WO2020158894A1 - Composition containing polysulfide compound - Google Patents

Abstract

The present invention addresses the problem of providing: a composition that contains a polysulfide compound having improved stability or a pharmaceutically acceptable salt thereof; an agent for improving the stability of the polysulfide compound or of a pharmaceutically acceptable salt thereof; and a method for improving the stability of the polysulfide compound or of a pharmaceutically acceptable salt thereof. The present invention makes it possible to provide a composition that contains a polysulfide compound having improved stability or a pharmaceutically acceptable salt thereof by causing a polysulfide compound or a pharmaceutically acceptable salt thereof to coexist with one or more compounds selected from the group consisting of stabilizing agents and unsaturated hydrocarbon compounds.

Description

Composition containing polysulfide compound

The present invention relates to a composition containing a polysulfide compound having improved stability, a stability improver for a polysulfide compound, and a method for improving the stability of a polysulfide compound.

Polysulfide compounds are used in industrial applications such as additives for elastomers, antioxidants for lubricating oils, intermediates for the production of organic chemicals, insecticides, bactericides, and cetane numbers and ignition performance of diesel fuels. It is useful as a diesel fuel additive for improvement. In recent years, polysulfide compounds have been clarified to exist in the body, and have been suggested to be involved in the control of redox signals and mitochondrial functions, and are expected to be applied to the medical and health fields. An antioxidant intraocular perfusion solution containing polysulfide is known (Patent Document 1). In addition, a method for producing a polysulfide compound for the purpose of application in the medical and health fields is also known (Patent Document 2).

A polysulfide compound used for industrial purposes can be produced by reacting mercaptan and elemental sulfur in the presence of a basic catalyst (Patent Document 3). However, the polysulfide compound produced in this manner is unreacted mercaptan, Since hydrogen sulfide and a basic catalyst remain, it is very unstable, and stabilization methods thereof have been studied (Patent Documents 4 to 8).

Alkyl hydrolysis of polysulfide compounds in the presence of an alkylating agent such as iodoacetamide (IAM) and β-(4-hydroxyphenyl)ethyliodoamide (HPE-IAM) is carried out by tyrosine and 4-acetamide having a hydroxyphenyl group. It is known to be suppressed by phenol or glycerol having a hydroxyl group, sucrose, methanol and ethanol (Non-Patent Document 1).

On the other hand, even a polysulfide compound containing no unreacted mercaptan, hydrogen sulfide and a basic catalyst, or an alkylating agent, is stable enough to be used for use as a drug or a dietary supplement. Required for compounds.

International Publication No. 2018/057768 International Publication No. 2018/117186 U.S. Pat. No. 3,308,166 US Pat. No. 5,155,275 US Pat. No. 5,206,439 US Pat. No. 5,403,961 US Pat. No. 5,530,163 US Pat. No. 5,218,147

Redox Biology 21 (2019) 101096, p.1-7

An object of the present invention is to provide a composition containing a polysulfide compound having improved stability, a stability improver for the polysulfide compound, and a method for improving the stability of the polysulfide compound.

The present invention relates to the following (1) to (11).
(1) [A] polysulfide compound or a pharmaceutically acceptable salt thereof, [B] stabilizer or a pharmaceutically acceptable salt thereof, and [C] unsaturated hydrocarbon compound or a pharmaceutically acceptable salt thereof. A composition containing one or more compounds selected from the group consisting of salts.
(2) The stabilizer (B) or a pharmaceutically acceptable salt thereof is one or more compounds selected from the group consisting of tar dyes, gardenia dyes, edetic acid and alginic acid, and salts thereof (1) Composition.
(3) The composition according to (1) or (2) above, wherein the stabilizer [B] or a pharmaceutically acceptable salt thereof is one or more compounds selected from the group consisting of gardenia dyes and salts thereof.
(4) The [C] unsaturated hydrocarbon compound or a pharmaceutically acceptable salt thereof is one or more compounds selected from the group consisting of carotenoid compounds, terpenoid compounds, and pharmaceutically acceptable salts thereof. The composition according to any one of (1) to (3).
(5) The composition according to any one of the above (1) to (4), wherein the polysulfide compound [A] or a pharmaceutically acceptable salt thereof is a free form of the polysulfide compound.
(6) An internal medicine whose dosage form is selected from the group consisting of powder, powder, fine granule, granule, pill, hard capsule, soft capsule, tablet, film, dry syrup, liquid, jelly and confectionery. The composition according to any one of (1) to (5) above, which is
(7) The composition according to the above (6), which is in the form of powder, powder, fine granules, granules, pills, tablets, films or confectionery, is further coated with a coating agent. And the composition.
(8) The composition according to any one of (1) to (5) above, wherein the dosage form is an external preparation selected from the group consisting of solutions, ointments, and creams.
(9) The composition according to any one of the above (6) to (8), which is encapsulated in a light-shielding packaging material or packaged with the packaging material.
(10) Containing one or more compounds selected from the group consisting of [B] stabilizer or a pharmaceutically acceptable salt thereof and [C] unsaturated hydrocarbon compound or a pharmaceutically acceptable salt thereof. , A stability improver for a polysulfide compound or a pharmaceutically acceptable salt thereof.
(11) A composition containing [A] a polysulfide compound or a pharmaceutically acceptable salt thereof, [B] a stabilizer or a pharmaceutically acceptable salt thereof, and [C] an unsaturated hydrocarbon compound or A method for stabilizing a polysulfide compound or a pharmaceutically acceptable salt thereof in the composition, which comprises blending one or more compounds selected from the group consisting of pharmaceutically acceptable salts thereof.

The composition of the present invention comprises [A] a polysulfide compound or a pharmaceutically acceptable salt thereof, [B] a stabilizer or a pharmaceutically acceptable salt thereof and [C] an unsaturated hydrocarbon compound or a pharmaceutical agent thereof. A composition containing one or more compounds selected from the group consisting of salts that are allowed to be used and having an unstable polysulfide compound has excellent stability.

When the composition of the present invention has a solid dosage form such as powder or powder, stability is further improved by forming a coating film on the surface of the composition with a coating agent. Can be improved. When the composition of the present invention is in a non-solid dosage form such as a liquid preparation or a jelly preparation, stability can be improved by using a light-shielding container as the container for the composition.

As described above, since the composition of the present invention is stable in itself, it is not necessary to package the composition of the present invention as described above by further packaging the composition of the present invention in a light shielding packaging material. , Can also be more stable. In the present invention, this can provide a composition that can sufficiently secure the stability of a pharmaceutical or health supplement containing a polysulfide compound without complicating its storage and management.

The polysulfide compound used in the present invention has the following general formula (I):

(In the formula (I), R ¹ and R ² are each selected from a structure having an independent thiol group, represent a part other than the thiol group, and n is an integer of 2 or more) is there. Examples of R ¹ and R ² include amino acids such as cysteine, homocysteine, N-acetylcysteine and their derivatives, peptides such as γ-glutamylcysteine, cysteinylglycine, reduced glutathione and their derivatives, albumin, thioredoxin, etc. And a derivative thereof, an in vivo thiol compound such as penicillamine, cysteamine, pantetheine, coenzyme A, lipoic acid, and basilthiol and a derivative thereof, and the like, but are not limited to these structures and salt forms.

n is not particularly limited as long as it is an integer of 2 or more, but is preferably 2 or more and 8 or less, more preferably 2 or more and 7 or less, still more preferably 2 or more and 6 or less, and particularly preferably 2 or more and 5 or less. Below, the most preferable integer is 2 or more and 4 or less.

The polysulfide compound used in the present invention is preferably a compound in which R ¹ and R ² are the same and are cysteine, N-acetyl cysteine, or reduced glutathione, and n is an integer of 2 or more and 4 or less. Can be mentioned. More preferably, R ¹ and R ² are the same and are N-acetyl cysteine or reduced glutathione, and n is 3 or 4, more preferably R ¹ and R ² are the same and are reduced glutathione. And a compound in which n is 3 is included.

Examples of the pharmaceutically acceptable salt of the polysulfide compound, the stabilizer and the unsaturated hydrocarbon compound used in the present invention include salts of inorganic acids such as hydrochloride, hydrobromide and phosphate; acetic acid. Of organic acids such as salt, oxalate, malonate, succinate, fumarate, maleate, lactate, malate, citrate, tartrate, carbonate, picrate, glutamate etc. Examples thereof include metal salts such as salts, sodium salts, potassium salts, magnesium salts, calcium salts, and ammonium salts, preferably inorganic salts, more preferably hydrochlorides.

The stabilizer used in the present invention is a pharmaceutically acceptable stabilizer, for example, tar dyes (food red No. 2, food red No. 3, food red No. 40, food red No. 102, food red No. 102). No. 104, food red No. 105, food red No. 106, food yellow No. 4, food yellow No. 5, food blue No. 1, food blue No. 2), turmeric pigment, gardenia pigment, safflower pigment, cochineal pigment, grape skin pigment, Benikouji pigment, lac pigment, red radish pigment, annatto pigment, capsicum pigment, Kouryan pigment, caramel pigment, Sikon pigment, spirulina pigment, chlorophyll, purple potato pigment, purple yam pigment, perilla pigment, blueberry pigment, aluminum lake food blue No. 1 , Aluminum lake food blue No. 2, aluminum lake food red No. 3, aluminum lake food yellow No. 4, aluminum lake food yellow No. 5, etc., colorant, talc, yellow ferric oxide, ferric oxide, yellow iron oxide, black oxide Metal oxides such as iron, titanium oxide, zinc oxide, ascorbic acid, ascorbyl palmitate, edetic acid, erythorbic acid, oryzanol, catechin, quercetin, propylgallate, dodecylgallate, ethylgallate, octylgallate, dibutylhydroxytoluene, butylhydroxy. Anisole, clove extract, enzyme-treated rutin, apple extract, sesame oil extract, dibutylhydroxytoluene, fennel extract, horseradish extract, seri extract, tea extract, tempeh extract, dokudami extract, tocotrienol, tocopherol , Rapeseed oil extract, Green coffee bean extract, Sunflower seed, Ferulic acid, Butylhydroxyanisole, Blueberry leaf extract, Propolis extract, Hego/Ginkgo extract, Hesperetin, Pepper extract, Boracae extract, Gallic acid , Bayberry extract, eucalyptus extract, rosemary extract and other antioxidants and salts thereof, fumaric acid, malic acid, tartaric acid, citric acid, edetic acid and other sequestering agents and salts thereof, mannitol, sorbitol, xylitol, Sugar alcohols such as maltitol, lactitol, glycerin and sucrose, monosaccharides (eg glucose, fructose, mannose, galactose etc.), disaccharides (eg lactose, trehalose etc.), oligosaccharides (eg raffinose, inulooligosaccharides, palatinose). Oligosaccharides, α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, etc.), polysaccharides (For example, starch, cellulose and the like) sugars, gums such as gum arabic and xanthan gum, alginates, chitin, chitosan, kidati aloe extract, guar gum, hydroxypropyl cellulose, casein, corn starch, carboxymethyl celluloses, gelatin, agar, Dextrin, methyl cellulose, polyvinyl alcohol, microfibrillar cellulose, microcrystalline cellulose, seaweed cellulose, polyacrylic acid, polyphosphoric acid, carrageenan, yeast cell wall, konjac potato extract, nata de coco, thickening stabilizers such as mannan, and the like, and the like. Preferred are tar dyes, gardenia dyes, edetic acid and alginic acid, and more preferred are gardenia dyes.

Since these stabilizers may have stereoisomers, those isomers are also included in the “stabilizer” here, and a mixture thereof is also included. Also, when stereoisomers exist in the acid and base forming a salt with the polysulfide compound, and in each component added to the polysulfide compound described below, each isomer and a mixture thereof are similarly included in the present invention. ..

In the present invention, two or more kinds of the above stabilizers may be contained.
The unsaturated hydrocarbon compound used in the present invention is a pharmaceutically acceptable unsaturated hydrocarbon compound, and examples thereof include tar dyes (for example, food red No. 2, food red No. 3, food red No. 40, food red Red No. 102, food red No. 104, food red No. 105, food red No. 106, food yellow No. 4, food yellow No. 5, food blue No. 1, food blue No. 2), turmeric pigment, gardenia pigment, safflower pigment, cochineal Pigments, grape skin pigments, Benzioji pigments, lac pigments, red radish pigments, annatto pigments, capsicum pigments, korian pigments, caramel pigments, shikon pigments, spirulina pigments, chlorophyll, purple potato pigments, purple yam pigments, perilla pigments, blueberry pigments, Aluminum Lake Food Blue No. 1, Aluminum Lake Food Blue No. 2, Aluminum Lake Food Red No. 3, Aluminum Lake Food Yellow No. 4, Aluminum Lake Food Yellow No. 5, etc. Colorants or pigments, retinal, thiamine, riboflavin, flavin adenine Vitamin and its derivatives such as dinucleotide, cyanocobalamin, nicotinic acid, nicotinic acid amide, ascorbic acid, ergocalciferol, tocopherol, ubiquinone, hesperidin, ferulic acid, γ-oryzanol, orotic acid, rutin, eriocitrin, N-acetyl Aromatic amino acids and derivatives thereof such as tryptophan, tryptophan, tryptophan methyl ester, tryptophan ethyl ester, and phenylalanine, and their polymers, derivatives such as bases and nucleic acids such as adenine, thymine, guanine, cytosine, and uracil, and their polymers, terpenoid compounds such as dl-menthol, l-menthol, dl-camphor, d-camphor, d-borneol, geraniol, cineole, citronellol, carvone, anethole, eugenol, limonene, linalool, linalyl acetate, squalene, squalane and the like Essential oils and the like, carotenoid compounds such as β-carotene, lycopene, astaxanthin, lutein, zeaxanthin, α-carotene and β-cryptoxanthin, and essential oils containing these, anthocyanidins, anthocyanins, flavanones, flavans, catechins, flavonols, quercetin, isoflavones, Flavonoid compounds such as isoflavan and their derivatives, sterols, phenols, cresols, benzoic acid, gallic acid, salicylic acid, tannic acid, phthalic acid, fumaric acid, and resi Examples thereof include tin and derivatives thereof, preferably tar dyes, gardenia dyes, carotenoid compounds, and terpenoid compounds, and more preferably carotenoid compounds and terpenoid compounds. In the present invention, two or more kinds of the above unsaturated hydrocarbon compounds may be contained.

However, from the stabilizers, unsaturated hydrocarbon compounds and pharmaceutically acceptable salts thereof used in the present invention, 1) a compound having a hydroxyphenyl group, 2) an alcohol having no unsaturated bond, Preferably 1 or less, more preferably 2 or less, still more preferably 3 or less, most preferably 4 or less unsaturated bond-containing alcohol, 3) a sugar having no unsaturated bond, preferably 1 or less. , More preferably 2 or less, even more preferably 3 or less, most preferably 4 or less unsaturated sugars, and 4) one selected from the group consisting of pharmaceutically acceptable salts of these compounds. The above compounds can be removed, and at least tyrosine, 4-acetamidophenol, methanol, ethanol, sucrose, glycerol and their pharmaceutically acceptable salts can be removed.

Examples of the coating agent used in the present invention include film-forming agents such as sucrose, gelatin, polyethylene glycol, methyl cellulose, hypromethalose phthalate ester, Eudragit, ceracetoate, hypromellose and ethyl cellulose. The coating agent may contain one or more kinds of compounds selected from the above-mentioned stabilizers, unsaturated hydrocarbon compounds and salts thereof.

Examples of the light-shielding packaging material used in the present invention include a packaging material obtained by molding a PHP (Press Through Package), an aluminum foil, a thermoplastic resin in which a light-absorbing substance is kneaded, or the like. Examples include a container coated with a substance, a metal container, an opaque container, a colored container, and the like.

The polysulfide compound, the stabilizer, the unsaturated hydrocarbon compound, the coating agent, and the packaging material having a light-shielding property used in the present invention can all be obtained as commercial products or can be produced according to known methods.

In the present invention, the weight ratio of the [B] component and the [C] component is not particularly limited, but is usually preferably in the range of 0.1 to 80,000 parts by weight relative to 1 part by weight of the [C] component, and It is preferably 0.1 to 40,000 parts by weight, more preferably 1 to 40,000 parts by weight.

Further, the total weight ratio of the [A] component, the [B] component and the [C] component is not particularly limited, but usually, the [B] component and the [C] component are added to 1 part by weight of the [A] component. The total amount is preferably in the range of 0.025 to 850 parts by weight, more preferably 0.025 to 450 parts by weight, and further preferably 0.25 to 100 parts by weight.

Alternatively, although the above weight ratio is not limited, when the composition of the present invention is an internal preparation, [A] component is usually 1 part by weight and [B] component is usually 2.5 parts by weight. It is preferably from about 800 parts by weight, more preferably from 5 to 400 parts by weight, further preferably from 5 to 50 parts by weight. The amount of the [C] component is usually 0.3 to 16 parts by weight, preferably 0.3 to 8 parts by weight, and more preferably 0.6 to about 1 part by weight of the [A] component. 4 parts by weight.

Further, in the case of mucous membrane application agents such as eye drops, eye ointments and nasal drops, the amount of [B] component is usually 0.025 to 320 parts by weight per 1 part by weight of [A] component. The amount is more preferably 0.025 to 164 parts by weight, further preferably 0.25 to 82 parts by weight. The amount of the component [C] is usually 0.0005 to 2 parts by weight, preferably 0.0005 to 1.5 parts by weight, and more preferably 0, relative to 1 part by weight of the component [A]. 0.0005 to 1 part by weight.

The composition of the present invention, in addition to the components [A], [B] and [C], may further contain various other components (pharmacologically active component, Bioactive ingredients, etc.) or can be used in combination therewith. The type of such an ingredient is not particularly limited, and for example, an active ingredient in various medicines described in the Pharmaceutical Manufacturing and Marketing Guide Separate Volume OTC Drug Manufacturing and Marketing Approval Standard 2012 (supervised by the Regulatory Science Society of Japan), for example, Histamine component, anti-allergic component, parasympathetic blockade component, sympathomimetic component, anti-inflammatory enzyme, antipyretic analgesic component, antitussive component, expectorant, mucosal protective component, anti-inflammatory component, decongestant component, fungicide, xanthine derivative, Examples include herbal medicines, vitamins and amino acids. In addition, compounds known as so-called supplement components, that is, vitamins, minerals, amino acids, fatty acids and the like may be included in the composition of the present invention.

Specific examples of the active ingredient in medicine include the following ingredients, but are not limited to these ingredients. The blending amount of these components is appropriately selected according to the type of formulation, the type of active ingredient, and the like.

Antioxidant: Vitamin A, Riboflavin, Vitamin C, Tocopherol, Coenzyme Q10, Magnesium, Iodine, Melatonin, α-Carotene, Astaxanthin, β-Carotene, Canthaxanthin, Cryptoxanthin, Lutein, Lycopene, Zeaxanthin, Fucoxanthin, Rubixanthin , Apigenin, luteolin, tangeretin, isorhamnetin, kaempferol, myricetin, proanthocyanidin, quercetin, rutin, nobiletin, eriodictythiol, hesperetin, naringenin, catechin, gallocatechin, epicatechin, epigallocatechin, theaflavin, thearbiginein, daidzein, daidzein, daidzein, daidzein, daidzein, daidzein, daidzein, daidzein, daidzein, daidzein, daizegine , Resveratrol, pterostibuben, cyanidin, delphinidin, malvidin, pelargonidin, peonidin, petunidin, chicoric acid, chlorogenic acid, cinnamic acid, ellagic acid, ellagitannin, gallic acid, gallotannin, rosmarinic acid, salicylic acid, ferulic acid, oleocanthal, Oleuropein, curcumin, silibinin, eugenol, tannin, eicosapentaenoic acid, docosahexaenoic acid, linoleic acid, linolenic acid, cysteine, γ-glutamylcysteine, glutathione, homocysteine, lipoic acid, allicin, isoallicin, sesamin, sesaminol, coumarin and the like.

Antihistamine or antiallergic ingredients: isothipendyl hydrochloride, iproheptin hydrochloride, difeterol hydrochloride, diphenylpyraline hydrochloride, diphenhydramine hydrochloride, triprolidine hydrochloride hydrate, triperenamine hydrochloride, tonzylamine hydrochloride, promethazine hydrochloride, metzirazine hydrochloride. Salt, diphenhydramine salicylate, diphenyldisulfonic acid carbinoxamine, alimemazine tartrate, diphenhydramine tannate, diphenylpyraline theoclate, carbinoxamine maleate, chlorpheniramine maleate, promethazine methylenedisalicylate, mequitazine, loratadine , Emedastine fumarate, levocabastine hydrochloride, epinastine hydrochloride, azelastine hydrochloride, ketotifen fumarate, acitazanolast hydrate, sodium cromoglycate, anlexanox, tranilast, pemirolast potassium, ibudilast and the like.

Bronchodilators: acridinium bromide, aminophylline hydrate, ipratropium bromide hydrate, indacaterol maleate, umeclidinium bromide, ephedrine hydrochloride, clenbuterol hydrochloride, glycopyrronium bromide, salbutamol sulfate, salmeterol xinafoate. , Fenoterol hydrobromide, Diprophylline, Tiotropium bromide hydrate, Tyloxapol, Tulobuterol, Theophylline, Terbutaline sulfate, Trimethoquinol hydrochloride hydrate, Fenoterol hydrobromide, Procaterol hydrochloride hydrate, Proxyphyrin, Formoterol Fumarate hydrate, isoprenaline hydrochloride, dl-methylephedrine hydrochloride, 1-isoprenaline hydrochloride and the like.

Bronchial asthma remedy: salmeterol xinafoate, fluticasone propionate, ciclesonide, vilanterol triphenylacetate, fluticasone furancarboxylic ester, formoterol fumarate hydrate, budesonide, beclomethasone propionate, mometasone furanate hydrate Thing, omalizumab, benralizumab, mepolizumab, etc.
Anti-inflammatory enzymes: lysozyme, serrapeptase, bromelain, pronase, etc.

Antitussive drug components: achloramide, cloperastine, pentoxyberine (carbetapentane), tipepidine, dibnate, dextromethorphan, codeine, dihydrocodeine, noscapine, etc.
Expectorant: potassium guaiacol sulfonate, guaifenesin, etc.
Mucosal protection components: Aminoacetic acid, dried aluminum hydroxide gel, aluminum-based mucosal protection agents such as dihydroxyaluminum/aminoacetate, magnesium aluminometasilicate, aluminum silicate, hydrotalcite, magnesium alumina hydroxide, aluminum hydroxide gel Aluminum hydroxide/sodium hydrogen carbonate coprecipitated product, aluminum hydroxide/magnesium carbonate mixed dry gel, aluminum hydroxide/calcium carbonate/magnesium carbonate coprecipitated product, magnesium carbonate, magnesium oxide, magnesium hydroxide, silica Magnesium-based mucosal protective agents such as magnesium acid, magnesium hydroxide/potassium aluminum sulfate coprecipitation products, etc.

Anti-inflammatory components: tranexamic acid, lysozyme, etc.
Decongestants: For example, tetrahydrozoline hydrochloride, naphazoline hydrochloride, naphazoline sulfate, epinephrine hydrochloride, ephedrine hydrochloride, methylephedrine hydrochloride and the like.
Bactericides: acrinol, cetylpyridinium, benzalkonium chloride, benzethonium chloride, chlorhexidine hydrochloride, chlorhexidine gluconate, alkyldiaminoethylglycine hydrochloride and the like.

Xanthine derivatives: caffeine, theophylline, aminophylline, theobromine, diprofeiline, proxyphylline, pentoxifylline and the like.
Herbal medicines and ingredients derived from herbal medicines: ginger, liquorice, carrots, mah, cinnamon, kayga, saishin, shinji, nantenjitsu, halibut, juniper, zenko, kyojutsu, shazenshi, goho, daijutsu, juniper daisies, sojutsu, gentian, fennel, onji, Oat, citrus, carrot, chimpanzee, clove, clove, senega, chazensou, shazin, etc.

Vitamin: Vitamin A (eg, retinal, retinol, retinoic acid, carotene, dehydroretinal, lycopene, etc.), vitamin B (eg, thiamine, thiamine disulfide, dicetiamine, octotiamine, cocotiamine, bis-ibutyamine, bisbenchamine) , Prosultiamine, benfotiamine, fursultiamine, riboflavin, flavin adenine dinucleotide, pyridoxine, pyridoxal, hydroxocobalamin, cyanocobalamin, methylcobalamin, deoxyadenocobalamin, folic acid, tetrahydrofolic acid, dihydrofolic acid, nicotinic acid, nicotinic acid amide , Nicotinyl alcohol, pantothenic acid, panthenol, biotin, choline, inositol, etc.), vitamin Cs (eg, ascorbic acid, erythorbic acid, or derivatives thereof), vitamin Ds (eg, ergocalciferol, cholecalciferol) , Hydroxycholecalciferol, dihydroxycholecalciferol, dihydrotaxosterol, etc.), vitamin Es (eg, tocopherol and its derivatives, ubiquinone derivatives, etc.), other vitamins (eg, hesperidin, carnitine, ferulic acid, γ-oryzanol) , Orotic acid, rutin, eriocitrin, etc.) etc.

Amino acids: valine, isoleucine, leucine, methionine, lysine, phenylalanine, tryptophan, threonine, arginine, glycine, alanine, serine, cysteine, asparagine, glutamine, proline, aspartic acid, glutamic acid, histidine L-aspartic acid potassium, L-aspartic acid. Magnesium, magnesium/potassium L-aspartate, aminoethyl sulfonic acid, sodium chondroitin sulfate, and their major metabolites and derivatives.

Others: For example, neostigmine methyl sulfate, sulfamethoxazole, sulfamethoxazole sodium, pranoprofen, etc.

-These components may be in a free form or a salt. Among them, for example, in the case of the oral administration, it is preferably at least one or more selected from belladonna total alkaloid, belladonna extract, isopropamide iodide, methylephedrine, pseudoephedrine, phenylephrine, lysozyme, glycyrrhizic acid, caffeine and salts thereof. In the case of eye drops, for example, chlorpheniramine maleate, sodium cromoglycate, tranilast, pemirolast potassium, dipotassium glycyrrhizinate, azulenesulfonic acid, ε-aminocaproic acid, berberine, pyridoxine, chondroitin sodium sulfate, pranoprofen. 1 or more types selected from.

The composition of the present invention may be selected from various dosage forms that can be applied to the efficacy of the polysulfide compound. Examples of the internal drug include powders, powders, fine granules, granules, pills, hard capsules, soft capsules, tablets [plain tablets, sugar-coated tablets, rapidly disintegrating tablets in the mouth, chewable tablets (chewable tablets), effervescent tablets. Tablets, troches, film-coated tablets, etc.], film agents, dry syrups, jellies, confectionery [including candy (candy), gummi agents, nougat agents, etc.], solid agents, liquid agents [suspension agents, Including emulsions, syrups, limonade agents, etc.] and the like. Examples of the external preparation include eye drops, eye ointments such as eye ointments (including eye drops that can be applied while wearing contact lenses), nasal drops, and creams, ointments, lotions, aerosols. Are listed.

The composition of the present invention contains various formulation additives according to the formulation to be applied. Examples of the oral drug include excipients, disintegrants, disintegration aids, binders, lubricants, superplasticizers, buffers, sustaining agents, stabilizing agents, antioxidants, reducing agents, and cooling agents. Agents, sweeteners, corrigents, fragrances, colorants, surfactants, plasticizers, solubilizing agents, suspending agents, dispersing agents, emulsifiers, buffers, solubilizing agents, brightening agents , Coating agents and the like. In the ophthalmic application, for example, thickeners, buffers, isotonic agents, preservatives, bactericides, antibacterial agents, stabilizers, chelating agents, preservatives, solubilizing agents, pH adjusting agents, surfactants. May be included. The external preparation may include, for example, a base, a preservative, a preservative, a surfactant, a pH adjuster, a solubilizing agent, a suspending agent, an antioxidant and the like.

Note that the content of these additives is not particularly limited and can be set arbitrarily. In the present invention, "stability", "stabilization" mainly means stability to heat and light, stabilization, for example, heat during formulation storage, light such as white fluorescent light and sunlight, It means stability and stabilization against decomposition by contact with a base and oxidation by contact with air.

The composition of the present invention is not particularly limited in the order of mixing, the preparation method, etc., as long as it contains the component [A] and one or more compounds selected from the group consisting of the component [B] and the component [C]. Alternatively, it can be prepared according to methods known to those skilled in the art.

Specifically, when the composition of the present invention is a solid agent, for example, the above ingredients, optionally other pharmacologically active ingredients or physiologically active ingredients, raw materials containing additives are granulated (for example, extrusion granulation, Granules can be produced by fluidized bed granulation, spray drying granulation, etc.), drying, and sieving. The granule may be a single granule containing the component [A] and one or more compounds selected from the group consisting of the component [B] and the component [C], or two or more granules having different compositions. The granules may be combined, or the granules containing the component [A] and the granules containing the component [B] may be combined into a granule. Further, using this granule, a capsule or tablet can be produced by a conventional method. Moreover, for example, after suspending each component with an appropriate amount of a dispersant, a capsule can be produced by a usual method. Here, it is preferable to employ a method in which the above components are sufficiently mixed.

When the composition of the present invention has a solid dosage form, the solid dosage may be produced and then coated with a coating agent. The coating agent may contain a stabilizer, and a plurality of coating agents having different compositions of the stabilizer may be used to form a multilayer coating.

When the composition of the present invention is a non-solid agent such as a liquid agent, for example, [A] component, one or more compounds selected from the group consisting of [B] component and [C] component, and optionally other After dissolving a raw material containing a pharmacologically active ingredient, a physiologically active ingredient or an additive with an appropriate amount of purified water, the pH is usually adjusted to 1.0 to 8.0, and then the remaining purified water is added to adjust the volume. A liquid agent can be manufactured by adjusting. Further, if necessary, it can be filtered and sterilized and then filled in a container. Here, it is preferable to employ a method in which the components are sufficiently mixed. The volume and viscosity of the liquid agent are not particularly limited, and may be subjected to treatments such as dilution and concentration according to known methods. Further, it may be a ready-to-use liquid preparation in which the raw material mixture of the liquid preparation is dissolved to be a liquid at the time of use.

Particularly when prepared as a liquid preparation, its pH is preferably adjusted to the range of 3.0 to 8.0 which is a commonly used range. As a container or packaging material for encapsulating, filling, or wrapping the composition of the present invention, for example, a PHP (Press Through Package), an aluminum foil, a thermoplastic resin in which a light-absorbing substance is kneaded, or the like is molded. The packaging material obtained in this way, a container coated with the substance, a metal container, an opaque container, a colored container and the like can be mentioned. Since the composition of the present invention itself has high light stability, it is possible to use a highly transparent container and packaging material. The container or packaging material for encapsulating, filling, or wrapping the above-described composition of the present invention can be appropriately selected depending on the purpose and application, but the composition of the present invention is only a single-use type packaging form. Instead, it is also useful as a multidose composition that is packaged in a multiple dose form and continuously used by the user.

The composition of the present invention has high light stability, and even when the light-shielding property of the product is reduced by opening the package, it is possible to suppress the decrease in the content of the polysulfide compound, and therefore it is particularly useful as a multi-dose composition. The composition of the present invention is, for example, a drug, a quasi drug, a food or drink, or a raw material thereof [for example, a pharmaceutical preparation, a quasi drug preparation, a food for specified health use, a nutritionally functional food, a food for the elderly, a special use. Foods, functional foods, health supplements (supplements), food preparations (eg, confectionery tablets)].

The composition of the present invention can be used without particular limitation depending on its form. For example, in the case of a composition for internal use, [A] polysulfide compound or a pharmaceutically acceptable salt thereof, and [B] stabilizer or a pharmaceutically acceptable salt thereof and [C] unsaturated hydrocarbon compound Alternatively, one or more compounds selected from the group consisting of pharmaceutically acceptable salts thereof, or a combination thereof can be used for the treatment of any disease for which administration is desired, and for maintaining or improving daily health. it can.

The present invention also provides a polysulfide compound containing one or more compounds selected from the group consisting of a stabilizer or a pharmaceutically acceptable salt thereof and an unsaturated hydrocarbon compound or a pharmaceutically acceptable salt thereof. Or a pharmaceutically acceptable salt thereof is stabilized, and since the action of the polysulfide compound or a pharmaceutically acceptable salt thereof is more effectively exerted, a stabilizer or a pharmaceutically acceptable salt thereof and There is provided a stability improver for a polysulfide compound, which comprises one or more compounds selected from the group consisting of unsaturated hydrocarbon compounds or pharmaceutically acceptable salts thereof.

The stability improver of the present invention contains one or more compounds selected from the group consisting of a stabilizer or a pharmaceutically acceptable salt thereof and an unsaturated hydrocarbon compound or a pharmaceutically acceptable salt thereof. There is no particular limitation as long as it is present, and the content, the type of components to be added and blended, the preparation method, the form, etc. are the same as those of the composition of the present invention. In addition, a composition containing a [A] polysulfide compound or a pharmaceutically acceptable salt thereof, a stabilizer or a pharmaceutically acceptable salt thereof and an unsaturated hydrocarbon compound or a pharmaceutically acceptable salt thereof Since the stability of the polysulfide compound is improved by containing one or more compounds selected from the group consisting of salts, the present invention provides a stabilizer, a pharmaceutically acceptable salt thereof and an unsaturated hydrocarbon. There is provided a method for stabilizing a composition containing a polysulfide compound, which comprises one or more compounds selected from the group consisting of compounds or pharmaceutically acceptable salts thereof.

As a method for stabilizing the composition, specifically, in the composition, [B] a stabilizer or a pharmaceutically acceptable salt thereof and [C] an unsaturated hydrocarbon compound or a pharmaceutically acceptable salt thereof are included in the composition. One or more compounds selected from the group consisting of [B] component and [C] component around the above [A] component together with one or more compounds selected from the group consisting of There is no particular limitation as long as the compound of 1 exists.

In the method for stabilizing the composition, the component [A] and one or more compounds selected from the group consisting of the component [B] and the component [C] may be added simultaneously or separately. The order is not particularly limited, but considering the decomposition of the [A] component, the mixing time of the [A] component and one or more compounds selected from the group consisting of the [B] component and the [C] component It is preferable that there is no difference. Further, in these methods, the types of the [A] component and one or more compounds selected from the group consisting of the [B] component and the [C] component used, their contents, and their content ratios, etc. The kinds of components added and blended with, the preparation method, the use, the formulation form, the administration target, and the like are the same as those of the composition of the present invention.

[Test Example 1]
After suspending 0.53 g of glutathione trisulfide dihydrate in 20 mL of water, 0.13 g of sodium hydrogen carbonate was added to dissolve glutathione trisulfide. Water was added to the solution to make 25 mL (final concentration 20 g/L), and the solution was diluted 2-fold with 500 mM phosphate buffer of each pH to adjust the pH to 5.0, 6.0, and 7 A test sample was prepared by adjusting to 0.5. The test sample was set on a light stability device (LT-120D3CJ manufactured by Nagano Science Co., Ltd.), and 4000 Lux of light was continuously irradiated for 3.5 hours using a D65 fluorescent lamp for color comparison/inspection as a light source, and an integrated irradiation amount of 14000 Lux. It was exposed to the light of hr. The light irradiation test was conducted at 25°C.

The residual ratio of glutathione trisulfide in each test sample was calculated by the following formula by measuring the glutathione trisulfide content by high performance liquid chromatography (HPLC).

HPLC analysis conditions Detector: Ultraviolet absorptiometry (wavelength 220 nm)
Column: LiChrosorb RP-18 (manufactured by Kanto Chemical Co., Inc.) inner diameter 4 mm, length 250 mm, particle diameter 5 μm
Column temperature: constant temperature around 40° C. Mobile phase: phosphate buffer/methanol solution (9:1) A solution to which 1 g of 1-heptanesulfonate was added per 1000 mL. (Phosphate buffer: 900 mL of water is added to 2 mL of phosphoric acid, pH is adjusted to 3 with sodium hydroxide (1→4), and water is further added to bring the total volume to 1000 mL).
Flow rate: 0.60 ml/min The results are shown in Table 1.

As shown in Table 1, it was found that glutathione trisulfide is easily photodegraded, and the higher the pH, the faster the photodegradation of glutathione trisulfide.

[Test Example 2]
Glutathione trisulfide solid (powder) was put into a sample tube for measurement, one sample tube was covered with aluminum foil, and the other was uncovered and set on a light stability device (LT-120D3CJ manufactured by Nagano Science Co., Ltd.), Using a D65 fluorescent lamp for color comparison/inspection as a light source, light of 4000 Lux was continuously irradiated for 300 hours, and exposed to light having an integrated irradiation amount of 1.2 million Lux·hr. The light irradiation test was performed at 4°C.

After the light irradiation, the solid of glutathione trisulfide was subjected to HPLC analysis, the area of the peak (HPLC area) detected by HPLC such as glutathione trisulfide was measured, and the HPLC purity of glutathione trisulfide was calculated by the following formula.
The HPLC analysis conditions were the same as in Test Example 1.

As shown in Table 2, it was found that glutathione trisulfide photodecomposes even in powder.

[Test Example 3]
(1) Test method Each of the components shown in Table 3 was treated with a glutathione trisulfide solution (10 g/L. Similarly to Test Example 1, a solution obtained by adding 0.13 g of sodium hydrogen carbonate to 0.53 g of glutathione trisulfide was adjusted to pH 7). It was dissolved or suspended in 2) diluted with a phosphate buffer solution of 0.5. It was filtered with a membrane filter (0.22 μm) and prepared as a liquid agent in a polypropylene tube (1.5 mL capacity) to give a test sample. This test sample was set in a light stability device (LT-120D3CJ manufactured by Nagano Science Co., Ltd.), and 4000 Lux light was continuously irradiated for 3.5 hours using a D65 fluorescent lamp for color comparison/inspection as a light source, and an integrated irradiation amount 14, It was exposed to light of 000 Lux·hr.

The residual rate of glutathione trisulfide was calculated by measuring the content of glutathione trisulfide by HPLC as in Test Example 1.
The gardenia dye and the food dye were purchased from Kyoritsu Foods Co., Ltd. and the dextrin was purchased from Wako Pure Chemical Industries, Ltd.

As shown in Table 3, it comprises a polysulfide compound or a pharmaceutically acceptable salt thereof, a stabilizer or a pharmaceutically acceptable salt thereof, and an unsaturated hydrocarbon compound or a pharmaceutically acceptable salt thereof. The coexistence of one or more compounds selected from the group improved the stability of the polysulfide compound. From this, the stabilization of the polysulfide compound with one or more compounds selected from the group consisting of a stabilizer or a pharmaceutically acceptable salt thereof, and an unsaturated hydrocarbon compound or a pharmaceutically acceptable salt thereof is It became clear that the present invention can be applied to various formulation forms without being limited to the formulation forms.

By allowing the polysulfide compound and one or more compounds selected from the group consisting of a stabilizer and an unsaturated hydrocarbon compound to coexist, a remarkable inhibitory effect on the reduction in the residual ratio of the polysulfide compound is recognized, and the stabilizer, It was confirmed that at least one compound selected from the group consisting of unsaturated hydrocarbon compounds can be used as a stabilizer for polysulfide compounds.
Below, the example of the manufacturing method of the composition of this invention is given.

[Example 1] Method for producing soft capsule containing glutathione trisulfide Each component described in Formula 1 in Table 4 is dispersed in a method known per se to fill a soft capsule to produce a soft capsule. The unit is parts by weight.

Example 2 Method for Producing Eye Drops Containing Glutathione Trisulfide An eye drop is produced by mixing the components described in Formulation 2 in Table 5 by a method known per se. The unit is parts by weight.

Example 3 Method for Producing Tablet Containing Glutathione Trisulfide 60.0 kg of glutathione trisulfide, 36.0 kg of microcrystalline cellulose, 6.6 kg of sucrose fatty acid ester, 1.2 kg of calcium phosphate and 20.0 kg of β-cyclodextrin were added. Mix. The resulting mixture is compression molded using a rotary compression molding machine to produce tablets with a diameter of 8 mm and 250 mg.

[Example 4] Method for producing enteric coated capsule containing glutathione trisulfide 20 kg of the mixture prepared in Example 3 and 0.2 kg of silicon dioxide were mixed and stirred, and the resulting mixture was put into a capsule filling machine, The No. 2 hard capsule made of gelatin is filled into 20000 tablets to obtain a hard capsule. The surface of the obtained hard capsule is coated with a zein solution to produce 20000 enteric-coated capsules.

[Example 5] Method for producing glutathione trisulfide-containing cosmetic lotion The following aqueous layer components (1) to (4) and (9) are mixed and dissolved by heating at 60°C. Next, the mixed and dissolved oil layer components (5) to (8) are added thereto, and the mixture is stirred and mixed until uniform and cooled, and then filtered to obtain a lotion.
(1) Glutathione trisulfide 0.1 g
(2) Propylene glycol 3.0g
(3) Sodium pyrrolidonecarboxylate 0.3 g
(4) Methyl paraben 0.1 g
(5) Polyoxyethylene polyoxypropylene alkyl ether 1.0 g
(6) Ethanol 10.0g
(7) Astaxanthin (8) Perfume proper amount (9) Purified water proper amount
Total amount 100.0g

[Example 6] Method for producing glutathione trisulfide-containing cream The following oil layer components (1) to (7) and aqueous layer components (8) to (11) were heated and dissolved at 80°C. Next, the oil layer component is gradually added to the water layer component while emulsifying with a homomixer, and the mixture is stirred and mixed until uniform, and cooled to obtain a cream.
(1) Beeswax 4.0g
(2) 5.0 g of cetanol
(3) Stearic acid 5.0 g
(4) Lanolin 3.0g
(5) Pristane 25.0g
(6) Polyoxyethylene stearyl ether 3.5g
(7) Glycer monostearate 1.5g
(8) Glutathione trisulfide 2.0 g
(9) Propylene glycol 10.0g
(10) Purified water proper amount (11) Fragrance, preservative proper amount
Total amount 100.0g

[Example 7] Method for producing beverage containing glutathione trisulfide Glutathione trisulfide 0.6 kg, erythritol 3 kg, citric acid 0.05 kg, carotenoid 0.05 kg, artificial sweetener 3 g, flavor 0.06 kg at a liquid temperature of 70°C It is stirred and dissolved in 50 L of water with, and after adjusting the pH to 3.3 with citric acid, it is sterilized using plate sterilization, filled in a bottle, and pasteurizer sterilized to produce a beverage.

Although the present invention has been described in detail using specific embodiments, it will be apparent to those skilled in the art that various modifications and variations can be made without departing from the spirit and scope of the present invention. This application is based on the Japanese patent application (Japanese Patent Application No. 2019-14744) filed on January 30, 2019, which is incorporated by reference in its entirety.

According to the present invention, a composition containing a polysulfide compound having improved stability or a pharmaceutically acceptable salt thereof, a stability improving agent for a polysulfide compound or a pharmaceutically acceptable salt thereof, and a polysulfide compound or a pharmaceutical agent thereof A method of improving the stability of an acceptable salt is provided.

Claims (11)

From [A] a polysulfide compound or a pharmaceutically acceptable salt thereof, [B] a stabilizer or a pharmaceutically acceptable salt thereof and [C] an unsaturated hydrocarbon compound or a pharmaceutically acceptable salt thereof A composition containing one or more compounds selected from the group consisting of: The composition according to claim 1, wherein the stabilizer [B] or a pharmaceutically acceptable salt thereof is one or more compounds selected from the group consisting of tar dyes, gardenia dyes, edetic acid and alginic acid, and salts thereof. Stuff. The composition according to claim 1 or 2, wherein the stabilizer [B] or a pharmaceutically acceptable salt thereof is one or more compounds selected from the group consisting of gardenia pigments and salts thereof. The unsaturated hydrocarbon compound [C] or a pharmaceutically acceptable salt thereof is one or more compounds selected from the group consisting of carotenoid compounds, terpenoid compounds and pharmaceutically acceptable salts thereof. The composition according to any one of 3 above. The composition according to any one of claims 1 to 4, wherein the [A] polysulfide compound or a pharmaceutically acceptable salt thereof is a free form of the polysulfide compound. The dosage form is an internal medicine selected from the group consisting of powders, powders, fine granules, granules, pills, hard capsules, soft capsules, tablets, films, dry syrups, liquids, jellies and confectionery. Item 6. The composition according to any one of items 1 to 5. The composition according to claim 6, which is a powder, a powder, a fine granule, a granule, a pill, a tablet, a film or a confectionery, and is further coated with a coating agent. Composition. The composition according to any one of claims 1 to 5, wherein the dosage form is an external preparation selected from the group consisting of solutions, ointments and creams. (9) The composition according to any one of (6) to (8), which is encapsulated in or wrapped in a light-shielding packaging material. A polysulfide compound containing one or more compounds selected from the group consisting of [B] a stabilizer or a pharmaceutically acceptable salt thereof and [C] an unsaturated hydrocarbon compound or a pharmaceutically acceptable salt thereof, or A stability improver for a pharmaceutically acceptable salt thereof. A composition containing [A] a polysulfide compound or a pharmaceutically acceptable salt thereof, [B] a stabilizer or a pharmaceutically acceptable salt thereof, and [C] an unsaturated hydrocarbon compound or a pharmaceutically acceptable salt thereof. A method for stabilizing a polysulfide compound or a pharmaceutically acceptable salt thereof in the composition, which comprises blending one or more compounds selected from the group consisting of: