Stabilization methods

Abstract

To provide a method for stabilizing belladonna or its extract in an aqueous solution containing the belladonna or its extract.SOLUTION: A method for stabilizing belladonna or its extract includes blending chlorpheniramine or a salt thereof of 3 pts.mass or more with belladonna or its extract of 1 pt.mass in an aqueous solution containing the belladonna or its extract.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to a method for stabilizing belladonna or an extract thereof, and a method for producing a pharmaceutical composition containing belladonna or an extract thereof. [Background technology]

[0002] Belladonna, also known as belladonna, is a herb of the Solanaceae family, and its rhizomes and roots are rich in alkaloids that have the effect of suppressing the parasympathetic nervous system. The alkaloid components extracted from belladonna are known as total belladonna alkaloids, and have anticholinergic effects and can reduce runny nose and tear secretion, so they are used in rhinitis medications and general cold remedies.

[0003] Other drugs known to be used in comprehensive cold medicines include the antihistamine d-chlorpheniramine maleate, and a pharmaceutical composition combining the total alkaloids of belladonna with d-chlorpheniramine maleate is also known (see, for example, Patent Document 1). However, there have been no reports on the problems associated with the total alkaloids of belladonna when producing this pharmaceutical composition. [Prior art documents] [Patent documents]

[0004] [Patent Document 1] Japanese Patent Application Laid-Open No. 2000-95707 Summary of the Invention [Problem to be solved by the invention]

[0005] From a safety perspective, the total alkaloids of belladonna must be incorporated into pharmaceuticals in trace amounts. To uniformly incorporate such extremely small amounts of active ingredients into pharmaceutical compositions, it is best to add them as a solution during the manufacturing process of the pharmaceutical. However, the total alkaloids of belladonna are unstable in aqueous solutions.

[0006] The present invention aims to provide a method for stabilizing belladonna or an extract thereof in an aqueous solution containing belladonna or an extract thereof, and a method for producing a pharmaceutical composition containing belladonna or an extract thereof using the stabilization method. [Means for solving the problem]

[0007] The present inventors have discovered that belladonna or an extract thereof can be stabilized in an aqueous solution containing belladonna or an extract thereof by adding 3 parts by mass or more of chlorpheniramine maleate to 1 part by mass of belladonna or an extract thereof, and have completed the present invention. That is, the present invention includes the following aspects. [1] A method for stabilizing belladonna or an extract thereof, characterized by compounding 3 parts by mass or more of chlorpheniramine or a salt thereof per 1 part by mass of belladonna or an extract thereof in an aqueous solution containing belladonna or an extract thereof. [2] The stabilization method described in [1], wherein belladonna or an extract thereof is total belladonna alkaloids. [3] The stabilization method according to [1] or [2], wherein the chlorpheniramine or a salt thereof is chlorpheniramine maleate or d-chlorpheniramine maleate. [4] A method for producing a pharmaceutical composition containing belladonna or an extract thereof and chlorpheniramine or a salt thereof, the method comprising the step of blending 3 parts by mass or more of chlorpheniramine or a salt thereof with 1 part by mass of belladonna or an extract thereof in an aqueous solution containing belladonna or an extract thereof. [5] The manufacturing method described in [4], wherein belladonna or its extract is total belladonna alkaloids. [6] The manufacturing method according to [4] or [5], wherein the chlorpheniramine or a salt thereof is chlorpheniramine maleate or d-chlorpheniramine maleate. [7] The manufacturing method according to any one of [4] to [6], wherein the pharmaceutical composition is in the dosage form of a tablet, capsule, granule, powder, or pill. [Effects of the Invention]

[0008] According to the present invention, in the production of a pharmaceutical composition containing belladonna or an extract thereof, belladonna or an extract thereof can be uniformly incorporated into the pharmaceutical composition, and the stability of belladonna or an extract thereof in an aqueous solution can be significantly improved. DETAILED DESCRIPTION OF THE INVENTION

[0009] The "belladonna or extract thereof" of the present invention contains, as its main medicinal ingredients, alkaloids such as hyoscyamine, atropine (l-hyoscyamine), norhyoscyamine, and scopolamine. Specific examples include belladonna cone, belladonna extract, belladonna iodide, and total belladonna alkaloids, with total belladonna alkaloids being preferred. These can be produced by known methods, or commercially available products can be used, such as those in accordance with the Japanese Pharmacopoeia.

[0010] In the present invention, "chlorpheniramine or a salt thereof" includes chlorpheniramine and its pharmaceutically acceptable salts, as well as solvates of chlorpheniramine and its pharmaceutically acceptable salts with water, alcohol, etc. These can be produced by known methods, or commercially available products can be used. Chlorpheniramine has an asymmetric carbon atom and therefore exists as optical isomers, but in the present invention, it may be a single optical isomer or a mixture of various optical isomers, such as the d-isomer or dl-isomer. Pharmaceutically acceptable salts of chlorpheniramine include, for example, organic acid salts such as maleate or fumarate, and inorganic acid salts such as hydrochloride or sulfate. "Chlorpheniramine or a salt thereof" includes, for example, chlorpheniramine, chlorpheniramine maleate (dl-chlorpheniramine maleate), and d-chlorpheniramine maleate, and is preferably chlorpheniramine maleate or d-chlorpheniramine maleate. These can be produced by known methods, or commercially available products can be used, such as chlorpheniramine maleate and d-chlorpheniramine maleate in accordance with the Japanese Pharmacopoeia.

[0011] Examples of aqueous solvents constituting the "aqueous solution" of the present invention include aqueous solvents commonly used in the field of pharmaceutical formulation. Specific examples include water such as purified water, sterile purified water, and water for injection as defined in the Japanese Pharmacopoeia, as well as mixed solvents containing a polar organic solvent and water. Examples of polar organic solvents include alcohols such as methanol, ethanol, and isopropanol, ketones such as acetone, and ethers such as tetrahydrofuran, with ethanol being preferred. Specific examples of mixed solvents containing a polar organic solvent and water include water containing 0.5 to 99.5% by volume of ethanol.

[0012] In the present invention, "stabilization of belladonna or its extract" means preventing or inhibiting the medicinal ingredients (such as alkaloids, particularly hyoscyamine and scopolamine) contained in belladonna or its extract from undergoing chemical changes (decomposition, structural changes, modifications, etc.) in aqueous solution, which would reduce their medicinal efficacy.

[0013] The method for stabilizing belladonna or an extract thereof of the present invention comprises incorporating 3 parts by mass or more, preferably 5 parts by mass or more, for example 10 parts by mass or more, preferably 5 parts by mass or more and 100 parts by mass or less, more preferably 5 parts by mass or more and 40 parts by mass or less, for example 10 parts by mass or more and 30 parts by mass or less, of chlorpheniramine or a salt thereof per 1 part by mass of belladonna or an extract thereof in an aqueous solution containing belladonna or an extract thereof.

[0014] The concentration of belladonna or an extract thereof in the aqueous solution is not particularly limited, but is, for example, 0.0001 to 20 parts by mass, preferably 0.005 to 10 parts by mass, and more preferably 0.01 to 5 parts by mass per 100 parts by mass of the aqueous solution.

[0015] The method for blending chlorpheniramine or a salt thereof into an aqueous solution containing belladonna or an extract thereof is not particularly limited, but can be carried out using a method commonly used in the manufacture of pharmaceuticals, for example, using various stirrers commonly used in pharmaceutical preparations (propeller stirrer, paddle stirrer, rotary stirrer, etc.). Furthermore, the temperature conditions, stirring conditions, time conditions, timing of addition, scale, etc. during blending are not particularly limited, and conditions commonly used in the field of formulation technology can be used.

[0016] The method for producing a pharmaceutical composition containing belladonna or an extract thereof and chlorpheniramine or a salt thereof of the present invention includes a step of blending 3 parts by mass or more, preferably 5 parts by mass or more, for example 10 parts by mass or more, preferably 5 parts by mass or more and 100 parts by mass or less, more preferably 5 parts by mass or more and 40 parts by mass or less, for example 10 parts by mass or more and 30 parts by mass or less, of chlorpheniramine or a salt thereof per 1 part by mass of belladonna or an extract thereof in an aqueous solution containing belladonna or an extract thereof.

[0017] In the method for producing the pharmaceutical composition of the present invention, the concentration of belladonna or its extract in the aqueous solution, the method for blending chlorpheniramine or its salt, temperature conditions, stirring conditions, time conditions, timing of addition, scale, etc. can be the same as those described for the stabilization method of the present invention above.

[0018] The content of "belladonna or an extract thereof" contained in the pharmaceutical composition of the present invention is not particularly limited and may be determined by appropriate consideration. For example, when the total alkaloids of belladonna are used, the content is 0.0001 to 1 part by mass, preferably 0.0005 to 0.5 parts by mass, and more preferably 0.001 to 0.1 parts by mass, based on 100 parts by mass of the entire pharmaceutical composition.

[0019] The content of "chlorpheniramine or a salt thereof" contained in the pharmaceutical composition of the present invention is not particularly limited and may be determined by appropriate consideration, but is, for example, 0.001 to 10 parts by mass, preferably 0.01 to 5 parts by mass, and more preferably 0.05 to 2 parts by mass, based on 100 parts by mass of the entire pharmaceutical composition.

[0020] The pharmaceutical composition of the present invention can be provided in various dosage forms by combining with pharmaceutically acceptable carriers or additives. For example, the dosage form of the pharmaceutical composition is a solid preparation, a semi-solid preparation, or a liquid preparation, preferably a tablet, a capsule, a granule, a powder, a pill, an oral liquid, a syrup, an oral jelly, or a film, more preferably a tablet, a capsule, a granule, a powder, or a pill.

[0021] Carriers or additives used in solid preparations such as tablets include, for example, excipients, disintegrants, fluidizing agents, binders, lubricants, colorants, pH adjusters, surfactants, stabilizers, acidulants, flavors, etc. Two or more of these carriers or additives may be appropriately mixed and used, and the amount contained in the pharmaceutical composition is an amount conventionally used in the technical field of formulation. Examples of excipients include starches such as corn starch, potato starch, wheat starch, rice starch, partially pregelatinized starch, pregelatinized starch, and porous starch; sugars or sugar alcohols such as lactose hydrate, sucrose, fructose, glucose, mannitol, sorbitol, erythritol, xylitol, trehalose, maltitol, powdered reduced maltose syrup, and lactitol; anhydrous calcium hydrogen phosphate, crystalline cellulose, powdered cellulose, precipitated calcium carbonate, and calcium carbonate. Examples of disintegrants that can be used include carmellose, carmellose calcium, sodium carboxymethyl starch, carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, crospovidone, low-substituted hydroxypropyl cellulose (L-HPC), and hydroxypropyl starch, and preferred are croscarmellose sodium and L-HPC. Examples of binders that can be used include hydroxypropyl cellulose, hydroxypropyl methylcellulose (hypromellose), polyvinylpyrrolidone, copolyvidone, powdered gum arabic, methylcellulose, low-substituted hydroxypropyl cellulose, carmellose sodium, dextrin, partially pregelatinized starch, pullulan, gum arabic, agar, gelatin, tragacanth, and sodium alginate, with hydroxypropyl cellulose and hydroxypropyl methylcellulose being preferred. Examples of the fluidizing agent include light anhydrous silicic acid, hydrous silicon dioxide, calcium silicate, magnesium silicate, magnesium aluminometasilicate, and talc, with light anhydrous silicic acid and magnesium aluminometasilicate being preferred. Examples of lubricants include stearic acid, magnesium stearate, calcium stearate, talc, and sucrose fatty acid esters. Examples of coloring agents include yellow ferric oxide, ferric oxide, Food Blue No. 1, Food Blue No. 2, Food Yellow No. 4, Food Yellow No. 5, Food Green No. 3, Food Red No. 2, Food Red No. 3, Food Red No. 102, Food Red No. 104, Food Red No. 105, Food Red No. 106, food lake color, riboflavin, riboflavin sodium phosphate, and titanium oxide. Examples of pH adjusters include citric acid, phosphoric acid, carbonic acid, tartaric acid, fumaric acid, acetic acid, amino acids, and salts thereof. Surfactants include sodium lauryl sulfate, polysorbate 80, polyoxyethylene (160) polyoxypropylene (30) glycol, and the like. Examples of stabilizers include tocopherol, tetrasodium edetate, nicotinamide, and cyclodextrins. Examples of acidulants include ascorbic acid, citric acid, tartaric acid, and malic acid. Examples of flavoring agents include L-menthol, mint oil, lemon oil, and vanillin.

[0022] The pharmaceutical composition of the present invention may contain other active ingredients besides the above-mentioned active ingredients, such as antipyretics, analgesics, rhinitis medications, antihistamines, antitussives, expectorants, bronchodilators, gastric mucosa protective agents, caffeines, vitamins, hypnotics and sedatives, phlegm dissolving agents, anti-inflammatory agents, anticholinergic agents, herbal medicines, and Chinese herbal prescriptions, as long as the effects of the present invention are not inhibited.

[0023] Examples of antipyretic analgesics include aspirin (acetylsalicylic acid), aluminum aspirin, acetaminophen, ibuprofen, salicylamide, sodium salicylate, ethenzamide, sazapyrine, lactylphenetidine, ketoprofen, isopropylantipyrine, and loxoprofen sodium. Medication for rhinitis includes pseudoephedrine hydrochloride, isopropamide iodide, dipotassium glycyrrhizinate, etc. Examples of antihistamines include diphenhydramine hydrochloride, diphenhydramine salicylate, diphenhydramine tannate, alimemazine tartrate, isothipendyl hydrochloride, promethazine methylenedisalicylate, diphenylpyraline hydrochloride, diphenylpyraline teoclate, difeterol hydrochloride, difeterol phosphate, triprolidine hydrochloride hydrate, tripelennamine hydrochloride, thondylamine hydrochloride, fenethazine hydrochloride, methdilazine hydrochloride, carbinoxamine diphenyldisulfonate, mebhydroline napadisilate, carbinoxamine maleate, iproheptine hydrochloride, promethazine hydrochloride, alimemazine tartrate, fenethazine tannate, clemastine fumarate, and mequitazine. Examples of narcotic antitussives include codeine phosphate hydrate, dihydrocodeine phosphate, etc. Examples of non-narcotic antitussives include alloclamide, isoaminil, eprazinone, oxeladin, clofedanol, clobutinol, cloperastine, dibunate, dimemorfan, tipepidine, dextromethorphan, noscapine, hydrocotalnin, pentoxyverine, benproperine, and fominoben, as well as salts and hydrates thereof. Examples of salts and hydrates thereof include alloclamide hydrochloride, cloperastine hydrochloride, cloperastine fendizoate, dibunate sodium, dimemorfan phosphate, tipepidine hibenzate, tipepidine citrate, dextromethorphan hydrobromide, dextromethorphan phenolphthalin salt, pentoxyverine citrate, and hydrates thereof. Examples of expectorants include potassium guaiacolsulfonate, bromhexine hydrochloride, guaifenesin, tipepidine citrate, L-carbocysteine, ammonium chloride, l-menthol, ammonia-fennel extract, and potassium cresolsulfonate. Examples of bronchodilators include dl-methylephedrine hydrochloride, dl-methylephedrine saccharin salt, trimetoquinol hydrochloride, phenylpropanolamine hydrochloride, methoxyphenamine hydrochloride, l-methylephedrine hydrochloride, pseudoephedrine hydrochloride, aminophylline, diprophylline, theophylline, and proxyphylline. Examples of gastric mucosa protective agents include glycine, aminoacetic acid, magnesium silicate, synthetic aluminum silicate, synthetic hydrotalcite, magnesium oxide, dihydroxyaluminum aminoacetate, aluminum hydroxide gel, dried aluminum hydroxide gel, aluminum hydroxide-magnesium carbonate mixed dried gel, co-precipitation product of aluminum hydroxide-sodium bicarbonate, co-precipitation product of aluminum hydroxide-calcium carbonate-magnesium carbonate, co-precipitation product of magnesium hydroxide-aluminum potassium sulfate, and magnesium carbonate. Examples of caffeine compounds include sodium caffeine benzoate, caffeine hydrate, and anhydrous caffeine. Examples of vitamins include vitamin B1 or its derivatives or salts thereof, vitamin B2 or its derivatives or salts thereof, vitamin C or its derivatives or salts thereof, and vitamin P (hesperidin) or its derivatives or salts thereof. Examples of hypnotics and sedatives include allylisopropylacetylurea and bromvalerylurea. Examples of sputum dissolving agents include lysozyme chloride, L-ethylcysteine ​​hydrochloride, and methylcysteine ​​hydrochloride. Examples of anti-inflammatory agents include lysozyme chloride, serraptase, glycyrrhizinic acid and its salts, and tranexamic acid and its salts. Examples of anticholinergic agents include isopropamide iodide. Examples of medicinal herbs include ephedra, nandina, scutellaria, onji, licorice, platycodon, rhododendron, rhododendron, rhododendron, zedoary, senega, fritillary, fennel, Phellodendron bark, coptis, zedoary, chamomile, cinnamon bark, gentian, bezoar, animal gall (including yutan), shanghai, ginger, atractylodes, clove, tangerine peel, atractylodes rhizome, jiru, ginseng, and ginseng. Examples of herbal prescriptions include Kakkonto, Kakkonto-ka-kikyo, Keipito, Kososan, Saiko-keipito, Sho-saikoto, Sho-seiryuto, Bakumondo-to, Hange-koboku-to, and Mao-to.

[0024] The pharmaceutical composition of the present invention is produced using the aqueous solution of belladonna or its extract containing chlorpheniramine or a salt thereof, according to a method generally used in the production of pharmaceuticals. For example, when the pharmaceutical composition is a solid preparation, the manufacturing method of the present invention may include a step of granulating the solution obtained by blending chlorpheniramine or a salt thereof in an aqueous solution containing belladonna or an extract thereof, together with active ingredients other than belladonna and chlorpheniramine, and additives such as excipients and binders, as necessary, and may further include a step of drying the obtained granules and a step of sizing the granules, as necessary. The granulation method is not particularly limited and can be a method commonly used in pharmaceutical formulations, such as those described in publications such as Granulation Handbook (edited by the Japan Powder Industry and Engineering Association, Ohmsha), Formulation Design for Oral Dosage Forms (edited by Mitsuru Hashida, Professor, Graduate School of Pharmaceutical Sciences, Kyoto University, Yakugyo Jihosha), Powder Compression Molding Technology (edited by the Powder Engineering, Formulation and Particle Design Committee, Nikkan Kogyo Shimbun), and Pharmaceutical Machinery Technology Handbook (2nd Edition, edited by the Editorial Committee for the 20th Anniversary Publication of the Pharmaceutical Machinery Technology Research Association, Pharmaceutical Machinery Technology Research Association). Granulation methods include, for example, extrusion granulation, tumbling granulation, agitation granulation, fluidized bed granulation, and spray drying granulation.

[0025] The manufacturing method of the present invention may further include a step of blending the granules obtained in the above granulation step with active ingredients other than belladonna and chlorpheniramine, and additives such as excipients, lubricants, and disintegrants. When the pharmaceutical composition of the present invention is a tablet, the manufacturing method of the present invention may include a step of tableting the above-mentioned granulated product or blend using a method described in publications such as the above-mentioned Granulation Handbook, for example, using various tablet presses commonly used for pharmaceutical preparations (e.g., rotary tablet presses, etc.) to form tablets. Furthermore, when the pharmaceutical composition of the present invention is a capsule, the production method of the present invention may include a step of filling the above-mentioned granules or blend into a capsule to form the capsule.

[0026] When the pharmaceutical composition of the present invention is a solid preparation, the manufacturing method of the present invention may include a step of coating the solid preparation with a coating base that is usually added by a conventional method. For example, a tablet may be coated with a coating base to form a film-coated tablet. Examples of coating bases include water-soluble bases such as hydroxypropyl methylcellulose (hypromellose), hydroxypropyl cellulose, methylcellulose, povidone, copolyvidone, polyvinyl alcohol, polyvinyl alcohol copolymers, and macrogol; water-insoluble bases such as ethyl cellulose; enteric bases such as hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, carboxymethylethylcellulose, cellulose acetate phthalate, methacrylic acid copolymers, acrylic acid copolymers, and carboxyvinyl polymers; gastrosoluble bases such as polyvinyl acetal diethylaminoacetate, aminoalkyl methacrylate copolymers, and polyvinyl acetate diethylaminoacetate; gum arabic, pullulan, carnauba wax, shellac, macrogols, glycerin fatty acid esters, and magnesium stearate. In the present invention, the coating base may be one type or two or more types. Furthermore, coating additives may be used in the coating, such as light-blocking agents, fluidizing agents, colorants, and plasticizers. Examples of plasticizers include copolyvidone, polyethylene glycol, triethyl citrate, castor oil, and polysorbate.

[0027] Carriers used in liquid preparations such as oral liquids include aqueous media (purified water, ethanol-containing purified water, etc.), alcohols (ethanol, glycerin, etc.), water-soluble polymers, etc., and are preferably purified water or ethanol-containing purified water. Carriers used in semi-solid preparations include oily bases (lipids such as vegetable oils, petrolatum, liquid paraffin, etc.), hydrophilic bases (emulsion bases), etc. Furthermore, examples of additives used in liquid formulations and semi-solid formulations include surfactants, solubilizers, bases, solubilizing agents, emulsifiers, suspending agents, stabilizers, reducing agents, antioxidants, preservatives, coloring agents, flavors, refreshing agents, fragrances, sweeteners, sweeteners, buffers, pH adjusters, etc. Two or more of these carriers or additives may be used in combination as appropriate, and the amount contained in the pharmaceutical composition is an amount conventionally used in the technical field of formulation.

[0028] When the pharmaceutical composition of the present invention is a liquid preparation, the manufacturing method of the present invention may include, for example, the steps of dissolving or dispersing active ingredients other than belladonna and chlorpheniramine and various additives in a carrier, filtering or sterilizing, and filling into a predetermined container. Also, when the pharmaceutical composition of the present invention is a semi-solid preparation, the manufacturing method of the present invention may include, for example, the steps of mixing active ingredients other than belladonna and chlorpheniramine and various additives with a carrier, sterilizing, filling into a predetermined container, and applying to a base. [Example]

[0029] The present invention will be described in more detail below with reference to examples, but the present invention is not limited to these examples.

[0030] (Examples 1 to 3 and Comparative Examples 1 to 2) The main components shown in Table 1 were weighed out in predetermined amounts and prepared using a 5% by volume aqueous solution of ethanol (200 or 400 mL) to obtain the desired aqueous solution. [Table 1]

[0031] (Test example) The resulting aqueous solution was stored at room temperature for a maximum of 18 hours. The stability of the total alkaloids in the solution was evaluated based on the residual percentage (%), comparing it with that immediately after storage. The residual percentage of the total alkaloids in the solution was calculated by quantifying the amounts of hyoscyamine and scopolamine by HPLC. The results of the comparative evaluation are shown in Table 2. [Table 2]

[0032] As shown in Table 2, the aqueous solution of total alkaloids of belladonna was unstable (Comparative Examples 1 and 2), but the solution stability of total alkaloids of belladonna was improved by adding d-chlorpheniramine maleate to the aqueous solution containing total alkaloids of belladonna (Examples 1, 2, and 3). d-Chlorpheniramine maleate was also stable in solution.

[0033] (Production Examples 1 to 6) The ingredients were mixed according to the formulation and blending ratio shown in Section A of Table 3 below, and compressed to obtain uncoated tablets. The obtained uncoated tablets were coated according to Section B to obtain coated tablets. [Table 3] [Industrial Applicability]

[0034] By using the stabilization method of the present invention, the stability of belladonna or an extract thereof in an aqueous solution can be significantly improved, and a pharmaceutical product containing belladonna or an extract thereof and chlorpheniramine or a salt thereof can be provided.

Claims

1. A method for stabilizing total alkaloids of belladonna, characterized by compounding 3 parts by mass or more of chlorpheniramine or a salt thereof per 1 part by mass of total alkaloids of belladonna in an aqueous solution containing the total alkaloids of belladonna.

2. 2. The method for stabilization according to claim 1, wherein the chlorpheniramine or a salt thereof is chlorpheniramine maleate or d-chlorpheniramine maleate.

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