Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
  • A61K9/4891—Coated capsules; Multilayered drug free capsule shells

Definitions

• the present invention relates to a soft capsule film and a soft capsule using the same.
• Soft capsule bathing agent (Patent Document 1) with improved solubility when poured into bath water, an adhesive surface with a slanted adhesive surface or a flange that forms the adhesive surface, reducing the gelatin film thickness
• Patent Document 2 having a larger width dimension has been reported.
• Patent Document 3 having a carrageenan, an acidic pH adjuster, and a neutralizing agent in the composition of the capsule film has been reported.
• JP-A-5-51315 JP 2001-288075 A International Publication No. 2010/146845 Japanese Patent Laid-Open No. 4-27352 Japanese Patent Laid-Open No. 7-145082 JP-A-8-99870 Special Table 2007-523904
• Patent Documents 1 and 2 are limited in the types and production methods of soft capsules, and may not provide sufficient solubility and storage stability.
• the method of patent document 3 is easy to preserve
• the present invention has been made in view of the above-described conventional problems and actual conditions, and has soft moldability and drought resistance, but quickly disintegrates and dissolves in the oral cavity or in the presence of water. It is intended to provide a film and a soft capsule using the same.
• Patent Documents 4 to 7 A number of techniques for adding carrageenan and gellan gum to a gelatin film have been reported (Patent Documents 4 to 7).
• Patent Documents 4 to 6 are techniques for achieving sustained drug release and enteric capsules. It is unexpected that the combination of gelatin and carrageenan or gellan gum produces the above effects. Further, Patent Document 7 does not take into consideration the film thickness reduction, particularly the heat resistance during drying.
• the present invention includes the following components (A) and (B): (A) Gelatin 50 to 70% by mass in the total amount of solids, (B) Carrageenan 1 to 10% by mass in the total amount of solids, The soft capsule film
• the present invention also includes the following components (A), (C) and (D): (A) Gelatin 50 to 70% by mass in the total amount of solids, (C) Gellan gum 1.5-10% by mass in the total amount of solids, (D) a water-soluble calcium salt, The soft capsule film
• the present invention it is possible to reduce the thickness of the film while maintaining the strength at the time of capsule molding and the heat resistance at the time of drying, and it is possible to provide a soft capsule having quick disintegration and solubility. Further, the soft capsule of the present invention can maintain good solubility even after storage.
• the gelatin (A) in the present invention is produced by, for example, heating and extracting crude collagen obtained by treating with skin, bone, tendon, etc. of cattle, pigs, chickens, fish, etc., and treating with acid or alkali. Is used. Further, modified gelatin such as gelatin hydrolyzate, oxygen decomposed product, succinylated gelatin, and phthalated gelatin can also be used. Any kind of gelatin can be preferably used.
• the gelatin jelly strength is preferably 200 to 300 g. The jelly strength can be measured according to JIS K-6503 (2001).
• the gelatin content is 50 to 70% by mass in terms of dry mass in the total amount of solids, taking into account the mechanical strength of the capsule, the uniformity of the coating film during molding, and the disintegration and solubility after molding. It is.
• the total amount of solid content is the total amount of components excluding water from the film composition.
• Carrageenan used in the present invention is a kind of galactan having a sulfate group, and is known to exist in red algae.
• Carrageenans can be classified mainly into three types, iota carrageenan, kappa carrageenan, and lambda carrageenan, depending on the gelation characteristics and structure.
• the Japanese food additive regulations stipulate three types: “refined carrageenan”, “processed Yukema algae” and “Yukema algae powder” (published by “Japan Food Additives Association” These are only different in the degree of purification, and are essentially all included in the carrageenan of the present invention.
• iota carrageenan and kappa carrageenan are preferably used from the viewpoint of gelation ability, and kappa carrageenan is particularly preferably used.
• Each carrageenan may be a pure product or may contain a standardized substance.
• a standardization substance 1 type, or 2 or more types selected from the group which consists of saccharides, such as sucrose, glucose, maltose, and lactose, and dextrin is mentioned.
• the carrageenan content described later does not include the standardizing substance.
• a carrageenan adjusted to a desired viscosity by decomposition with an acidic pH adjusting agent described in International Publication No. 2010/146845 (Patent Document 3) and further stopping by a neutralizing agent can also be used.
• an acidic pH adjusting agent such as citric acid
• a neutralizing agent such as dipotassium hydrogen phosphate
• the viscosity C-type viscometer, liquid temperature 75 ° C., rotor no. 1, 100 mPa ⁇ s in case of 100 mPa ⁇ s or less
• a carrageenan prepared by adjusting rotor No. 1) to 30 to 150 mPa ⁇ s, preferably 50 to 100 mPa ⁇ s can be mentioned.
• the content of (B) carrageenan is 1 to 10% by mass, more preferably 3 to 9.8% by mass, particularly 3 to 6% by mass, based on the gelation strength. .
• the mass ratio [(A) :( B)] in the total solid content of (A) gelatin (dry mass) and (B) carrageenan is 100 from the viewpoint of film strength and moldability. : 2 to 100: 20 is preferable, 100: 4 to 100: 17 is more preferable, and 100: 5 to 100: 15 is still more preferable.
• Gellan gum used in the present invention is a sugar composed of glucose, glucuronic acid, and rhamnose, and is known to be produced from Pseudomonas elodea .
• Gellan gum may be either a native type or a deacylated type from which the acetyl group and glyceryl group of glucose are removed, but it is preferable to use a deacylated type from the viewpoint of film strength and moldability.
• the content of (C) gellan gum is 1.5 to 10% by mass in the total amount of solids from the viewpoint of gelling strength, but is further 3 to 6% by mass, particularly 3 to 5% by mass. preferable.
• gelatin (dry weight) and (C) the content mass ratio [(A) :( C)] in the total solid content of gellan gum are in terms of film strength and moldability.
• 100: 2 to 100: 11 are preferred, 100: 2.2 to 100: 11 are more preferred, 100: 3 to 100: 10 are more preferred, and 100: 5 to 100: 8 are even more preferred.
• water-soluble calcium salt (D) used in the present invention examples include calcium ascorbate, calcium acetate, calcium lactate, calcium gluconate, calcium succinate, calcium citrate, and calcium chloride. These can be used alone or in combination of two or more.
• the content of the (D) water-soluble calcium salt is preferably 1% by mass or more, more preferably 1.3% by mass or more, as calcium with respect to (C) gellan gum, from the viewpoint of gelling strength. 5 mass% or more is still more preferable. Even if calcium is excessive, there is no particular effect.
• various additives used in the soft capsule film for example, water-soluble polymers other than plasticizer, gelatin, carrageenan, gellan gum, starches, natural dyes, synthetic dyes, Various sweeteners, preservatives, water activity lowering agents, pH adjusting agents and the like can be blended.
• the plasticizer is not particularly limited, and examples thereof include glycerin, sorbitol, erythritol, propylene glycol, and polyethylene glycol. Of these, glycerin and sorbitol are preferable.
• the content of the plasticizer in the soft capsule film of the present invention is preferably 15 to 40% by mass in the total solid content from the viewpoint of flexibility.
• water-soluble polymer examples include sodium alginate, pullulan, glucomannan, gum arabic, and farcellan.
• starches include unmodified starch, modified starch, and starch degradation products. It is done.
• the contents of water-soluble polymers other than gelatin, carrageenan and gellan gum, and starches are each 1% by mass or less in the total amount of solids. It is preferable.
• the soft capsule film of the present invention can be produced according to a conventional method.
• (A) gelatin and (B) carrageenan, or (A) gelatin and (C) gellan gum and (D) water-soluble calcium salt, and if necessary, various additives are stirred and dispersed in water, After stirring and dissolving at 98 ° C., vacuum degassing may be performed.
• (B) carrageenan 75 ° C or higher is preferable
• (C) gellan gum is used, 95 ° C or higher is preferable.
• the stirring may be performed by a stirrer, but it is not always necessary to perform the stirring continuously, and the worker may stir with a stirring rod at regular intervals.
• the pH may be adjusted as appropriate, and the pH of the coating solution (100-fold diluted solution, 70 ° C.) is preferably 6.0 or more when (B) carrageenan is used.
• the pH of the coating solution is preferably 6.0 or more when (B) carrageenan is used.
• C In the case of gellan gum, it is not particularly limited.
• (B) carrageenan when used, particularly when kappa carrageenan is used, it is possible to improve the gel strength and increase the film strength at the time of capsule molding.
• potassium ions are more preferably contained.
• the potassium ion source include alkaline potassium salts such as potassium carbonate, potassium hydroxide, tripotassium phosphate, dipotassium hydrogen phosphate, potassium lactate and potassium acetate.
• a soft capsule can be obtained by forming such a soft capsule film into a predetermined shape and drying it.
• the soft capsule can be produced by, for example, a conventionally used method for producing a soft capsule, for example, a punching method using a rotary die type soft capsule filling machine, a flat plate method, a dropping method, or the like. Especially, it is preferable to manufacture by the dripping method from the point of formulation property.
• a seamless capsule can be produced by ejecting a liquid flow into a coagulation liquid from a multiple nozzle such as a double nozzle or a triple nozzle and including the capsule contents with a soft capsule film. .
• the film ratio (%) of the soft capsule of the present invention is preferably 9% or less, more preferably 7% or less, from the viewpoint of disintegration and solubility.
• a film rate is a ratio of the mass of the film with respect to the whole capsule.
• the relationship between the coating rate of soft capsules and the particle size is that when the particle size increases at the same coating rate, the capsule itself becomes heavy, and since the coating is soft in the undried state, deformation is likely to occur in the drying process. It may burst. Therefore, from the viewpoint of moldability, disintegration and solubility, when the soft capsule has a particle size of more than 5 mm, for example, when the particle size is 5.5 mm or more, the coating rate is preferably 9% or less. . When the soft capsule has a particle size of 5 mm or less, the coating rate is preferably 9% or less, and more preferably 7% or less.
• solubility of the soft capsule of the present invention is usually within 50 seconds, preferably within 30 seconds, when the capsule is put into, for example, still water at 35 to 39 ° C.
• the soft capsule of the present invention can be used for various uses such as pharmaceuticals, quasi-drugs, and foods, and the composition of the capsule contents is appropriately determined according to the use.
• the content may be in the form of a solution, a suspension, a paste, a powder, a granule or the like.
• a capsule is illustrated. Each of these components can be contained in any part of the capsule.
• waxes and waxes shellac wax, beeswax, carnauba wax, whale wax, lanolin, liquid lanolin, reduced lanolin, hard lanolin, cyclic lanolin, lanolin wax, candelilla wax, molasses, montan wax, shellac wax, rice wax, etc.
• the hardened oil it is possible to contain a hardened vegetable oil obtained by hydrogenating vegetable fats, hardened beef fat, hardened tallow oil, and the like.
• mineral oil liquid paraffin, petrolatum, paraffin, ozokelide, ceresin, microcrystalline wax and the like can be contained.
• fatty acids lauric acid, myristic acid, palmitic acid, stearic acid, behenic acid, oleic acid, linoleic acid, conjugated linoleic acid, linolenic acid, docosahexaenoic acid, eicosapentaenoic acid, 12-hydroxystearic acid, undecylenic acid, tall oil , Natural fatty acids such as lanolin fatty acid, isononanoic acid, caproic acid, 2-ethylbutanoic acid, isopentanoic acid, 2-methylpentanoic acid, 2-ethylhexanoic acid, isopentanoic acid and the like, and fats and oils containing these fatty acids as fatty acid composition Etc. can be contained.
• vitamin A group retinol, retinal (vitamin A1), dehydroretinal (vitamin A2), carotene, lycopene (provitamin A), vitamin B group: fursultiamine, thiamine hydrochloride, thiamine sulfate (vitamin B1 ), Riboflavin (vitamin B2), pyridoxine (vitamin B6), cyanocobalamin, methylcobalamin (vitamin B12), folic acid, nicotinic acids, pantothenic acids, biotins, choline, inositols, vitamin C group: ascorbic acid or its derivatives, Vitamin D group: Ergocalciferol (vitamin D2), cholecalciferol (vitamin D3), dihydrotaxosterol, vitamin E group: vitamin E or its derivatives, ubiquinones, vitamin K group: phytonadione (bi Min K1), menaquinone (vitamin K2), menate
• pepper tincture red pepper oil, nonyl acid vanillamide, cantalis tincture, ginger tincture, ginger oil, mint oil, l-menthol, camphor, benzyl nicotinate, and the like can be contained.
• benzophenone derivatives (2-hydroxy-4-methoxybenzophenone, 2-hydroxy-4-methoxybenzophenone-5-sulfonic acid, 2-hydroxy-4-methoxybenzophenone-5-sulfonic acid sodium, dihydroxydimethoxy Benzophenone, dihydroxydimethoxybenzophenone-sodium sulfonate, 2,4-dihydroxybenzophenone, tetrahydroxybenzophenone, etc.
• paraaminobenzoic acid derivatives paraaminobenzoic acid, ethyl paraaminobenzoate, glyceryl paraaminobenzoate, amyl paradimethylaminobenzoate, para Octyl dimethylaminobenzoate
• methoxycinnamate derivatives ethyl paramethoxycinnamate, isopropyl paramethoxycinnamate, paramethoxycinnamon
• whitening agents paraaminobenzoic acid derivatives, salicylic acid derivatives, anthranilic acid derivatives, coumarin derivatives, amino acid compounds, benzotriazole derivatives, tetrazole derivatives, imidazoline derivatives, pyrimidine derivatives, dioxane derivatives, camphor derivatives, furan derivatives, pyrone derivatives, nucleic acids Derivatives, allantoin derivatives, nicotinic acid derivatives, vitamin C or derivatives thereof (vitamin C phosphate magnesium salt, vitamin C glucoside, etc.), vitamin E or derivatives thereof, kojic acid or derivatives thereof, oxybenzone, benzophenone, arbutin, guaiazulene, shikonin , Baicalin, baicalein, berberine, placenta extract, ellagic acid, lucinol and the like.
• vitamin C or a derivative thereof vitamin C phosphate magnesium salt, vitamin C glucoside, etc.
• hydroquinone or a derivative thereof hydroquinone benzyl ether, etc.
• kojic acid or a derivative thereof vitamin E or a derivative thereof, N -Acetyltyrosine or its derivatives, glutathione, hydrogen peroxide, zinc peroxide, placenta extract, ellagic acid, arbutin, lucinol, silk extract, plant extract (camomile, mulberry, gardenia, touki, garlic, clara, mugwort, honeysuckle, Kihada, Dokudami, Matsuhodo, pearl barley, nettle, hop, hawthorn, eucalyptus, yarrow,retea, keihi, mankei, hamamelis, carraguwa or yamagwa, life-prolonging grass, bell
• phenylmercury hexachlorophene As a melanin reduction or decomposition substance, phenylmercury hexachlorophene, mercuric oxide, mercuric chloride, hydrogen peroxide solution, zinc peroxide, hydroquinone or a derivative thereof can be contained.
• hydroquinone As a turnover promoting action and cell activator, hydroquinone, lactic acid bacteria extract, placenta extract, ganoderma extract, vitamin A, vitamin E, allantoin, spleen extract, thymus extract, yeast extract, fermented milk extract, plant extract (aloe, ougone) , Horsetail, gentian, burdock, shikon, carrot, hamamelis, hops, yokoinin, mandarin duck, sea bream, pearl millet, red snapper, achacha, hypericum, cucumber, red pepper, mannen wax, parsley) and the like.
• succinic acid As astringents, succinic acid, allantoin, zinc chloride, zinc sulfate, zinc oxide, calamine, zinc paraphenol sulfonate, potassium aluminum sulfate, resorcin, ferric chloride, tannic acid (including catechin compounds), etc. can be included is there.
• SOD active oxygen scavenger
• catalase catalase
• glutathione peroxidase glutathione peroxidase
• Anti-inflammatory agents include ictamol, indomethacin, kaolin, salicylic acid, sodium salicylate, methyl salicylate, acetylsalicylic acid, diphenhydramine hydrochloride, d-camphor, dl-camphor, hydrocortisone, guaiazulene, camazulene, chlorpheniramine maleate, glycyrrhizic acid or its salts , Glycyrrhetinic acid or a salt thereof, licorice extract, sicon extract, age extract, propolis and the like.
• Antibacterial / bactericidal / disinfectant agents include acrinol, sulfur, calcium gluconate, chlorhexidine gluconate, sulfamine, mercurochrome, lactoferrin or its hydrolyzate, alkyldiaminoethylglycine chloride solution, triclosan, sodium hypochlorite, chloramine T, salashi Powder, iodine compound, iodoform, sorbic acid or its salt, propionic acid or its salt, salicylic acid, dehydroacetic acid, parahydroxybenzoic acid esters, undecylenic acid, thiamine lauryl sulfate, thiamine lauryl nitrate, phenol, cresol, p- Chlorophenol, p-chloro-m-xylenol, p-chloro-m-cresol, thymol, phenethyl alcohol, O-phenylphenol, Irgasan CH3565,
• glycerin As humectants, glycerin, propylene glycol, 1,3-butylene glycol, polyethylene glycol, glycerin tricaprycapric acid, glycolic acid ( ⁇ -hydroxy acid), hyaluronic acid or its salt, chondroitin sulfate or its salt, water-soluble chitin or its Derivatives or chitosan derivatives, pyrrolidone carboxylic acid or salts thereof, sodium lactate, urea, sorbitol, amino acids or derivatives thereof (valine, leucine, isoleucine, threonine, methionine, phenylalanine, tryptophan, lysine, glycine, alanine, asparagine, glutamine, serine, Cysteine, cystine, tyrosine, proline, hydroxyproline, aspartic acid, glutamic acid, hydroxylysine, arginine, ornithine, hist
• glycolic acid citric acid, malic acid, tartaric acid, lactic acid, ferulic acid, phytic acid and the like can be contained.
• selenium disulfide for hair, selenium disulfide, alkylisoquinolinium bromide, zinc pyrithione, biphenamine, thianthol, castari tincture, pepper tincture, pepper tincture, quinine hydrochloride, strong ammonia water, potassium bromate, sodium bromate, thioglycol It can contain an acid or the like.
• natural animal fragrances such as musk, civet, castorium, ambergris, anise essential oil, angelica essential oil, ylang ylang essential oil, iris essential oil, fennel essential oil, orange essential oil, cananga essential oil, caraway essential oil, cardamom essential oil, guayakwood essential oil, cumin Essential oil, black letter essential oil, cinnamon essential oil, cinnamon essential oil, geranium essential oil, copaiba balsam essential oil, coriandel essential oil, perilla essential oil, cedarwood essential oil, citronella essential oil, jasmine essential oil, gingergrass essential oil, cedar essential oil, spearmint essential oil, western peppermint essential oil, large Perfume essential oil, tuberose essential oil, clove essential oil, orange flower essential oil, winter green essential oil, trout balsam essential oil, buttery essential oil, rose essential oil, palmarosa essential oil, persimmon essential oil, hiba essential oil, sandalwood essential oil, petit gren essential oil, bay essential oil
• soft capsules are packaged and stored in packaging forms such as bottling packaging, PTP packaging, and pouches.
• Gelatin 1 Acid-treated gelatin derived from pig skin (jelly strength 270 g)
• Gelatin 2 Cattle bone-derived alkali-treated gelatin (jelly strength 240 g)
• Kappa Carrageenan CT-1000 (Mitsubishi Corporation Foodtech)
• Gellan Gum Kelco Gel (CP Kelco)
• Calcium lactate Food additive, calcium lactate hexahydrate (manufactured by Taihei Chemical Industrial Co., Ltd.), with a molecular weight of 308.29, so the calcium content is about 13%.
• Glycerin Food additive grade (manufactured by Sakamoto Pharmaceutical Co., Ltd.) Erythritol: (Mitsubishi Chemical Foods) Propylene glycol: (made by ADEKA) Sorbitol: D-sorbitol solution (manufactured by Mitsubishi Corporation Foodtech) Potassium carbonate: anhydrous potassium carbonate (manufactured by Kanto Chemical)
• Examples 1 to 9 and Comparative Examples 1 to 8 Production of soft capsules by the dropping method [Preparation method]
• a gelatin aqueous solution was prepared by mixing solids, gelatin, kappa carrageenan, gellan gum, calcium lactate, glycerin and erythritol in the amounts (parts by mass) shown in Table 1 and Table 2 and purified water.
• MCT oil medium-chain fatty acid triglyceride, manufactured by Kao Corporation
• each gelatin aqueous solution liquid temperature: 70 to 90 ° C from 7 to 20 ° C from the outer nozzle.
• the soft capsule of the present invention was excellent in the film strength at the time of capsule molding and the heat resistance at the time of drying although the film rate was low. Moreover, the solubility was good and the storage stability was also excellent. On the other hand, Comparative Example 1 with less gelatin was difficult to spheroidize and could not be encapsulated. Conversely, Comparative Example 4 with much gelatin was crushed by heat and its own weight during drying, and could not be encapsulated. In Comparative Examples 2 and 3, which have a large amount of kappa carrageenan, the gelation is too early, so that the moldability is poor, the capsule having a large thickness deviation (uneven thickness) is conspicuous, the yield is low, and the storage stability is also a problem. there were.
• Comparative Examples 5 and 7 with a small amount of gellan gum were inferior in solubility due to the high coating rate, and deformation was observed after storage.
• Comparative Example 4 Comparative Examples 6 and 8 were crushed by heat and dead weight during drying and could not be encapsulated.
• Examples 10 to 17 Production of soft capsules by the dropping method [Preparation method] An aqueous gelatin solution was prepared by mixing solids, gelatin, kappa carrageenan, potassium carbonate, glycerin and erythritol in the amounts (parts by mass) shown in Table 3 and purified water. Subsequently, seamless capsules having a diameter of about 5 to 7 mm were produced in the same manner as in Example 1. Table 3 shows the coating rate of the seamless capsule. Each capsule was subjected to an evaluation test in the same manner as in Example 1, and the results are shown in Table 3.
• the soft capsule of the present invention was excellent in film strength at the time of capsule molding, heat resistance at the time of drying, good solubility, and excellent storage stability.
• Examples 14 to 17 in which potassium carbonate was further added to the coating solution the coating strength at the time of capsule molding and the heat resistance at the time of drying were excellent.
• Comparative Examples 9 to 13 capsule molding in MCT oil was possible, but it was crushed by heat during drying and deformed significantly.
• the comparative example 11 has burst.
• Comparative Examples 14, 16 and 18 having a capsule particle diameter of 5 mm were lighter in weight than Comparative Examples 9 to 13 having a capsule particle diameter of 7 mm, and thus the degree of deformation was small. Deformation was recognized to the extent that it was damaged. In Comparative Examples 15 and 17, deformation was observed during drying, the solubility was poor, and deformation was observed after storage.

Landscapes

• Health & Medical Sciences (AREA)
• Epidemiology (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Chemical & Material Sciences (AREA)
• Medicinal Chemistry (AREA)
• Pharmacology & Pharmacy (AREA)
• Engineering & Computer Science (AREA)
• Life Sciences & Earth Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• General Health & Medical Sciences (AREA)
• Public Health (AREA)
• Veterinary Medicine (AREA)
• Medicinal Preparation (AREA)
• Cosmetics (AREA)

Applications Claiming Priority (2)

Publications (1)

Family

ID=48697492

Family Applications (1)

Country Status (3)

Cited By (7)

Families Citing this family (2)

Citations (8)

• 2012
  • 2012-12-27 WO PCT/JP2012/083793 patent/WO2013100013A1/fr not_active Ceased
  • 2012-12-27 JP JP2013551769A patent/JPWO2013100013A1/ja active Pending
  • 2012-12-27 TW TW101150678A patent/TW201332589A/zh unknown

Patent Citations (8)

Also Published As

Similar Documents

Legal Events