Dextromethorphan pharmaceutical composition for sublingual application and application thereof

Abstract

The invention belongs to the field of pharmacy, and particularly provides a pharmaceutical composition and a method for treating neurological disorders through sublingual administration, and the pharmaceutical composition comprises dextromethorphan or pharmaceutically acceptable salts thereof for sublingual administration.

Description

Technical Field

[0001] The invention belongs to the field of pharmaceuticals, and in particular relates to a sublingually administered dextromethorphan pharmaceutical composition and application thereof. Background Art

[0002] Dextromethorphan (DM) has been used as a cough suppressant for more than 70 years. In the past decade, dextromethorphan has also been studied for a variety of neurological diseases, including Parkinson's disease (PD), stroke, acute brain injury, neuropathic pain, etc. However, dextromethorphan has a severe first-pass effect when administered orally, that is, the molecule is easily metabolized by the liver into inactive ingredients when taken orally. Studies have shown that quinidine or bupropion enhances the oral absorption of dextromethorphan by inhibiting the activity of liver metabolic enzymes. In 2010, the FDA approved the combination of dextromethorphan and quinidine for the treatment of pseudobulbar affective disorder (PBA), with the trade name Nuedexta®; in 2022, the FDA approved the combination of dextromethorphan and bupropion for the treatment of major depressive disorder (MDD), with the trade name Auvelity®.

[0003] Taking Nuedexta® as an example, the FDA Review document shows that in a single-dose experiment in beagle dogs, DM was orally administered at 10 mg / kg, and AUC (0-t) is 153 ng•hr / mL, Cmax is 49 ng / mL; DM and quinidine are taken orally at 10 / 2 mg / Kg, and the AUC of DM is (0-t) 300 ng•hr / mL, Cmax is 88 ng / mL, and absorption is increased by 1 times; in a single-dose experiment in humans, DM took 30 mg orally, AUC (0-t) is 17.8 ng•hr / mL, Cmax is 2.9 ng / mL; DM and quinidine are taken orally at 30 / 10 mg / kg, AUC (0-t) It is 451.7 ng•hr / mL, Cmax is 63.7 ng / mL, and absorption is increased by about 25 times.

[0004] However, safety concerns with either compound, quinidine or bupropion, limit the use of dextromethorphan in the treatment of neurological disorders. Quinidine has proarrhythmic effects by directly inhibiting the myocardium and delaying the conduction of myocardial repolarization. When used to maintain sinus rhythm after cardioversion, quinidine may increase mortality by about three times, although this conclusion is based on a small sample size. In addition, quinidine prolongs the QT interval in a dose-dependent manner, which also increases the risk of arrhythmias. Bupropion, another drug commonly co-administered with dextromethorphan, can induce seizures, and the risk of inducing seizures is dose-dependent.

[0005] Therefore, it is necessary to develop a safer dextromethorphan formulation for the treatment of cough symptoms or neurological diseases associated with cough symptoms to reduce side effects. Summary of the invention

[0006] The present invention provides a sublingually administered pharmaceutical composition (also referred to as a sublingual preparation), which comprises dextromethorphan ((+)-3-methoxy-17-methyl-9α,13α,14α-morphinan) or a pharmaceutically acceptable salt thereof.

[0007] Alternatively, the present invention provides use of dextromethorphan or a pharmaceutically acceptable salt thereof in preparing a pharmaceutical composition for sublingual administration.

[0008] According to the present invention, the sublingually administered pharmaceutical composition can treat a neurological disorder or reduce a coughing condition or symptoms associated with a coughing condition.

[0009] According to the present invention, the content of dextromethorphan ((+)-3-methoxy-17-methyl-9α,13α,14α-morphinan) or a pharmaceutically acceptable salt thereof in the sublingually administered pharmaceutical composition is about 0.01 wt % to about 25 wt %, preferably about 1-25 wt %.

[0010] According to the present invention, the pharmaceutically acceptable salt is an acid salt of dextromethorphan.

[0011] According to the present invention, the pharmaceutically acceptable salt is dextromethorphan hydrobromide.

[0012] According to the present invention, dextromethorphan is in the free base form.

[0013] According to the present invention, the pharmaceutical composition is in the dosage form of a pill, tablet, film, hydrogel, strip or liquid.

[0014] According to the present invention, the pharmaceutical composition further comprises a penetration enhancer.

[0015] According to the present invention, the penetration enhancer is L-arginine.

[0016] According to the present invention, the content of the penetration enhancer in the sublingually administered pharmaceutical composition is about 0.5-20 wt %, preferably about 2-15 wt %, and more preferably about 5-10 wt %.

[0017] According to the present invention, the sublingual pharmaceutical composition comprises about 0.01 wt %-25 wt %, preferably about 1-25 wt % of dextromethorphan and about 0.5-20 wt %, preferably about 2-15 wt %, more preferably about 5-10 wt % of a penetration enhancer (e.g., L-arginine), and is preferably in the form of a tablet.

[0018] According to the present invention, the pharmaceutical composition further comprises an excipient (filler).

[0019] According to the present invention, the excipients include sweeteners, flavoring agents (corrigents), taste-masking agents, binders, dispersants, lubricants, disintegrants or a combination thereof.

[0020] According to the present invention, the binder is an agent that provides cohesive properties to the powder material through particle-particle bonding, including, for example, matrix binders (dry starch, dry sugar), film binders (starch paste, cellulose, bentonite, sucrose), chemical binders (e.g., polymeric cellulose derivatives such as carboxymethyl cellulose, etc.), syrup, corn syrup, water-soluble polysaccharides (e.g., gum arabic, tragacanth, guar gum, alginate, etc.), gelatin, gelatin hydrolyzate, agar, sucrose, dextrose, non-cellulose binders (e.g., PEG, pregelatinized starch, sorbitol, glucose, etc.), preferably gelatin.

[0021] According to the present invention, lubricants include talc, magnesium stearate, fumed silica (Carbosil, Aerosil), micronized silica (Syloid No. FP 244, Grace USA), preferably magnesium stearate.

[0022] According to the present invention, the dispersant includes polyethylene glycol-4000, polyethylene glycol-6000, povidone / polyvinylpyrrolidone (PVP-K30) and Poloxamer 188, preferably PVP-K30.

[0023] According to the present invention, the disintegrant comprises cross-linked sodium carboxymethylcellulose, starch, starch derivatives, clay, gum, cellulose, cellulose derivatives, alginates, sodium starch glycolate and microcrystalline cellulose, and cross-linked polyvinyl pyrrolidone (PVPP), preferably PVPP.

[0024] According to the present invention, the sweetener is selected from sucrose, fructose, sorbitol, aspartame, neotame, acesulfame potassium, sucralose, saccharin, saccharin sodium, xylitol and combinations thereof.

[0025] According to the present invention, the flavoring agent is selected from citric acid, mint, methyl salicylate, mannitol, fruit flavoring and combinations thereof.

[0026] According to the present invention, the taste masking agent is selected from amber flakes, β-cyclodextrin, cellulose acetate butyrate, carbopol polymer, ethyl cellulose, polymethacrylate, polystyrene, polyvinyl acetate dispersion, PEG-5M, sodium starch glycolate, sodium acetate, trehalose, vinyl acetate and combinations thereof.

[0027] According to the present invention, the pharmaceutical composition comprises about 1 mg to about 100 mg of dextromethorphan or a pharmaceutically acceptable salt thereof (unit dose, the same below).

[0028] According to the present invention, the pharmaceutical composition comprises about 5 mg to about 40 mg of dextromethorphan or a pharmaceutically acceptable salt thereof.

[0029] According to the present invention, the pharmaceutical composition comprises about 10 mg of dextromethorphan or a pharmaceutically acceptable salt thereof.

[0030] According to the present invention, the pharmaceutical composition comprises about 20 mg of dextromethorphan or a pharmaceutically acceptable salt thereof.

[0031] The present invention also provides a pharmaceutical composition, wherein when the pharmaceutical composition is sublingually administered to a subject, the pharmaceutical composition of the present invention provides the same or higher exposure to dextromethorphan (AUC 1.0045 / ml) than after oral administration of a pharmaceutical composition comprising an equal amount of dextromethorphan or a pharmaceutically acceptable salt thereof and a compound that inhibits cytochrome P450 isozyme CYP2D6. (0-t) ).

[0032] The present invention also provides a pharmaceutical composition, wherein when the pharmaceutical composition is sublingually administered to a subject, the pharmaceutical composition provides a higher exposure to dextromethorphan (AUC 1.004) than after oral administration of a pharmaceutical composition comprising an equal amount of dextromethorphan or a pharmaceutically acceptable salt thereof. (0-t) ).

[0033] The present invention also provides a pharmaceutical composition, wherein when the pharmaceutical composition is sublingually administered to a subject, the pharmaceutical composition provides at least about 1.5 times, at least about 20 times, at least about 30 times, or at least about 40 times the AUC when compared to oral administration of a pharmaceutical composition comprising an equal amount of dextromethorphan or a pharmaceutically acceptable salt thereof. (0-t) .

[0034] According to the present invention, the pharmaceutical composition of the present invention is a sublingual tablet, comprising an acid salt of dextromethorphan (e.g., dextromethorphan hydrobromide), a penetration enhancer (e.g., L-arginine), a flavoring agent (e.g., citric acid or mannitol), a sweetener (e.g., saccharin sodium or neotame), and optionally other excipients (e.g., gelatin, PVP-K30 / PVPP, magnesium stearate).

[0035] The present invention also provides a method for treating a nervous system disease (or a neurological disorder), comprising sublingually administering a therapeutically effective amount of dextromethorphan or a pharmaceutically acceptable salt thereof to a subject in need thereof.

[0036] According to the method of the present invention, the nervous system diseases (or neurological disorders) include pseudobulbar affective disorder, depression, Parkinson's disease, stroke, acute brain injury, neuropathic pain, nicotine addiction, and Alzheimer's disease.

[0037] The methods of the present invention reduce dextromethorphan exposure (AUC (0-t) ) is increased by at least about 1.5 times, at least about 20 times, at least about 30 times, or at least about 40 times.

[0038] According to the methods of the present invention, the subject is a mammal.

[0039] According to the methods of the present invention, the subject is a human.

[0040] According to the methods of the present invention, dextromethorphan or a pharmaceutically acceptable salt is present in an amount of up to about 20 mg.

[0041] According to the methods of the present invention, dextromethorphan or a pharmaceutically acceptable salt is present in an amount of up to about 50 mg.

[0042] According to the methods of the present invention, dextromethorphan or a pharmaceutically acceptable salt is administered sublingually up to two times, or up to three times per day.

[0043] According to the methods of the present invention, dextromethorphan or a pharmaceutically acceptable salt is administered sublingually every day or every other day.

[0044] According to the present invention, dextromethorphan or a pharmaceutically acceptable salt is administered continuously for at least about 30 days.

[0045] The present invention also provides a method for reducing a coughing condition or symptoms associated with a coughing condition comprising sublingually administering to a subject in need thereof a therapeutically effective amount of dextromethorphan or a pharmaceutically acceptable salt thereof.

[0046] The methods of the present invention reduce dextromethorphan exposure (AUC (0-t) ) is increased by about 20 times, or at least about 1.5 times, at least about 20 times, at least about 30 times, or at least about 40 times.

[0047] According to the method of the present invention, symptoms are assessed by frequency of cough, severity of cough, volume or noise level of cough, hoarseness, sore throat, dyspnea, airway congestion, wheezing, respiratory constriction, respiratory inflammation, muscle spasm associated with cough, sputum production, syncope, insomnia, vomiting, subconjunctival hemorrhage (red eye), cough defect, cough urination, abdominal hernia, pelvic hernia, chondritis, tibia fracture or any combination thereof.

[0048] According to the methods of the present invention, the subject is a mammal.

[0049] According to the methods of the present invention, the subject is a human.

[0050] According to the method of the present invention, when administered sublingually, dextromethorphan exposure (AUC (0-t)) is higher than the same amount of dextromethorphan or a pharmaceutically acceptable salt thereof administered orally.

[0051] According to the methods of the present invention, dextromethorphan or a pharmaceutically acceptable salt is present in an amount of about 0.1-10 mg.

[0052] According to the methods of the present invention, dextromethorphan or a pharmaceutically acceptable salt is administered sublingually up to twice per day, or up to three times per day.

[0053] According to the methods of the present invention, dextromethorphan or a pharmaceutically acceptable salt is administered sublingually every day or every other day.

[0054] According to the methods of the present invention, dextromethorphan or a pharmaceutically acceptable salt is administered continuously for at least about 30 days.

[0055] The method according to the present invention comprises sublingually administering the pharmaceutical composition of the present invention. DETAILED DESCRIPTION OF THE INVENTION

[0057] The present invention generally relates to compositions and methods for treating neurological disorders. In particular, the present invention provides compositions and methods for treating neurological disorders, comprising sublingually administering a composition comprising dextromethorphan or a pharmaceutically acceptable salt thereof to a subject in need thereof.

[0058] The chemical structure of dextromethorphan ((+)-3-methoxy-17-methyl-9α,13α,14α-morphinan) is shown below:

[0059] .

[0060] Dextromethorphan or a pharmaceutically acceptable salt thereof can be formulated into a number of sublingual dosage forms, such as tablets, films, hydrogels, and solutions. Without being bound by any theory, by sublingual administration of the pharmaceutical composition of dextromethorphan of the present invention, the plasma concentration of dextromethorphan is higher than the plasma concentration of the composition containing the same amount of dextromethorphan when administered orally. In some embodiments, the sublingual administration method of the present invention does not require the administration of liver enzyme inhibitors, such as quinidine or bupropion.

[0061] Unless otherwise defined, all terms used herein have the same meanings as commonly understood by one of ordinary skill in the art.

[0062] definition

[0063] In this application, the use of the singular includes the plural unless expressly stated otherwise. It must be noted that, as used in the specification, the singular forms "a", "an", and "the" include plural referents unless the context clearly dictates otherwise. In this application, the use of "or" means "and / or" unless expressly stated otherwise. Furthermore, the use of the term "includes" as well as other forms such as "includes", "including", and "comprising" are not limiting.

[0064] Reference in the specification to "some embodiments," "an embodiment," "one embodiment," or "other embodiments" means that a particular feature, structure, or characteristic described in connection with the embodiment is included in at least some embodiments of the invention, but not necessarily in all embodiments.

[0065] As used in this specification and claims, the words "comprising" (and any form of including, such as "including" and "containing"), "having" are inclusive or open-ended, and do not exclude additional, unrecited elements or method steps. It is contemplated that any embodiment discussed in this specification can be implemented in any method or combination of the invention, and vice versa. In addition, the compositions of the invention can be used to implement the methods of the invention.

[0066] Unless otherwise stated or apparent from the context, as used herein, the term "about" in reference to a number or numerical range is understood to refer to the stated number and to that number + / - 10%.

[0067] The term "pharmaceutically acceptable salt" used in the present invention refers to any salt that is pharmaceutically acceptable and has the desired pharmacological properties. Such salts include salts that can be derived from inorganic or organic acids, or salts of inorganic or organic bases, including amino acids, which are not toxic or undesirable in any way. Suitable inorganic salts include those formed with alkali metals, such as sodium and potassium, magnesium, calcium and aluminum. Suitable organic salts include those formed with organic bases such as amine bases, such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, etc. Such salts also include acid addition salts formed by inorganic acids (e.g., hydrochloric acid and hydrobromic acid) and organic acids (e.g., acetic acid, citric acid, maleic acid and alkane and arene sulfonic acids, such as methanesulfonic acid, benzenesulfonic acid, sulfonic acid and phosphoric acid). When there are two acidic groups, pharmaceutically acceptable salts can be monoacid monosalts or disalts; and similarly, in the presence of more than two acidic groups, some or all of these groups can be salified.

[0068] Composition

[0069] The present invention provides a composition comprising dextromethorphan ((+)-3-methoxy-17-methyl-9α, 13α, 14α-morphinan) or a pharmaceutically acceptable salt. The present invention also provides a pharmaceutical composition comprising the composition described herein. In some embodiments, the pharmaceutical composition provided by the present invention is formulated for sublingual administration or application (in the present invention, the terms "administration" and "application" are used interchangeably and have the same meaning). In some embodiments, the pharmaceutical composition is formulated as a neutral or salt form. In some embodiments, the pharmaceutical composition comprises a salt. In some embodiments, the pharmaceutical composition comprises a pharmaceutically acceptable salt. In some embodiments, the salt is a pharmaceutically acceptable salt. Pharmaceutically acceptable salts include salts formed with free amino groups, such as those derived from hydrochloric acid, phosphoric acid, acetic acid, oxalic acid or tartaric acid, and those formed with free carboxyl groups, such as those derived from sodium, potassium, ammonium, calcium, ferric hydroxide, isopropylamine, triethylamine, 2-ethylaminoethanol, histidine or procaine. In some embodiments, the salt or pharmaceutically acceptable salt may include hydrochloric acid (HCl) salt, hydrobromide salt, orthophosphate salt, benzoate salt, ascorbate salt, mandelate salt, aspartate salt, carbonate salt, citrate salt, formate salt, glutamate salt, lactate salt, laurate salt, maleate salt, palmitate salt, phosphate salt, or any combination thereof. In some embodiments, salts or pharmaceutically acceptable salts may include, but are not limited to, metal salts such as sodium salts, potassium salts, cesium salts, etc.; alkaline earth metal salts such as calcium salts, magnesium salts, etc.; organic amine salts such as triethylamine salts, pyridine salts, methylpyridine salts, ethanolamine salts, triethanolamine salts, dicyclohexylamine salts, N,N'-dibenzylethylenediamine salts, etc.; inorganic acid salts such as hydrochlorides, hydrobromides, phosphates, sulfates, etc.; organic acid salts such as citrates, lactates, tartrates, maleates, fumarates, mandelates, acetates, dichloroacetates, trifluoroacetates, oxalates, formates, etc.; sulfonates such as methanesulfonates, benzenesulfonates, p-toluenesulfonates, etc.; and / or amino acid salts such as arginine salts, aspartates, glutamates, etc. In some embodiments, the salt or pharmaceutically acceptable salt is hydrobromide.

[0070] In some embodiments, the composition of the present invention comprises dextromethorphan or a pharmaceutically acceptable salt thereof in an amount of about 0.01% to about 25% by weight of the total composition. In some embodiments, the dextromethorphan or a pharmaceutically acceptable salt thereof of the present invention is present in an amount of about 0.01% to about 0.1%, about 0.01% to about 1%, about 0.01% to about 5%, about 0.01% to about 10%, about 0.01% to about 15%, about 0.01% to about 20%, about 0.01% to about 25%, about 0.1% to about 1%, about 0.1% to about 5%, about 0.1% to about 10%, about 0.1% to about 15%, about 0.01% to about 20%, about 0.01% to about 25%, about 0.1% to about 1%, about 0.1% to about 5%, about 0.1% to about 10%, about 0.1% to about 15%, about 0. The invention also provides an amount of 1% to about 20%, about 0.1% to about 25%, about 0.5% to about 1%, about 0.5% to about 5%, about 0.5% to about 10%, about 0.5% to about 15%, about 0.5% to about 20%, about 0.5% to about 25%, about 1% to about 5%, about 1% to about 10%, about 1% to about 15%, about 1% to about 20%, about 1% to about 25%, about 5% to about 10%, about 5% to about 20%, about 5% to about 25%, about 10% to about 20%, about 20% to about 25%. In some embodiments, the compound described herein, or a pharmaceutically acceptable salt thereof, is present in an amount of about 0.01%, about 0.02%, about 0.03%, about 0.04%, about 0.05%, about 0.06%, about 0.07%, about 0.08%, about 0.09%, about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, or about 25% of the total weight of the composition or pharmaceutical composition described herein.

[0071] In some embodiments, the composition or pharmaceutical composition of the present invention comprises an excipient. In some embodiments, the excipient is a pharmaceutically acceptable excipient. Non-limiting examples of excipients include solvents, buffers, preservatives, stabilizers, adhesives, compacting agents, lubricants, chelating agents, dispersants, disintegrants, flavoring agents, sweeteners, coloring agents or suspending agents. In some embodiments, the excipient is a solvent. In some embodiments, the solvent comprises water. In some embodiments, the excipient is a sweetener. In some embodiments, the sweetener is sucrose, fructose, sorbitol, aspartame, neotame, acesulfame potassium, sucralose, saccharin, saccharin sodium, xylitol or a combination thereof. In some embodiments, the excipient is a flavoring agent. In some embodiments, the flavoring agent is citric acid, extracts of various essential oils or menthol, wintergreen, peppermint, sweet mint, spearmint, vanillin, cherry, butterscotch, chocolate, cinnamon, clove, lemon, orange, raspberry, rose, spices, violet, herbs, fruits, strawberries, grapes, pineapple, vanilla, peppermint, peach, kiwi, papaya, mango, coconut, assorted fruits, apples, coffee, plums, watermelons, nuts, green tea, grapefruit, bananas, butter, chamomile, masked aromatic acids, and mixtures thereof. In some embodiments, the excipient is a taste masking agent. In some embodiments, the taste masking agent is ammonium bromide, β-cyclodextrin, cellulose acetate butyrate, carbopol polymer, ethylcellulose, polymethacrylate, polystyrene, polyvinyl acetate dispersion, PEG-5M, sodium starch glycolate, sodium acetate, trehalose, or vinyl acetate.

[0072] In some embodiments, the compositions or pharmaceutical compositions disclosed herein include preservatives. Exemplary preservatives include antibacterial or antifungal compounds. Examples of preservatives include, but are not limited to, octadecyl dimethyl benzyl ammonium chloride, hexamethyl ammonium chloride, benzalkonium chloride (a mixture of alkyl benzyl dimethyl ammonium chlorides, wherein the alkyl group is a long-chain compound) and benzethonium chloride.

[0073] In some embodiments, the composition or pharmaceutical composition of the present invention comprises a surfactant. The surfactant can reduce the surface tension of a liquid, the interfacial tension between two liquids, or the interfacial tension between a liquid and a solid. The surfactant can be a detergent, a wetting agent, an emulsifier, a foaming agent, a dispersant, or any combination thereof. In some embodiments, the surfactant comprises a polysorbate emulsifier. In some embodiments, polysorbate is a PEG (polyethylene glycol)-acylated dehydrated sorbitan esterified with one or more fatty acids. In some embodiments, the surfactant is selected from: polysorbate 20 (polyoxyethylene 20 dehydrated sorbitan monolaurate), polysorbate 60, polysorbate 80, or any combination thereof.

[0074] In some embodiments, the composition or pharmaceutical composition of the present invention comprises a permeation enhancer. A "permeation enhancer" is a natural or synthetic compound that promotes the absorption of an active agent through a mucosal surface (e.g., the surface of the intestine). In some embodiments, the permeation enhancer of the present invention is isopropyl palmitate, isopropyl myristate, isopropyl stearate, propylene glycol, octyl stearate, tridecyl neopentanoate, benzyl alcohol, linoleic acid, α-linolenic acid, oleic acid, cod liver oil, methanol, menthol derivatives, squalene, glycerol derivatives, urea, sodium taurocholate, or a combination thereof. In some embodiments, the permeation enhancer of the present invention is L-arginine.

[0075] In some embodiments, the composition or pharmaceutical composition provided by the invention is administered to a subject in need thereof in a form suitable for sublingual administration. In some embodiments, the composition or pharmaceutical composition provided by the invention is a solid composition or a liquid composition. In some embodiments, the composition or pharmaceutical composition provided by the invention is in the form of a pill, tablet, lozenge, gel, film, hydrogel or solution.

[0076] In some embodiments, the dextromethorphan or a pharmaceutically acceptable salt thereof is present in the pharmaceutical composition of the present invention in an amount of up to about 100 mg. In some embodiments, the dextromethorphan or a pharmaceutically acceptable salt thereof is present in the pharmaceutical composition of the present invention in an amount of up to about 50 mg.

[0077] In some embodiments, the dextromethorphan or a pharmaceutically acceptable salt thereof described herein is present in the pharmaceutical composition described herein in an amount of about 5 mg to about 20 mg, about 10 mg to 25 mg, about 15 mg to 30 mg, about 20 mg to about 35 mg, about 25 mg to about 40 mg, about 30 mg to about 45 mg, about 35 mg to about 50 mg, about 40 mg to about 55 mg, about 45 mg to about 60 mg, about 50 mg to about 65 mg, about 55 mg to about 70 mg, about 60 mg to about 75 mg, about 65 mg to about 80 mg, about 70 mg to about 85 mg, about 75 mg to about 90 mg, about 80 mg to about 95 mg, or about 85 mg to about 100 mg.

[0078] In some embodiments, the dextromethorphan or a pharmaceutically acceptable salt thereof of the present invention is present in the pharmaceutical composition of the present invention in an amount of about 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.6 mg, 0.8 mg, 0.9 mg, 1.0 mg, 1.1 mg, 1.2 mg, 1.3 mg, 1.4 mg, 1.5 mg, 1.6 mg, 1.7 mg, 1.8 mg, 1.9 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg g, 8mg, 9mg, 10mg, 11mg, 12mg, 13mg, 14mg, 15mg, 16mg, 17mg, 18mg, 19mg, 20mg, 21mg, 22mg, 23mg, 24mg, 25mg, 26m g, 27mg, 28mg, 29mg, 30mg, 35mg, 40mg, 45mg, 50mg, 55mg, 60mg, 65mg, 70mg, 75mg, 80mg, 85mg, 90mg, 95mg, 100mg.

[0079] In some embodiments, the dextromethorphan or a pharmaceutically acceptable salt thereof is present in the pharmaceutical composition of the present invention in an amount of about 50 mg. In some embodiments, the dextromethorphan or a pharmaceutically acceptable salt thereof is present in the pharmaceutical composition of the present invention in an amount of about 40 mg. In some embodiments, the dextromethorphan or a pharmaceutically acceptable salt thereof is present in the pharmaceutical composition of the present invention in an amount of about 20 mg. In some embodiments, the dextromethorphan or a pharmaceutically acceptable salt thereof is present in the pharmaceutical composition of the present invention in an amount of about 10 mg.

[0080] In some embodiments, the liquid composition described in the present invention comprises about 0.0001% (w / v) to about 50% (w / v), about 0.01% (w / v) to about 20% (w / v), about 0.01% to about 10% (w / v), about 0.001% (w / v) to about 1% (w / v), about 0.1% (w / v) to about 0.5% (w / v), about 1% (w / v) to about 3% (w / v), about 3% (w / v) to about 5% (w / v), about 5% (w / v) to about 7% (w / v), about 7% (w / v) to about 10% (w / v), about 10% (w / v) to about 15% (w / v), about 15% (w / v) to about 20% (w / v), about 20% (w / v) to about 30% (w / v), about 30% (w / v) to about 40% (w / v), or about 40% (w / v) to about 50% (w / v) of dextromethorphan, or a pharmaceutically acceptable salt thereof.

[0081] In some embodiments, the solid composition described herein comprises at least about 5% (w / w), at least about 10% (w / w), at least about 20% (w / w), at least about 50% (w / w), at least about 70% (w / w), at least about 80%, about 10% (w / w) to about 30% (w / w), about 10% (w / w) to about 20% (w / w), about 20% (w / w) to about 30% (w / w), about 30% (w / w). % (w / w) to about 50% (w / w), about 30% (w / w) to about 40% (w / w), about 40% (w / w) to about 50% (w / w), about 50% (w / w) to about 80% (w / w), about 50% (w / w) to about 60% (w / w), about 70% (w / w) to about 80% (w / w), or about 80% (w / w) to about 90% (w / w) of dextromethorphan, or a pharmaceutically acceptable salt thereof.

[0082] Treatment

[0083] The present invention provides a method of treating a disease or condition comprising administering to a subject sublingually a therapeutically effective amount of dextromethorphan or a pharmaceutically acceptable salt thereof, a composition, or a pharmaceutical composition of the present invention. In some embodiments, the subject is a mammal. In some embodiments, the mammal is a dog, a cat, a sheep, a llama, a pig, a goat, a sheep, a horse, a cow, a human, or a non-human primate. In some embodiments, the subject is a human. In some embodiments, the subject is a patient in need thereof.

[0084] In some embodiments, the disease or condition is a neurological disorder. In some embodiments, neurological disorders are pseudobulbar effects, depressive disorders, Parkinson's disease, stroke, acute brain injury, neuropathic pain, nicotine addiction, Alzheimer's disease. In some embodiments, the sublingual administration of dextromethorphan or a pharmaceutically acceptable salt, composition or pharmaceutical composition of the present invention reduces the external display or internal sensation caused or accompanied by various other problems (such as "premenstrual syndrome" (PMS), Tourette syndrome) occurring in people with certain types of mental illness. Although such problems may not be considered as emotional instability clinically, they involve performance that looks similar enough to emotional instability to indicate that dextromethorphan can provide effective treatment for at least some patients suffering from such problems.

[0085] The present invention also provides a method for treating a cough condition or symptoms associated with a cough condition. A cough condition refers to a vagus nerve-based disorder in which an individual has a sudden reflex (cough reflex) that can be repeatedly and physiologically designed to clear the large respiratory passages from any of a variety of irritants, particles, microorganisms or other organisms, secretions, etc., and is usually accompanied by a unique sound. In some embodiments, coughing includes inhalation, forced exhalation against the sound of a closing door, and the release of air from the lungs, which follows the opening of the glottis. The cough reflex is triggered by stimulating two types of afferent nerves, myelinated rapidly adapting receptors and unmyelinated C-fibers with terminals in the lungs. In some embodiments, the cough condition is an acute cough condition, a subacute cough condition, a chronic cough condition, a non-productive cough condition, a productive cough condition, or a cough associated with a disease or disorder. In some embodiments, symptoms of a coughing condition include, but are not limited to, coughing, hoarseness, sore throat, dyspnea, respiratory congestion, respiratory contraction, respiratory inflammation, sputum production, syncope, insomnia, vomiting, subconjunctival hemorrhage (red eyes), cough defect, cough urination, abdominal hernia, pelvic hernia, chondritis, lower rib fractures, or any combination thereof. In some embodiments, symptoms associated with a coughing condition are determined by a person of ordinary skill in the art by considering factors including, but not limited to, the location of the coughing condition, the cause of the coughing condition, the severity of the coughing condition, and the tissues or organs affected by the coughing condition. In some embodiments, sublingual administration of dextromethorphan or a pharmaceutically acceptable salt thereof reduces the frequency or severity of the coughing condition. In some embodiments, in order to achieve the effects described in the present invention, by administering dextromethorphan sublingually to a subject, a lower dose of dextromethorphan is required compared to the dose of dextromethorphan required for oral administration.

[0086] Dosing and dosing regimen

[0087] As described above, the compositions and pharmaceutical compositions of the present invention are formulated for sublingual administration. Without being bound by any theory, by sublingual administration of the pharmaceutical composition of dextromethorphan of the present invention, the plasma concentration of dextromethorphan is higher than the plasma concentration of the composition containing the same amount of dextromethorphan when administered orally. In some embodiments, the sublingual administration method of the present invention does not require the administration of liver enzyme inhibitors, such as quinidine or bupropion. Again, without wishing to be bound by theory, in some embodiments of the present invention, the administration of the pharmaceutical composition of dextromethorphan of the present invention in the oral cavity, such as by sublingual administration or oral administration, results in a higher plasma concentration of dextromethorphan than that of oral administration.

[0088] In some embodiments, the compositions and pharmaceutical compositions are designed to dissolve in a small amount of saliva. After placing the pharmaceutical composition of the present invention in the mouth under the tongue, the patient should avoid eating, drinking, and possibly talking in order to keep the tablet in place and avoid swallowing of saliva, as saliva may contain dissolved drug. After placing the pharmaceutical composition of the present invention in the oral cavity, adjacent to the surface of the cheek, the patient should avoid eating, drinking, and possibly talking in order to keep the tablet in place and avoid swallowing of saliva, as saliva may contain dissolved drug.

[0089] The therapeutically effective amount of dextromethorphan or a pharmaceutically acceptable salt thereof may vary depending on the circumstances. In some embodiments, the composition or pharmaceutical composition is administered sublingually at a dose comprising about 0.1 mg to about 100 mg of dextromethorphan or a pharmaceutically acceptable salt thereof.

[0090] In some embodiments, the composition or pharmaceutical composition is administered at a dose comprising about 0.1 mg to about 10 mg of dextromethorphan. In some embodiments, the composition or pharmaceutical composition is administered at a dose comprising about 0.1 mg to about 1 mg, about 0.5 mg to about 1.5 mg, about 1 mg to about 2 mg, about 1.5 mg to about 2.5 mg, about 2 mg to about 3 mg, about 2.5 mg to about 3.5 mg, about 3 mg to about 4 mg, about 3.5 mg to about 4.5 mg, about 4 mg to about 5 mg, about 4.5 mg to about 5.5 mg, about 5 mg to about 6 mg, about 5.5 mg to about 6.5 mg, about 6 mg to about 7 mg, about 6.5 mg to about 7.5 mg, about 7 mg to about 8 mg, about 7.5 mg to about 8.5 mg, about 8 mg to about 9 mg, about 8.5 mg to about 9.5 mg, or about 9 mg to about 10 mg of dextromethorphan or a pharmaceutically acceptable salt thereof.

[0091] In some embodiments, the composition or pharmaceutical composition is administered sublingually at a dose comprising 1 mg to about 100 mg of dextromethorphan or a pharmaceutically acceptable salt thereof. In some embodiments, the composition or pharmaceutical composition is administered at a dose comprising, in some embodiments, about 5 mg to about 15 mg, about 10 mg to about 20 mg, about 15 mg to 25 mg, about 20 mg to about 30 mg, about 30 mg to about 40 mg, about 40 mg to about 50 mg, about 50 mg to about 60 mg, about 60 mg to about 70 mg, about 70 mg to about 80 mg, about 80 mg to about 90 mg, or about 90 mg to about 100 mg of dextromethorphan or a pharmaceutically acceptable salt thereof.

[0092] In some embodiments, the total daily dose for treating the conditions described herein is about 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1.0 mg, 1.1 mg, 1.2 mg, 1.3 mg, 1.4 mg, 1.5 mg, 1.6 mg, 1.7 mg, 1.8 mg, 1.9 mg, 2.0 mg, 2.1 mg, 2.2 mg. g, 2.3mg, 2.4mg, 2.5mg, 2.6mg, 2.7mg, 2.8mg, 2.9mg, 3.0mg, 3.1mg, 3.2mg, 3.3mg, 3.4mg, 3.5m g, 3.6mg, 3.7mg, 3.8mg, 3.9mg, 4.0mg, 4.1mg, 4.2mg, 4.3mg, 4.4mg, 4.5mg, 4.6mg, 4.7mg, 4.8m g, 4.9mg, 5.0mg, 5.1mg, 5.2mg, 5.3mg, 5.4mg, 5.5mg, 5.6mg, 5.7mg, 5.8mg, 5.9mg, 6.0mg, 6.1m g, 6.2mg, 6.3mg, 6.4mg, 6.5mg, 6.6mg, 6.7mg, 6.8mg, 6.9mg, 7.0mg, 7.1mg, 7.2mg, 7.3mg, 7.4m In some embodiments, the total daily dose for treating the conditions described herein is about 10 mg, 15 mg, 20 mg, 21 mg, 22 mg, 23 mg, 24 mg, 25 mg, 26 mg, 27 mg, 28 mg, 29 mg or 30 mg of dextromethorphan or a pharmaceutically acceptable salt thereof. In some embodiments, the total daily dose for treating the conditions described herein is about 30 mg, 31 mg, 32 mg, 33 mg, 34 mg, 35 mg, 36 mg, 37 mg, 38 mg, 39 mg, or 40 mg of dextromethorphan or a pharmaceutically acceptable salt thereof. In some embodiments, the total daily dose for treating the conditions described herein is about 40 mg, 41 mg, 42 mg, 43 mg, 44 mg, 45 mg, 46 mg, 47 mg, 48 mg, 49 mg, or 50 mg of dextromethorphan or a pharmaceutically acceptable salt thereof.In some embodiments, the total daily dose for treating the conditions described herein is about 50 mg, 51 mg, 52 mg, 53 mg, 54 mg, 55 mg, 56 mg, 57 mg, 58 mg, 59 mg, or 60 mg of dextromethorphan or a pharmaceutically acceptable salt thereof. In some embodiments, the total daily dose for treating the conditions described herein is about 60 mg, 61 mg, 62 mg, 63 mg, 64 mg, 65 mg, 66 mg, 67 mg, 68 mg, 69 mg, or 70 mg of dextromethorphan or a pharmaceutically acceptable salt thereof. In some embodiments, the total daily dose for treating the conditions described herein is about 70 mg, 71 mg, 72 mg, 73 mg, 74 mg, 75 mg, 76 mg, 77 mg, 78 mg, 79 mg, or 80 mg of dextromethorphan or a pharmaceutically acceptable salt thereof. In some embodiments, the total daily dose for treating the conditions described herein is about 80 mg, 81 mg, 82 mg, 83 mg, 84 mg, 85 mg, 86 mg, 87 mg, 88 mg, 89 mg or 80 mg of dextromethorphan or a pharmaceutically acceptable salt thereof. In some embodiments, the total daily dose for treating the conditions described herein is about 90 mg, 91 mg, 92 mg, 93 mg, 94 mg, 95 mg, 96 mg, 97 mg, 98 mg, 99 mg or 100 mg of dextromethorphan or a pharmaceutically acceptable salt thereof.

[0093] In some embodiments, the composition or pharmaceutical composition of the present invention is administered to a subject in a single dose or multiple doses. In some embodiments, the composition or pharmaceutical composition of the present invention is administered once a day, up to twice a day, or up to three times a day. In some embodiments, the composition or pharmaceutical composition of the present invention is administered every 8 hours. In some embodiments, the composition or pharmaceutical composition of the present invention is administered every other day. In some embodiments, the composition or pharmaceutical composition of the present invention is administered to a subject over a period of 1, 2, 3, 4, 5, 6, 7 days or more or several weeks. In certain embodiments, the composition or pharmaceutical composition of the present invention is administered in a time period of about 1 week to about 2 weeks, about 2 weeks to about 3 weeks, about 3 weeks to about 4 weeks, about 4 weeks to about 5 weeks, about 5 weeks to about 6 weeks, about 6 weeks to about 7 weeks, about 7 weeks to about 8 weeks, about 8 weeks to about 9 weeks, about 9 weeks to about 10 weeks, about 10 weeks to about 11 weeks, about 11 weeks to about 12 weeks, about 12 weeks to about 24 weeks, about 24 weeks to about 48 weeks, about 48 weeks or about 52 weeks or longer. In some cases, the frequency of administration of the composition or pharmaceutical composition of the present invention is once a day, twice a day, once a week, once every three weeks, once every four weeks (or once a month), once every 8 weeks (or once every 2 months), once every 12 weeks (or once every 3 months) or once every 24 weeks (once every 6 months). In some embodiments of the present invention, the composition or pharmaceutical composition of the present invention is independently administered in the first time period, the intermediate dose of the second time period and the low dose of the third time period with an initial dose. In some embodiments, the initial dose is higher than the intermediate dose, and the intermediate dose is higher than the high dose. In some embodiments, the first, second, and third time periods are independently about 1 week to about 2 weeks, about 2 weeks to about 3 weeks, about 3 weeks to about 4 weeks, about 4 weeks to about 5 weeks, about 5 weeks to about 6 weeks, about 6 weeks to about 7 weeks, about 7 weeks to about 8 weeks, about 8 weeks to about 9 weeks, about 9 weeks to about 10 weeks, about 10 weeks to about 11 weeks, about 11 weeks to about 12 weeks, about 12 weeks to about 24 weeks, about 24 weeks to about 48 weeks, about 48 weeks or about 52 weeks or longer.

[0094] In some embodiments, the composition or pharmaceutical composition is administered up to twice a day, or up to three times a day. In some embodiments, the composition or pharmaceutical composition is administered every day. In some embodiments, the composition or pharmaceutical composition is administered every other day. In some embodiments, the composition or pharmaceutical composition is administered daily for about 1 to 10 days, followed by twice a day.

[0095] Pharmacokinetics

[0096] In some embodiments, dextromethorphan plasma levels are enhanced by sublingual administration compared to oral administration. In some embodiments, dextromethorphan plasma levels are the same or higher by sublingual administration compared to oral administration of the same amount of dextromethorphan and a compound that inhibits the cytochrome P450 isozyme CYP2D6 ("CYP inhibitor").

[0097] In some embodiments, the AUC of dextromethorphan on the first day after sublingual administration is (0-t) is the AUC achieved by oral administration of the same amount of dextromethorphan (0-t) at least about 1.5 times, 2 times, 3 times, 4 times, 5 times, 6 times, 7 times, 8 times, 9 times, 10 times, 11 times, 12 times, 13 times, 14 times, 15 times, 16 times, 17 times, 18 times, 19 times, 20 times, 21 times, 22 times, 23 times, 24 times, 25 times, 26 times, 27 times, 28 times, 29 times, 30 times, 31 times, 32 times, 33 times, 34 times, 35 times, 36 times, 37 times, 38 times, 39 times, 40 times, 41 times, 42 times, 43 times, 44 times, 45 times, 46 times, 47 times, 48 ​​times, 49 times, or 50 times as much.

[0098] In some embodiments, the Cmax of dextromethorphan on the first day following sublingual administration is at least about 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 11-fold, 12-fold, 13-fold, 14-fold, 15-fold, 17-fold, 18-fold, 19-fold, 20-fold, 21-fold, 22-fold, 23-fold, 24-fold, 25-fold, 26-fold, 27-fold, 29-fold, 30-fold, 31-fold, 32-fold, 33-fold, 34-fold, 35-fold, 36-fold, 37-fold, 38-fold, 39-fold, 40-fold, 41-fold, 42-fold, 43-fold, 44-fold, 45-fold, 46-fold, 47-fold, 48-fold, 49-fold, or 50-fold the Cmax achieved by oral administration of the same amount of dextromethorphan.

[0099] Beneficial Effects

[0100] Sublingual administration can significantly increase the oral absorption of dextromethorphan, significantly reduce the liver overload effect, and eliminate the need for liver enzyme inhibitors. BRIEF DESCRIPTION OF THE DRAWINGS

[0101] Reference is made to the following drawings, without limitation, for a better understanding of the features and advantages of the present invention:

[0102] Figure 1 Shown is a single-dose curve for male beagle dogs, with T1 formulation 10 mg sublingually vs T2 formulation 10 mg sublingually vs T1 formulation 10 mg orally (n=3);

[0103] Figure 2Shown is a graph of single-dose curves in male cynomolgus monkeys, T3 10 mg sublingually vs T3 10 mg orally (n=3);

[0104] Figure 3 Shown are single-dose profiles for male beagle dogs with T4 formulation 20 mg sublingually vs T5 formulation 20 mg sublingually (n=6). DETAILED DESCRIPTION

[0105] The following description and examples illustrate embodiments of the present invention in detail. It should be understood that the present invention is not limited to the specific embodiments described below, and therefore can be varied. Those skilled in the art will recognize that there are many variations and modifications included within its scope.

[0106] Example 1

[0107] Comparative bioavailability study in dogs, oral and sublingual DM solution, and sublingual API + Arg solution

[0108] prescription

[0109] The prescription is shown in Table 1 below.

[0110] Table 1:

[0111]

[0112] Experimental methods:

[0113] Prescription preparation process:

[0114] T1: DM was directly dissolved in ultrapure water, and the sample concentration was 10 mg / mL.

[0115] T2: L-arginine and citric acid monohydrate were first dissolved in ultrapure water, then added into DM and stirred until completely dissolved. The sample concentration was 10 mg / mL.

[0116] Bioavailability Experiment Design:

[0117] This experiment used 3 male beagle dogs, with a single dose, a 3-cycle design, and a 7-day washout period.

[0118] In cycle 1, 1 mL of T1 preparation was administered sublingually to 3 beagle dogs, and the dogs' mouths were fixed with a clamp for 10 min after administration.

[0119] In cycle 2, 1 mL of T2 preparation was administered sublingually to 3 beagle dogs, and the dogs' mouths were fixed with a clamp for 10 min after administration.

[0120] In cycle 3, 1 mL of T1 preparation was administered to 3 beagle dogs via gavage tube, and the tube was flushed with 20 mL of water.

[0121] The experiments were performed in accordance with the Guide for the Care and Use of Laboratory Animals.

[0122] Detection:

[0123] About 0.5 mL of blood sample was collected into a centrifuge tube containing K2-EDTA anticoagulant. Within 60 minutes after blood collection, the blood was centrifuged (8000 rpm for 5 minutes) and plasma was collected. After centrifugation, the plasma was transferred to a 96-well plate or centrifuge tube and stored at ≤-15°C until LC-MS / MS detection. The pharmacokinetic parameters of each group were calculated using a non-compartmental model.

[0124] The blood sampling points in cycles 1 and 2 were before administration (0 h), 5 min, 10 min, 15 min, 20 min, 25 min, 30 min, 1 h, 2 h, 3 h, 4 h, 6 h, 8 h, 10 h, and 24 h.

[0125] The blood sampling points in cycle 3 were before administration (0 h), 10 min, 20 min, 30 min, 1 h, 2 h, 3 h, 4 h, 6 h, 8 h, 10 h, and 24 h.

[0126] result:

[0127] The pharmacokinetic parameters are shown in Table 2 and Figure 1 .

[0128] Sublingual administration T1 absorption is significantly better than oral gavage T1 (intragastric gavage, ig), AUC (0-t) An increase of about 19 times.

[0129] Sublingual administration T2 absorption is higher than T1, AUC (0-t) The increase was about 30%, proving that arginine has a certain sublingual penetration-enhancing effect.

[0130] Table 2:

[0131]

[0132] Example 2

[0133] Comparative study on bioavailability in monkeys, Comparative study on bioavailability of oral and sublingual DM solution

[0134] prescription

[0135] The prescription is shown in Table 3 below.

[0136] Table 3:

[0137]

[0138] Experimental methods

[0139] Prescription preparation process:

[0140] T3: DM was directly dissolved in ultrapure water, and the sample concentration was 16.67 mg / mL.

[0141] Bioavailability Experiment Design

[0142] This experiment used three male crab-eating monkeys, with a single dose, a two-cycle design, and a washout period of 4 days.

[0143] Cycle 1: Three cynomolgus monkeys were orally gavaged with 0.6 mL of T3 formulation.

[0144] Cycle 2: 3 cynomolgus monkeys were given 0.6 mL of T3 preparation sublingually.

[0145] Sublingual administration in monkeys was performed under anesthesia, with Zoletil® 50 selected as the anesthetic.

[0146] The experiments were performed in accordance with the Guide for the Care and Use of Laboratory Animals.

[0147] Detection

[0148] About 0.5 mL of blood sample was collected into a centrifuge tube containing K2-EDTA anticoagulant. Within 60 minutes after blood collection, the blood was centrifuged (2000 rpm for 5 minutes) and plasma was collected. After centrifugation, the plasma was transferred to a 96-well plate or centrifuge tube and stored at ≤-15°C until LC-MS / MS detection. The pharmacokinetic parameters of each group were calculated using a non-compartmental model.

[0149] The blood sampling points in cycle 1 were before administration (0 h), and 10 min, 20 min, 30 min, 1 h, 2 h, 3 h, 4 h, 6 h, 8 h, 10 h, and 24 h after administration.

[0150] The blood sampling points in cycle 2 were before administration (0 h), and 5 min, 10 min, 15 min, 20 min, 25 min, 30 min, 1 h, 2 h, 3 h, 4 h, 6 h, 8 h, 10 h, and 24 h after administration.

[0151] result

[0152] See Table 4 and Figure 2, T3 preparations are absorbed faster when administered sublingually (T3 (sublingual, sl)) than when administered orally (T3 (intragastric gavage, ig)). The PK parameters in Table 4 show that sublingual T3 absorption is 30 times higher than oral administration. Only one monkey could detect absorption data for oral absorption of T3, and no absorption data was detected for the other two monkeys.

[0153] Table 4:

[0154]

[0155] Example 3

[0156] Comparative experiment on the formulation of DM freeze-dried tablets, sublingual tablets and bioavailability in dogs

[0157] prescription

[0158] The prescriptions are shown in Tables 5 and 6 below.

[0159] Table 5:

[0160]

[0161] Table 6:

[0162]

[0163] Experimental methods

[0164] Prescription preparation process:

[0165] T4: Weigh all materials in a beaker, place in a 37℃ water bath, stir and dissolve; then transfer to 0.5mL / piece plastic blisters, place in the freeze dryer cold trap at -60℃ overnight and freeze; the next day, transfer the blisters to the upper freeze-drying area of ​​the freeze dryer, place a foam board at the bottom for insulation, and drain overnight to obtain the sample (during the freeze-drying process, a circle of vials should be placed around the blisters, with water frozen overnight inside to maintain a low temperature environment around the blisters).

[0166] T5: First, mix dextromethorphan hydrobromide, PVPP, and neotame evenly; then add mannitol and mix evenly; then add magnesium stearate and mix evenly; finally, use a 6 mm round punch to press the tablets.

[0167] Experimental methods

[0168] Bioavailability Experiment Design

[0169] This experiment used 6 male beagle dogs, with a single dose, a 2-cycle design, and a 7-day washout period.

[0170] Cycle 1: 6 beagles were given one tablet of T4 preparation sublingually, and the dogs' mouths were fixed with a clamp for 10 min after administration.

[0171] Cycle 2: 6 beagles were given one tablet of T5 preparation sublingually, and the dogs' mouths were fixed with a clamp for 10 minutes after administration.

[0172] The experiments were performed in accordance with the Guide for the Care and Use of Laboratory Animals.

[0173] Detection

[0174] About 0.5 mL of blood sample was collected into a centrifuge tube containing EDTA-K2 anticoagulant. Within 60 minutes after blood collection, the blood was centrifuged (8000 rpm for 5 minutes) and plasma was collected. After centrifugation, the plasma was transferred to a 96-well plate or centrifuge tube and stored at ≤-15°C until LC-MS / MS detection. The pharmacokinetic parameters of each group were calculated using a non-compartmental model.

[0175] The blood sampling points in cycles 1 and 2 were before administration (0 h), 10 min, 20 min, 30 min, 1 h, 2 h, 3 h, 4 h, 6 h, 8 h, 10 h, and 24 h.

[0176] result

[0177] The pharmacokinetic parameters are shown in Table 7 and Figure 3 .

[0178] Table 7:

[0179]

[0180] There was no significant difference in the absorption of sublingual T4 compared with sublingual T5.

[0181] The foregoing description, in conjunction with the accompanying drawings, illustrates a number of representative embodiments. Of course, various modifications, additions, and alternative designs will be apparent to those skilled in the art based on the above teachings without departing from the essence and spirit of the present invention. All changes that fall within the meaning of equivalents of the claims are intended to fall within the scope of the present invention.

Claims

1. Use of dextromethorphan ((+)-3-methoxy-17-methyl-9α,13α,14α-morphinan) or a pharmaceutically acceptable salt thereof as the sole active ingredient in the preparation of a pharmaceutical composition for sublingual administration.

2. The use according to claim 1, wherein the pharmaceutically acceptable salt is an acidic salt of dextromethorphan.

3. The use according to claim 2, wherein the pharmaceutically acceptable salt is dextromethorphan hydrobromide.

4. The use according to claim 1, wherein the dextromethorphan is in the form of a free base.

5. The use according to claim 1, wherein the pharmaceutical composition is in the form of a pill, tablet, film, hydrogel, strip or liquid.

6. The use according to claim 1, wherein the pharmaceutical composition further comprises a penetration enhancer.

7. The use according to claim 6, wherein the penetration enhancer is L-arginine.

8. The use according to claim 1, wherein the pharmaceutical composition further comprises an excipient.

9. The use according to claim 8, wherein the excipient comprises a sweetener, a flavoring agent, a taste masking agent, a binder, a dispersant, a lubricant, a disintegrant or a combination thereof.

10. The use according to claim 9, wherein the sweetener is selected from sucrose, fructose, sorbitol, aspartame, neotame, acesulfame potassium, sucralose, saccharin, saccharin sodium, xylitol or a combination thereof.

11. The use according to claim 9, wherein the flavoring agent is selected from citric acid, mint, methyl salicylate, mannitol, fruit flavoring or a combination thereof.

12. The use of claim 9, wherein the taste masking agent is selected from amberlite, β-cyclodextrin, cellulose acetate butyrate, carbopol polymer, ethyl cellulose, polymethacrylate, polystyrene, polyvinyl acetate dispersion, PEG-5M, sodium starch glycolate, sodium acetate, trehalose, vinyl acetate or a combination thereof.

13. The use according to any one of claims 1 to 12, wherein the pharmaceutical composition comprises 1 to 100 mg of dextromethorphan or a pharmaceutically acceptable salt thereof.

14. The use according to any one of claims 1 to 12, wherein the pharmaceutical composition comprises 5 mg to 40 mg of dextromethorphan or a pharmaceutically acceptable salt thereof.

15. The use according to any one of claims 1 to 12, wherein the pharmaceutical composition comprises 10 mg or 20 mg of dextromethorphan or a pharmaceutically acceptable salt thereof.

16. The use according to any one of claims 1 to 12, wherein the pharmaceutical composition is used to treat a neurological disorder in a subject.

17. The use according to claim 16, wherein the neurological disorder is pseudobulbar effect, depressive disorder, Parkinson's disease, stroke, acute brain injury, neuropathic pain, nicotine addiction or Alzheimer's disease.

18. The use according to claim 16, wherein the subject is a mammal.

19. The use according to claim 16, wherein the subject is a human.

20. The use of claim 16, wherein the dextromethorphan or a pharmaceutically acceptable salt thereof is present in an amount of 1-100 mg.

21. The use of claim 16, wherein the dextromethorphan or a pharmaceutically acceptable salt thereof is present in an amount of up to 20 mg.

22. The use of claim 16, wherein the dextromethorphan or a pharmaceutically acceptable salt thereof is present in an amount of up to 50 mg.

23. The use of claim 16, wherein the dextromethorphan or a pharmaceutically acceptable salt is administered sublingually up to twice a day or up to three times a day.

24. The use of claim 16, wherein the dextromethorphan or a pharmaceutically acceptable salt is administered sublingually every day or every other day.

25. The use of claim 16, wherein dextromethorphan or a pharmaceutically acceptable salt thereof is administered continuously for at least 30 days.

26. The use according to any one of claims 1 to 12, wherein the pharmaceutical composition is used to treat a cough condition in a subject or to reduce symptoms associated with a cough condition.

27. The use according to claim 26, wherein the symptoms are assessed by frequency of cough, severity of cough, volume or noise level of cough, hoarseness, sore throat, dyspnea, respiratory congestion, wheezing, respiratory constriction, respiratory inflammation, muscle spasm associated with cough, sputum production, syncope, insomnia, vomiting, subconjunctival hemorrhage, cough defect, cough urination, abdominal hernia, pelvic hernia, chondritis, tibia fracture or any combination thereof.

28. The use of claim 26, wherein the subject is a mammal.

29. The use of claim 26, wherein the subject is a human.

30. The use of claim 26, wherein the dextromethorphan or a pharmaceutically acceptable salt thereof is present in an amount of 0.1-10 mg.

31. The use of claim 26, wherein the dextromethorphan or a pharmaceutically acceptable salt is administered sublingually up to twice a day, or up to three times a day.

32. The use of claim 26, wherein the dextromethorphan or a pharmaceutically acceptable salt is administered sublingually every day or every other day.

33. The use of claim 26, wherein dextromethorphan or a pharmaceutically acceptable salt thereof is administered continuously for at least 30 days.

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