges from about 0 to about 95% by weight of the composition. In an embodiment, the diluent according to the present invention is present in an amount of about 90% or less, 80% or less, e.g. 70% or less, 60% or less, 50% or less, 40% or less, 30% or less, 20% or less.

[0088] Various useful binders include, but are not limited to, acacia, guar gum, xanthan gum, alginic acid, sodium alginate, dextrin, carbomer, maltodextrin, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), hydroxyethyl methylcellulose, carboxymethyl cellulose sodium, cottonseed oil, povidone (PVP), Ceratonia, dextrose, polydextrose, starch, gelatin, guar gum, pregelatinized starch, hydrogenated vegetable oil type I, maltodextrin, microcrystalline cellulose, polyethylene oxide, polymethacrylates and mixtures thereof. Binder can be present in powder form or as a dispersion or mixture of both, in intra and/or extra granular part of the composition. The amount of binder ranges from about 0 to about 50% by weight of the composition. In an embodiment, the binder is present in an amount of about 50% or less, 40% or less, e.g. 30% or less, 20% or less, 10% or less, 5% or less.

[0089] Various useful disintegrants and/or super-disintegrants include, but are not limited to, croscarmellose sodium, carboxymethyl cellulose sodium, carboxymethyl cellulose calcium, povidone, crospovidone, polacrilin potassium, sodium starch glycolate, alginic acid, sodium alginate, calcium phosphate, colloidal silicon dioxide, docusate sodium, guar gum, low substituted hydroxypropyl cellulose, magnesium aluminum silicate, methylcellulose, microcrystalline cellulose, silicified microcrystalline cellulose, starch, pre-gelatinized starch and/or combinations thereof. The disintegrant can be present in intra-granular or extra-granular parts or both (intra and extra granular) parts of the composition. The amount of disintegrant ranges from about 0 to about 40% by weight of the composition. In an embodiment, the disintegrant is present in an amount of about 40% or less, 30% or less, e.g. 20% or less, 10% or less.

[0090] Pharmaceutically acceptable lubricants include, but are not limited to, stearic acid, zinc stearate, sucrose stearate, sodium benzoate, hydrogenated vegetable oil, calcium stearate, adipic acid, glyceryl palmitostearate, glycerine monostearate, mediumchain triglycerides, glyceryl behenate, sodium lauryl sulphate, sodium stearyl fumarate, magnesium lauryl sulphate, magnesium stearate, polyethylene glycol. The amount of lubricant ranges from about 0 to about 10% by weight of the composition. In an embodiment, the lubricant is present in an amount of about 10% or less, e.g. 5% or less, 2% or less.

[0091] Pharmaceutically acceptable adsorbents include, but are not limited to, silica, microcrystalline cellulose, cellulose, silicified microcrystalline cellulose, clay, talc, starch, pregelatinized starch, calcium carbonate, dicalcium phosphate, magnesium carbonate, silicon dioxide, amorphous silica, hydrated silicon dioxide, fumed silica, colloidal silicon dioxide, magnesium aluminum silicate, magnesium silicate, calcium silicate, or a mixture thereof. One non-limiting adsorbent is silica. In an embodiment, the adsorbent is present in an amount of about 40% or less, e.g. 30% or less, 20% or less, 5% or less, 2% or less.

[0092] Various useful surfactants include, but not limited to, sodium lauryl sulphate, polysorbate (e.g. polysorbate 20, polysorbate 40, polysorbate 60, and polysorbate 80), cetrimide, cetyl alcohol, stearyl alcohol, cetyl stearyl alcohol, cholesterol, polyethylene glycols, polyglycerin fatty acid esters such as decaglyceryl monolaurate and decaglyceryl monomyristate, sorbitan fatty acid esters such as sorbitan monostearate, polyoxyethylene sorbitan fatty acid ester such as polyoxyethylene sorbitan monooleate, polyoxyethylene alkyl ether such as polyoxyethylene lauryl ether, polyoxyethylene castor oil, polyoxyethylene polyoxypropylene block copolymers such as poloxamer (such as poloxamer 124, poloxamer 188, poloxamer 237, poloxamer 338, and poloxamer 407), and combinations thereof. The amount of surfactant ranges from about 0 to about 30% by weight of the composition. In an embodiment, the surfactant is present in an amount of about 30% or less, e.g. 20% or less, 10% or less, 5% or less, or 2% or less.

[0093] Suitable pH regulating agents includes, but are not limited to, disodium hydrogen phosphate, sodium dihydrogen phosphate and the equivalent potassium salt, alkaline oxides (potassium oxide, sodium oxide, barium oxide, magnesium oxide and aluminium oxide), sodium hydroxide, potassium hydroxide, calcium hydroxide, calcium oxide, citrate, phosphate, borate salts, organic and inorganic acids such as citric acid, lactic acid, acetic acid, formic acid, oxalic acid, uric acid, malic acid, tartaric acid, succinic acid, benzoic acid, sorbic acid, ascorbic acid, phosphoric acid, boric acid, hydrochloric acid, sulphuric acid, nitric acid, phosphoric acid, hydrobromic acid, hydroiodic acid or hydrofluoric acid, as known in the art such as those described above, carbonate salts (sodium carbonate, potassium carbonate, calcium carbonate, ammonium carbonate, or magnesium carbonate), bicarbonate salts (sodium bicarbonate, potassium bicarbonate, calcium bicarbonate, ammonium bicarbonate, or magnesium bicarbonate), basic amino acids (arginine, histidine, lysine, glycine), amino sugars (N-acetylglucosamine, galactosamine, glucosamine, sialic acid, or meglumine). Binary buffer systems are also included in the ambit of the present invention. The amount of pH regulating agent ranges from about 0 to about 20% by weight of the composition. In an embodiment, the pH regulating agent is present in an amount of about 20% or less, e.g. 10% or less, 5% or less, 3% or less.

[0094] Suitable glidants include, but are not limited to, calcium silicate, magnesium silicate, magnesium trisilicate, stearic acid and its derivatives or esters like magnesium stearate, calcium stearate, and sodium stearate and the corresponding esters such as sodium stearyl fumarate, talc, colloidal silicon dioxide, tribasic calcium phosphate, starch, starch derivatives or mixtures thereof. The amount of glidant ranges from about 0 to about 20% by weight of the composition. In an embodiment, the glidant is present in an amount of about 20% or less, e.g. 10% or less, 5% or less, 3% or less. [0095] Various useful solubilizing agents, permeation/penetration enhancers include, but are not limited to, alcohols, polyethylene glycols, cyclodextrins (cyclodextrin analogs, such as but not limited to, alpha-, beta-, and gamma-cyclodextrin analogs and their derivatives such as sulfobutylether-P-cyclodextrin (SBECD)), sodium lauryl sulfate, hydroxypropylmethylcellulose, hydroxypropyl cellulose, sodium carboxymethylcellulose, povidone, sucrose laurate or sucrose oleate, sodium dodecyl sulfate (SDS) or palmitoyl carnitine chloride (PCC) and citric acid or any combination or mixtures thereof. The amount of solubilizing agent, permeation/penetration enhancer ranges from about 0 to about 70% by weight of the composition. In an embodiment, the solubilizing agent, permeation enhancer is present in an amount of about 60% or less, 50% or less, 40% or less, 30% or less, 20% or less, 10% or less, e.g. 5% or less, 3% or less, 2% or less.

[0096] Various useful preservatives include, but are not limited to, citric acid, butylated hydroxyanisole, vitamin C, vitamin E, parabens (methylparaben, propylparaben), phenyl ethyl alcohol, sorbic acid, benzyl alcohol, alkyl benzyl dimethylammonium chloride with a chain length of from Csto Cis in the alkyl moiety, m-cresol or alkyl-4- hydroxybenzoate. The amount of preservatives ranges from about 0 to about 20% by weight of the composition. In an embodiment, the preservatives are present in an amount of about 20% or less, e.g. 10% or less, 5% or less, 3% or less.

[0097] Various useful flavoring agents include, but are not limited to, mint powder, peppermint, menthol, vanillin, aspartame, acesulfame potassium, saccharin sodium, aromatics and/or natural oils, synthetic flavor oils, extracts from plants, leaves, flowers, fruits, and combinations thereof, commercially available orange, grape, cherry and bubble gum flavors, tutti-frutti flavors and mixtures thereof. The amount of flavoring agents ranges from about 0 to about 20% by weight of the composition. In an embodiment, the flavoring agents are present in an amount of about 10% or less, e.g. 5% or less, 3% or less, 2% or less, or 1% or less.

[0098] Various useful sweetening agents include, but are not limited to, sugars such as sucrose, sucralose, glucose, dextrose, maltose, fructose, artificial sweeteners (such as saccharin, saccharin sodium, aspartame, acesulfame, acesulfame potassium, neohesperidine dihydrochalcone, monoammonium glycyrrhizinate, sugar alcohols (such as mannitol, xylitol, lactitol, maltitol syrup), thaumatin and mixtures thereof, present conveniently in an amount of from about 0 to about 65% by weight of the composition. In an embodiment, the sweetening agents are present in an amount of about 65% or less, e.g. 60% or less, 50% or less, 40% or less, 30% or less, 20% or less, 10% or less, 5% or less, 3% or less, 2% or less, or 1% or less.

[0099] Various useful taste-masking agents include, but are not limited to, amberlite, Opadry® AMB TAN, polymethacrylates (such as Eudragit® LI 00), sodium starch glycolate (Primojel®), carbopol polymers, PEG-5M, sodium acetate, ethylcellulose, beta-cyclodextrin, polyvinyl acetate dispersion, trehalose, vinyl acetate, polystyrene, cellulose acetate butyrate. In an embodiment, the taste-masking agents are present in an amount of about 40% or less, e.g. 30% or less, 20% or less, 10% or less, 5% or less, 3% or less, 2% or less, or 1% or less.

[0100] Various other excipients or inert ingredients such as antioxidants, acidulants, effervescent agents, salivating agents, water-soluble and/or water-dispersible carrier materials, bio/mucoadhesion promoting agents, stabilizers, emulsifiers, plasticizers, suspending agents, and coloring agents are also covered under the ambit of the present invention. The amount of these excipients may range from about 0 to about 90% by weight of the composition. In an embodiment, these excipients are present in an amount of about 90% or less, 80% or less, e.g. 70% or less, 60% or less, 50% or less, 40% or less, 30% or less, 20% or less, 10% or less.

[0101] The following examples are provided to illustrate embodiments of the disclosure but they are by no means intended to limit its scope.

[0102] EXAMPLES: Brexanolone sublingual tablets were prepared by using the quantitative formula as given in Table 1, 2, and 3 (Quantity /Tablet (%w/w))

Table 1: Examples (Ex.) 1-2

Procedure: Wet granulation.

Table 2: Examples (Ex.) 3-8

Procedure: i) Diluent and disintegrant were sifted through a suitable sieve, ii) solubilizing agent and binder were dispersed into a suitable solvent (such as ethanol or water or mixtures), iii) drug was dispersed into the solution of step ii), iv) pH regulating agent (such as citric acid or IN Hydrochloric acid and/or sodium hydroxide was added in an above solution of step iii), v) step i) blend was granulated using the dispersion of step iv), vi) wet granules were dried followed by passing the dried granules through a suitable sieve, vii) dried granules were blended with suitable excipients such as a diluent, sweetener, disintegrant, glidant, flavor (optional), and lubricant and were further sifted through a suitable sieve, viii) the blend of step vii) was compressed into tablets using suitable punches.

The sublingual tablet composition of brexanolone prepared using quantitative compositions as per the above-mentioned tables exhibits desirable formulation technical attributes such as dissolution (not less than 75% of drug release in 30 minutes or less), pH (from about 2 to 7.5), and disintegration time (within 300 seconds).

Table 3: Examples (Ex.) 9-15

Procedure: i) The solubilizing agent was added to the solvent and was stirred to dissolve completely, ii) Drug was added to the solvent and further stirred to dissolve completely, iii) The solution of step i) was added to the solution of step ii) and was stirred to dissolve completely, iv) Excipients such as diluents, disintegrants, and adsorbents/glidants were sifted through a suitable sieve, v) The mixture of step iv) was granulated using the solution of step iii), vi) The wet mass was dried in a dryer for a suitable time period, vii) Sweeteners and lubricant were sifted through a suitable sieve and were mixed with the material of step vi) to form a uniform blend, viii) The blend of step vii) was compressed using suitable tooling.

The tablets of Examples 10-15 have ratios of drug to solubilizing agent as set forth below:

Results: The results of assay, disintegration time and dissolution profile of the above formulations are presented below in Tables 4 and 5. The dissolution profile was measured in 900 ml of 6.8 phosphate buffer and 0.5% sodium lauryl sulfate (SLS) using a USP II apparatus (Paddle) at a temperature of 37±0.5°C and a rotation speed of 50 revolutions per minute. The inventors observed that not all of the developed sublingual formulations were able to achieve desired technical attributes such as disintegration and dissolution profile. The sublingual formulations having a ratio of drug and solubilizing agents of 1 :25 or more were not able to achieve desired disintegration time and accordingly found not to be suitable for sublingual administration.

Table 4

Claims

WHAT IS CLAIMED:

1. A sublingual pharmaceutical composition comprising: a) brexanolone or its pharmaceutically acceptable salts thereof in an amount of about 0.01% to about 30% by weight; b) one or more solubilizing agents selected from the group consisting of cyclodextrin, sodium lauryl sulfate, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, or mixtures thereof in an amount from about 0.01% to about 60% by weight; c) one or more diluents selected from the group consisting of mannitol, lactose, microcrystalline cellulose, sucrose, starch, pregelatinized starch, maize starch, guar gum, xylitol, sorbitol, maltodextrin, mixture of mannitol and maize starch, mixture of microcrystalline cellulose and guar gum, polydextrose, isomalt, or mixtures thereof in an amount from about 5% to about 80% by weight; d) one or more disintegrants selected from the group consisting of croscarmellose sodium, crospovidone, sodium starch glycolate, and low substituted hydroxypropyl cellulose, or mixtures thereof in an amount from about 0.5% to about 20% by weight; and e) at least one or more other pharmaceutically acceptable excipients; wherein the weight ratio of brexanolone to the solubilizing agent is from about 1 : 10 to about 1 :24.

2. The sublingual pharmaceutical composition according to claim 1, wherein the composition is a sublingual tablet, and is not an orally disintegrating tablet.

3. The sublingual pharmaceutical composition according to claim 1, wherein the composition dissolves within about 300 seconds in the mouth of a subject upon placement under the tongue.

4. The sublingual pharmaceutical composition according to claim 1, wherein the amount of brexanolone in the composition ranges from about 0.1 mg to about 30 mg.

5. The sublingual pharmaceutical composition according to claim 1, wherein the amount of brexanolone in the composition ranges from about 5 mg to about 10 mg.

6. The sublingual pharmaceutical composition according to claim 1, wherein the brexanolone and solubilizing agent have a weight ratio of about 1 : 15.

34 The sublingual pharmaceutical composition according to claim 1, wherein the brexanolone and disintegrant have a weight ratio from about 0.5: 10 to 10:0.5. The sublingual pharmaceutical composition according to claim 1, wherein one or more other pharmaceutically acceptable excipients are selected from the group consisting of binder, surfactant, pH regulating agent, glidant, adsorbent, lubricant, sweetener, taste masking agent, and flavoring agent. The sublingual pharmaceutical composition according to claim 1, wherein the pH of the composition is 2 to 7.5. The sublingual pharmaceutical composition according to claim 1, wherein the composition is prepared by the wet granulation process. The sublingual pharmaceutical composition according to claim 1, wherein the composition further comprises one or more sweetening agents selected from the group consisting of sucrose, dextrose, sucralose, sorbitol, fructose, mannitol, saccharin sodium, aspartame, thaumatin, and combination thereof in an amount of about 0.1% to about 20% by weight of the composition. The sublingual pharmaceutical composition according to claim 1, wherein the composition further comprises one or more flavoring agents selected from the group consisting of orange, grape, lime, vanilla, bubble gum, peppermint, tutti-frutti, strawberry, and combination thereof in an amount of about 0.01% to about 10% by weight of the composition. The sublingual pharmaceutical composition according to claim 1, further comprises from about 0.01% to about 3% by weight of one or more glidants. The sublingual pharmaceutical composition according to claim 1, further comprises from about 0.01% to about 3% by weight of one or more lubricants. The sublingual pharmaceutical composition according to claim 1, wherein the composition is stable and comprises less than 2% of total impurities. The sublingual pharmaceutical composition according to claim 1, wherein the composition is self-administered by a patient. A sublingual tablet pharmaceutical composition comprising: a) brexanolone in an amount of about 0.01% to about 10% by weight; b) one or more solubilizing agents selected from the group consisting of beta-

35 cyclodextrin, sodium lauryl sulfate, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, or mixtures thereof in an amount from about 0.01% to about 40% by weight; c) one or more diluents selected from the group consisting of mannitol, lactose, microcrystalline cellulose, sucrose, starch, pregelatinized starch, maize starch, guar gum, xylitol, sorbitol, maltodextrin, mixture of mannitol and maize starch, mixture of microcrystalline cellulose and guar gum, polydextrose, isomalt, or mixtures thereof in an amount from about 5% to about 80% by weight; d) one or more disintegrants selected from the group consisting of croscarmellose sodium, crospovidone, sodium starch glycolate, and low substituted hydroxypropyl cellulose, or mixtures thereof in an amount from about 0.5% to about 15% by weight; and e) at least one or more other pharmaceutically acceptable excipients; wherein the weight ratio of brexanolone to the solubilizing agent is from about 0.1 :15 to 15:0.1 and the composition exhibits an in-vitro dissolution rate of not less than 75% of drug release within 30 minutes when measured in 900 ml of 6.8 phosphate buffer and 0.5% sodium lauryl sulfate using a USP II apparatus (Paddle) at a temperature of 37±0.5°C and a rotation speed of 50 revolutions.

18. The sublingual pharmaceutical composition according to claim 17, wherein the one or more other pharmaceutically acceptable excipients comprises one or more sweetening and flavoring agents in an amount of about 0.1% to about 10% by weight of the composition.

19. A method of treating and/or preventing depression by administering brexanolone while increasing the bioavailability of the brexanolone compared to an orally administered dosage form by avoiding first-pass metabolism, the method comprising administering a sublingual pharmaceutical composition placed under the tongue or inserted into the buccal cavity, the sublingual pharmaceutical composition being in the form of a tablet consisting of: a. brexanolone; b. beta-cyclodextrin, wherein the weight ratio of brexanolone to beta-cyclodextrin is from about 1 : 10 to 1 :24; c. one or more diluents selected from the group consisting of mannitol, microcrystalline cellulose, maize starch, guar gum, or mixtures thereof in an amount from about 5% to about 80% by weight; and d. one or more disintegrants selected from the group consisting of croscarmellose sodium, crospovidone, and low substituted hydroxypropyl cellulose, or mixtures thereof in an amount from about 0.5% to about 15% by weight; wherein the composition has a disintegration time of about 30 seconds to about 300 seconds or less and the composition exhibits an in-vitro dissolution rate of at least 75% drug release within 30 minutes when measured in 900 ml of 6.8 phosphate buffer and 0.5% sodium lauryl sulfate using a USP II apparatus (Paddle) at a temperature of 37±0.5°C and a rotation speed of 50 revolutions.

20. A sublingual tablet pharmaceutical composition comprising: a) brexanolone in an amount of about 0.01% to about 10% by weight; b) beta-cyclodextrin in an amount from about 0.01% to about 40% by weight; c) one or more diluents selected from the group consisting of mannitol, microcrystalline cellulose, maize starch, guar gum, or mixtures thereof in an amount from about 5% to about 80% by weight; and d) one or more disintegrants selected from croscarmellose sodium, crospovidone, and low substituted hydroxypropyl cellulose, or mixtures thereof in an amount from about 0.5% to about 15% by weight; wherein the composition has a disintegration time of about 30 seconds to about 300 seconds and the composition exhibits an in-vitro dissolution rate of not less than 75% of drug release within 30 minutes when measured in 900 ml of 6.8 phosphate buffer and 0.5% sodium lauryl sulfate using a USP II apparatus (Paddle) at a temperature of 37±0.5°C and a rotation speed of 50 revolutions.