Titanium oxide-free light-blocking film containing sodium sulfate

Abstract

The present invention relates to a film and a capsule which do not contain titanium oxide and which have light-blocking properties and improved mechanical strength. The film and capsule are produced using a composition comprising a film-forming polymer and a whitening agent. The film-forming polymer is selected from the group consisting of cellulose derivatives, gelatin, and pullulan. The whitening agent comprises a salt and a surfactant, wherein the salt is sodium sulfate or a combination of sodium sulfate and a white pigment, wherein the white pigment is not titanium dioxide. The light-blocking film and capsule having improved mechanical strength are obtained by molding the composition into a film and a capsule, respectively, and then drying the film and capsule at 55°C or lower.

Description

Light-shielding coating containing sodium sulfate but not titanium oxide

[0001] The present invention relates to a film-forming composition for use in pharmaceutical preparations, etc., which whitens during film formation by the combination of a surfactant and a salt and provides a film with high mechanical strength. The present invention also relates to applications of this film-forming composition to preparations such as capsules, orally dispersible films, tablets coated with the film-forming composition, granules, film products, printing inks, etc.

[0002] Furthermore, the present invention relates to a light-blocking capsule manufactured from a film-forming composition with a high degree of whitening, which can block light and ultraviolet rays, maintain the stability and quality of the active ingredient for a long period of time, and also has high mechanical strength.

[0003] Coloring has been conventionally applied to pharmaceutical preparations, health foods, and the like, to enhance their distinctiveness, to impart a beautiful appearance, to impart light-shielding properties to maintain quality, etc. In particular, for preparations containing light-unstable components, a light-shielding agent is usually added to the capsule shell or coating film to form a white light-shielding film, and further, if necessary, edible dyes (such as Blue No. 1, Yellow No. 5, Red No. 3, etc.) or pigments such as ferric oxide or aluminum lake are added to impart a desired color to the light-shielding film.

[0004] There are various whitening agents that provide light blocking properties, but the most commonly used is titanium oxide (TiO ２ Titanium dioxide is a white pigment that has excellent whiteness, hiding power (opacity), coloring power, and extremely high chemical stability, and has long been used in the pharmaceutical and cosmetic industries.

[0005] However, in 2020, the European Union (EU) designated titanium dioxide as a "carcinogen category 2," which led to a ban on its use in the European food market from 2022. (https: / / www.jetro.go.jp / biznews / 2022 / 08 / 817e100825b5eb14.html) Furthermore, the EU is expected to ban the use of titanium dioxide in pharmaceuticals by around 2025. As a result, capsules containing titanium dioxide have begun to be avoided, particularly in the health food industry, and the development of sunscreens to replace titanium dioxide has become even more desirable.

[0006] Therefore, light-shielding coating compositions that do not use titanium oxide and contain one or more water-soluble calcium salts and a coating base of a water-soluble cellulose polymer have been investigated (Patent Document 1). However, the use of water-soluble calcium salts is restricted to 1.0% or less of the food in terms of calcium in the "Standards and Criteria for Food Additives, etc., Part 2, Additives" usage standards, which means that the white coloring density is limited.

[0007] Also known as light-shielding coatings that do not use titanium oxide are water-soluble metal compounds containing monovalent to trivalent metals (at least one metal selected from the group consisting of sodium, potassium, calcium, magnesium, aluminum, manganese, iron, cobalt, nickel, copper, strontium, and barium), and non-transparent coatings containing water-soluble cellulose derivatives (Patent Document 2). However, to obtain opaque films or sheets using this method, the composition must be molded and then heated at a high temperature of 60°C or higher to dry and solidify.

[0008] Furthermore, a light-blocking coating that does not use titanium oxide is also known, which contains a film-forming polymer component (a water-soluble cellulose derivative) and a whitening agent consisting of a surfactant or a surfactant and a water-soluble salt, wherein the surfactant is selected from polyhydric alcohol fatty acid esters, polyethylene glycol, polypropylene glycol, polyalkylene oxide derivatives, alkyl sulfate ester salts, and saponin (Patent Document 3). However, it has been shown that drying the coating at a high temperature of 60°C in an oven results in a greater degree of whitening than natural drying at room temperature (see Tables 2 and 4 of Patent Document 3).

[0009] Patent Document 4 discloses the use of sodium salts in the manufacture of edible, light-blocking embedded wall materials based on hydroxypropyl methylcellulose. Specifically, the raw materials used were 5-20% HPMC, 0.1-2% sodium salts (sodium dihydrogen phosphate, disodium hydrogen phosphate, sodium citrate, sodium lactate), 0.1-2% plasticizer, 0-1.5% gelling agent, and the remainder was water. It was also shown that the tensile properties of the film were good when the sodium dihydrogen phosphate content was 5% or less. However, since Patent Document 4 specifically describes only the above four sodium salts, it is impossible to predict whether other sodium salts will also whiten the film under low-temperature drying conditions. In fact, Patent Document 2 (Table 2) shows that sodium chloride does not become opaque unless the drying temperature is 60°C or higher. Furthermore, Patent Document 3 (Formulation 2-7 in Table 2 and Formulations 4-3, 4-4, and 4-10 in Table 4) also shows that sodium malate causes only a low degree of whitening when naturally dried at room temperature. As such, the degree of whitening of the film under low-temperature drying conditions varies depending on the salt, and cannot be uniformly predicted.

[0010] Patent Document 5 discloses a method for producing capsules by preparing a solution containing a plant cellulose derivative (preferably hydroxypropylmethylcellulose), titanium dioxide, sodium sulfate, a medicinal adhesive, and a medicinal lubricant, supplying the solution to a capsule production line, and drying the solution at 50-70°C and a relative humidity of 40-60%. This manufacturing method is specifically designed for inhalable hollow capsules, as it aims to prevent capsule powder from entering the capsule cavity when the capsule is punctured with a medicinal spray device, reduce adhesion of medicinal powder to the capsule cavity, and achieve a medicinal utilization rate of 90% or more. Although sodium sulfate is used in these capsules, titanium oxide, which is well known as a whitening agent, is used instead. Therefore, the disclosure in this document does not suggest that sodium sulfate acts as a whitening agent, or that it whitens the capsule coating, especially under low-temperature drying conditions.

[0011] WO2004 / 054619A1 WO2008 / 156027A1 JP 2020-19761 A Chinese Patent Publication No. 108576785 Chinese Patent Publication No. 112107562

[0012] In the aforementioned Patent Document 3, when whitening a water-soluble cellulose derivative with a whitening agent, gelation by drying at room temperature was found to produce insufficient whitening compared to thermal gelation at 60°C (i.e., drying at 60°C or higher). Therefore, thermal gelation was adopted for the production of coatings. However, the inventors discovered that the white coating produced by the thermal gelation method lacked sufficient mechanical strength. After drying, the cross section of the coating formed two layers. The upper part of the cross section of the coating obtained by thermal gelation was colorless and transparent, while the lower part was filled with salt, forming a white layer with a weak sponge structure. As a result, the overall strength of the coating was weak, and it was found to be particularly unsuitable for the production of capsules.

[0013] The present invention solves this problem of reduced film strength by modifying the method for producing films using cellulose derivatives as film-forming polymers. Specifically, the inventors discovered that producing a film by gelling a cellulose derivative solution and drying it at 55°C or below, particularly at room temperature, results in a cellulose derivative film with significantly improved mechanical strength. This method can also be applied to film-forming polymers such as gelatin and pullulan.

[0014] On the other hand, Patent Document 3 reports that when a film is formed by thermal gelation of a cellulose derivative composition containing a whitening agent, i.e., by drying at room temperature rather than drying at an elevated temperature such as 60°C, sufficient whitening cannot be obtained. However, the present inventors have found that when a salt containing sodium sulfate and a surfactant are used in combination as a whitening agent, a sufficiently whitened film can be obtained even by gelation by drying at room temperature. The present invention is characterized by using a salt containing sodium sulfate and a surfactant as whitening agents, thereby obtaining a film with an excellent degree of whitening and improved mechanical strength.

[0015] Sodium sulfate has traditionally been used as a food additive and pharmaceutical. Many types of surfactants are also registered as food additives and pharmaceutical additives. Therefore, the whitening agent used in the present invention can be safely used in the food and pharmaceutical fields. The whitening technology of the present invention not only allows the degree of whitening and the degree of light blocking to be adjusted depending on the amount of surfactant or salt, including sodium sulfate, added, but also allows for flexible coloring by combining with other coloring materials. The present invention can provide beautiful white and / or light-blocking colored coatings with improved mechanical strength, and corresponding capsules, without using titanium oxide. For the health food market in particular, safe and beautiful colored light-blocking capsules can be provided by combining them with natural pigments, such as gardenia.

[0016] This technology can be used for compositions containing cellulose derivatives, gelatin, and pullulan as film-forming polymers, and the preferred cellulose derivative is hypromellose (hydroxypropyl methylcellulose), a common raw material for capsule shells. It can also be used for coloring purposes other than capsule shells, such as capsule band seals, orally disintegrating film formulations, coatings for tablets and granules, edible film products, and food inks.

[0017] The degree of whitening can be adjusted by the type and amount of surfactant used in combination with the salt.

[0018] The present invention was completed based on the above findings and includes the following aspects. Aspect [1]: A film comprising a film-forming polymer and a whitening agent, wherein the film-forming polymer is selected from the group consisting of a cellulose derivative, gelatin, and pullulan, the whitening agent comprises a salt and a surfactant, the salt is sodium sulfate or a combination of sodium sulfate and a white pigment other than titanium oxide, and the film does not contain titanium oxide. Aspect [2]: The film according to Aspect [1], wherein the film is obtained by molding a film-forming composition comprising the film-forming polymer, the whitening agent, and water into a film and drying the molding at 55°C or less. Aspect [3]: The film according to Aspect [1] or [2], wherein the cellulose derivative is hydroxypropyl methylcellulose, preferably selected from the group consisting of HPMC2910, HPMC2906, HPMC2208, and combinations thereof. Aspect [4]: ​​The coating according to any one of Aspects [1] to [3], comprising a salt in an amount of 0.1 to 20% by weight, the weight percentage being based on the weight of the film-forming polymer. Aspect [5]: The coating according to any one of Aspects [1] to [4], wherein the surfactant is selected from the group consisting of fatty acid esters of polyhydric alcohols, polyethylene glycol, polypropylene glycol, polyalkylene oxide derivatives, and alkyl sulfate salts, preferably selected from the group consisting of sucrose fatty acid esters, sorbitan fatty acid esters, glycerin fatty acid esters, polyoxysorbitan fatty acid esters, polyethylene glycol 4000, polyoxyethylene polyoxypropylene glycol, polyoxyethylene alkyl ethers, polyoxyethylene fatty acid esters, and sodium lauryl sulfate, more preferably selected from the group consisting of sucrose monolaurate, sucrose palmitate, sorbitan monolaurate, polysorbate 80, macrogol 4000, polyoxyethylene (105) polyoxypropylene (5) glycol, and polyoxyethylene (160) polyoxypropylene (30) glycol, and even more preferably the surfactant is sucrose monolaurate or sorbitan monolaurate.Aspect [6]. The coating according to any one of Aspects [1] to [5], comprising 0.1 to 20 wt. % of a surfactant, said wt. % being based on the weight of the film-forming polymer. Aspect [7]. The coating according to any one of Aspects [1] to [6], comprising a gelling agent, or a combination of a gelling agent and a gelling aid. Aspect [8]. The coating according to any one of Aspects [1] to [7], wherein the gelling agent is selected from the group consisting of carrageenan, gellan gum, agar, pectin, gelatin, xanthan gum, locust bean gum, curdlan, alginic acid, sodium alginate, guar gum, gum arabic, glucomannan, tamarind seed gum, furcellaran, tara gum, and karaya gum, and preferably the gelling agent is gellan gum or carrageenan. Aspect [9]. The coating according to aspect [7] or [8], wherein the gelling aid is K. ＋ and / or Ca ２＋The coating is a salt comprising the above-mentioned compound, preferably a water-soluble salt, more preferably potassium chloride or calcium chloride. Aspect

[10] . The coating according to any one of Aspects [1] to [9], wherein the white pigment is selected from the group consisting of calcium carbonate, magnesium carbonate, magnesium oxide, tricalcium phosphate, calcium stearate, magnesium stearate, and combinations thereof. Aspect

[11] . The coating according to Aspect

[10] , wherein the white pigment is calcium carbonate. Aspect

[12] . The coating according to any one of Aspects [1] to

[11] , wherein the film-forming polymer is a cellulose derivative. Aspect

[13] . The coating according to any one of Aspects [1] to

[12] , wherein the coating is colored a color other than white by the addition of a non-white dye or pigment. Aspect

[14] . A capsule suitable for oral administration comprising the coating according to any one of Aspects [1] to

[12] , wherein the capsule is preferably a hard capsule shell. Aspect

[15] . The capsule according to Aspect

[14] , colored a color other than white by the addition of a non-white dye or pigment. Aspect

[16] . A film-forming composition for forming the film or capsule according to any one of Aspects [1] to

[15] , the film-forming composition comprising a film-forming polymer, a whitening agent, and water. Aspect

[17] . A method for producing the film according to any one of Aspects [1] to

[13] using the film-forming composition according to Aspect

[16] , the method comprising the following steps: i. Adding a film-forming polymer to water to obtain a dispersion. The water temperature for obtaining the dispersion is preferably 80°C or higher. ii. Adding an aqueous solution containing a whitening agent, adding optional ingredients to the dispersion, and mixing the obtained mixture. iii. Forming the obtained mixture into a film and drying at 55°C or lower. Aspect

[18] : A method for producing a hard capsule shell body and cap suitable for joining together to provide the capsule of Aspect

[14] or

[15] by dip-molding using the film-forming composition of Aspect

[16] , the method comprising the steps of: i. adding a film-forming polymer to water to obtain a dispersion;The water temperature for obtaining the dispersion is preferably 80°C or higher; ii. A whitening agent and optional ingredients are added to the dispersion, and the resulting mixture is mixed; iii. A capsule body mold and a cap mold are immersed in the mixture in parallel or succession, and each mold is removed from the mixture to obtain each mold whose surface is covered with the mixture. The mixture covering the mold surface is then dried at 55°C or lower; iv. The body and cap are removed from their respective molds, and any unnecessary portions of the cap and body that may have formed during dip molding are cut off. Aspect

[19] . The method according to Aspect

[18] , characterized in that in an additional subsequent step, the cap and body are fitted together to form a capsule shell.

[0019] The water-soluble film-forming polymer used in the present invention is selected from the group consisting of cellulose derivatives, gelatin, and pullulan, which are used as film-forming polymers for hard capsule shells of pharmaceuticals and foods, or as coatings for pharmaceutical and food preparations. Preferably, the film-forming polymer is gelatin or a cellulose derivative, more preferably a cellulose derivative.

[0020] The cellulose derivative is preferably hypromellose (hydroxypropyl methylcellulose, HPMC), and examples thereof include HPMC2910, which contains about 29% methoxy groups and about 10% hydroxypropoxyl groups, HPMC2906, which contains about 29% methoxy groups and about 6% hydroxypropoxyl groups, and HPMC2208, which contains about 22% methoxy groups and about 8% hydroxypropoxyl groups. These various types of hypromellose may be used alone as the cellulose derivative, or may be used in combination.

[0021] The whitening agent comprises a salt and a surfactant, the salt comprising sodium sulfate or sodium sulfate and calcium carbonate. In one embodiment of the invention, the whitening agent consists of a salt and a surfactant.

[0022] As used herein, the term "surfactant" refers to a substance having a water-compatible portion (hydrophilic group) and an oil-compatible portion (lipophilic group / hydrophobic group) in the molecule. The surfactant used in the present invention is selected from fatty acid esters of polyhydric alcohols, polyethylene glycols, polypropylene glycols, polyalkylene oxide derivatives, alkyl sulfate ester salts, etc.

[0023] Examples of the fatty acid esters of the above polyhydric alcohols include sucrose fatty acid esters, sorbitan fatty acid esters, glycerin fatty acid esters, polyoxysorbitan fatty acid esters (e.g., sucrose monolaurate (SE), sucrose palmitate, sorbitan monolaurate (SML; CAS 1338-39-2), polysorbate 80 (polyoxyethylene sorbitan monooleate), polyethylene glycols include polyethylene glycol 4000 (macrogol 4000), polyalkylene oxide derivatives include polyoxyethylene polyoxypropylene glycol, polyoxyethylene alkyl ethers, polyoxyethylene fatty acid esters (e.g., polyoxyethylene(105)polyoxypropylene(5)glycol, polyoxyethylene(160)polyoxypropylene(30)glycol), and alkyl sulfates include sodium lauryl sulfate. A particularly preferred surfactant is sorbitan monolaurate (SML).

[0024] These surfactants can be used alone or in combination of two or more. Combinations of surfactants are also collectively referred to as "surfactants" herein. The whiteness can be changed depending on the amount of surfactant added.

[0025] The amount of surfactant is preferably in the range of 0.1 to 20 wt%, 0.2 to 20 wt%, 0.3 to 20 wt%, 0.4 to 10 wt%, or 0.4 to 5 wt%, where wt% is based on the weight of the film-forming polymer, with narrower ranges being preferred over broader ranges. Surfactant amounts within these ranges can be used to modify the whiteness. If too much surfactant is used, e.g., greater than 20 wt%, the film becomes more brittle and breaks more easily. Conversely, if too little surfactant is used, e.g., less than 0.1 wt%, whitening may not occur at all or may occur with a very light color, resulting in a less effective light-blocking effect.

[0026] The salt used in the present invention is sodium sulfate or a combination of sodium sulfate and calcium carbonate. Preferably, the salt is sodium sulfate. When the salt is a combination of sodium sulfate and calcium carbonate, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90% by weight of the salt is sodium sulfate, which together with the remaining portion of the salt, calcium carbonate, totals 100% by weight. The weight percentages are based on the weight of the salt. Whiteness can be altered by varying the amount of salt added. The amount of salt is preferably 0.1 to 20%, 0.2 to 20%, 0.3 to 20%, 0.4 to 12.5%, or 0.4 to 8.5% by weight, based on the weight of the film-forming polymer.

[0027] In one embodiment, the total amount of surfactant and salt is at least 0.6 wt%, preferably at least 0.75 wt%, more preferably at least 0.85 wt%, based on the weight of the film-forming polymer. The total amount of surfactant and salt is no more than 20 wt%, preferably at least 15 wt%, more preferably at least 13 wt%, based on the weight of the film-forming polymer. Any lower limit for the total amount of surfactant and salt can be combined with an upper limit for the total amount of surfactant and salt.

[0028] The film-forming composition and the film therewith may contain a gelling agent or a combination of a gelling agent and a gelling aid. Preferably, when the film-forming composition of the present invention is used as a dipping liquid (also called a capsule dipping liquid) to produce a hard capsule shell, the hard capsule shell can be prepared using a gelling agent or a combination of a gelling agent and a gelling aid. Examples of gelling agents can be selected from the group consisting of carrageenan, gellan gum, agar, pectin, gelatin, xanthan gum, locust bean gum, curdlan, alginic acid, sodium alginate, guar gum, gum arabic, glucomannan, tamarind seed gum, furcellaran, tara gum, and karaya gum. Other gelling agents known to those skilled in the art can also be used. The gelling agent is preferably used in an amount of 0 to 10%, preferably 0 to 5%. Any gelling aid known to those skilled in the art can be used, but a preferred gelling aid is K ＋ and / or Ca ２＋ Therefore, preferably, the gelling aid is K ＋ and / or Ca ２＋ and preferably a water-soluble salt thereof. ＋ and / or Ca ２＋ As the salt containing the compound (I), the respective salts, preferably water-soluble salts such as potassium chloride, potassium acetate, calcium chloride, etc., more preferably potassium chloride or calcium chloride, can be suitably used, but are not limited to these. Preferably, the gelation of the film-forming composition is carried out by a gelling agent or a combination of a gelling agent and a gelling aid; and / or preferably, the gelation of the film-forming composition is not carried out by thermal gelation at temperatures above 55°C; and / or preferably, after the film-forming composition and / or film is formed, the film is not exposed to temperatures above 55°C until the film-forming composition gels to obtain the film; and / or preferably, the gelation of the film-forming composition is not carried out in the absence of a gelling agent or a combination of a gelling agent and a gelling aid.

[0029] Optional ingredients include plasticizers, pH adjusters, sweeteners, acidulants, preservatives, flavorings, etc., which can be added to the film-forming composition as needed and, accordingly, to the film. Examples of plasticizers include triethyl citrate, glycerin, propylene glycol, D-mannitol, D-sorbitol, trehalose, polyethylene glycol, triacetin, and phthalate esters. Examples of pH adjusters include phosphoric acid, hydrochloric acid, citric acid, glycine, gluconic acid, succinic acid, acetic acid, tartaric acid, lactic acid, fumaric acid, boric acid, maleic acid, sulfuric acid, malic acid, ammonia, hydroxides, amines, and salts thereof.

[0030] The film-forming compositions and resulting films of the present invention may contain optional white pigments other than titanium oxide, such as calcium carbonate, magnesium carbonate, magnesium oxide, tricalcium phosphate, calcium stearate, and / or magnesium stearate.

[0031] In one embodiment, the film-forming compositions and associated coatings of the present invention contain TiO in any form. ２ In one embodiment, the film-forming compositions and associated films of the present invention do not contain the white colorant calcium carbonate (CaCO ３ In one embodiment, the film-forming compositions and associated films of the present invention are free of CaCO ３ In one embodiment, the film-forming compositions and associated coatings of the present invention do not contain calcium oxide (CaO), which is a white colorant. In one embodiment, the film-forming compositions and associated coatings of the present invention do not contain CaO. In one embodiment, the film-forming compositions and associated coatings of the present invention do not contain any white colorants (also referred to as white colorants) other than whitening agents.

[0032] Non-white pigments, such as black or chromatic pigments, can be added to the film-forming compositions of the present invention and the resulting films, where chromatic refers to any color other than black, white, or gray.

[0033] In the case of coating pharmaceutical or health food preparations, the chromatic dye may be any dye that can be used in the pharmaceutical or food fields, such as laked tar dyes, water-soluble tar dyes, and natural dyes.

[0034] Specifically, laked tar dyes include Food Blue No. 1 Aluminum Lake, Food Blue No. 2 Aluminum Lake, Food Red No. 2 Aluminum Lake, Food Red No. 3 Aluminum Lake, Food Red No. 40 Aluminum Lake, Food Yellow No. 4 Aluminum Lake, Food Yellow No. 5 Aluminum Lake, Food Green No. 3 Aluminum Lake, etc. Water-soluble tar dyes include Food Blue No. 1, Food Blue No. 2, Food Yellow No. 4, Food Yellow No. 5, Food Red No. 2, Food Red No. 3, Food Red No. 40, Food Red No. 102, etc., Food Red No. 104, Food Red No. 105, Food Red No. 106, Food Green No. 3, etc. Natural colorants include caramel color, gardenia color, safflower color, turmeric color, monascus color, carotene, beet red, tomato color, cochineal color, lac color, perilla color, red cabbage color, red radish color, red gomu color, adzuki bean color, purple sweet potato color, purple yam color, purple corn color, grape skin color, various berry color, grape juice color, Haematococcus algae color, chili pepper color, annatto color, spirulina color, cacao color, persimmon color, sorghum color, onion color, and tamari. Examples of pigments include cedar pigment, green tea powder, squid ink, phaffia pigment, pecan nut pigment, rutin, logwood pigment, saffron pigment, Japanese bush warbler pigment, tea pigment, seaweed pigment, hibiscus pigment, paprika powder, plum pigment, cherry pigment, chicory pigment, fruit juice, vegetable juice, red currant pigment, marigold pigment, chlorella powder, norbixin sodium, sodium iron chlorophyllin, sodium copper chlorophyllin, copper chlorophyll, naked barley green leaf extract powder, naked barley green leaf juice dried powder, naked barley green leaf extract, etc.

[0035] Other chromatic pigments include methylrosaniline chloride, carmine, photosensitizer No. 201, Permanent Violet-R-Special, methylene blue, riboflavin butyrate, riboflavin, riboflavin sodium phosphate, ferric oxide, yellow ferric oxide, black ferric oxide, etc. For the purpose of imparting pearly luster, pearl pigments made from an appropriate amount of fish scale foil, the mother-of-pearl layer of shellfish, mica, fine powder of silicon dioxide, etc. can be used.

[0036] Acidulants and flavorings can also be added. Acidulants include adipic acid, itaconic acid, citric acid, trisodium citrate, glucono-delta-lactone, gluconic acid, potassium gluconate, sodium gluconate, succinic acid, monosodium succinate, disodium succinate, sodium acetate, tartaric acid, lactic acid, sodium lactate, acetic acid, phytic acid, fumaric acid, malic acid, and phosphoric acid. Preservatives include benzoic acid, sodium benzoate, parahydroxybenzoic acid esters, sodium sulfite, sodium hyposulfite, sodium metabisulfite, potassium metabisulfite, propionic acid, calcium propionate, sodium propionate, Styrax japonica extract, Artemisia capillaris extract, milt protein extract, sorbic acid compounds, sodium dehydroacetate, nisin, sulfur dioxide, pectin hydrolysate, and ε-polylysine.

[0037] Further, as the fragrance, various essences, flavors, peppermint, menthol, mint, cinnamon, fennel, camphor, etc. may be mentioned.

[0038] The hard capsule shell of the present invention can be produced by a conventional capsule manufacturing method, preferably dip molding. As an example, the procedure for producing a hard capsule shell is as follows: (1) A film-forming polymer is added to water, preferably at 80°C or higher, to form a dispersion, preferably at about 65°C. An aqueous solution containing various additives is added and mixed, and the mixture is cooled to preferably about 60°C. (2) A mold for the body and a mold for the cap are immersed in the mixture, either in parallel or sequentially, and then removed from the mixture to obtain each mold, whose surface is covered with the mixture. The mixture covering the mold surface is then dried, preferably at 40°C or below. (3) The cap and body are removed from their respective molds, and unnecessary portions of the cap and body formed during dip molding are cut off. (4) The body and cap are combined to produce a hard capsule shell. Dispersion refers to a state in which a solute that is insoluble in a solvent is stirred in the solvent and stably dispersed (dispersion is also called dispersion). In this case, the solvent is hot water at 50° C. or higher, and the solute is HPMC particles that are insoluble in hot water.

[0039] The surfactant to be combined with the salt is preferably selected optimally depending on the type of film-forming polymer that can be made into an aqueous solution. Surfactants that provide a particularly high degree of whitening and excellent light-blocking properties are sucrose monolaurate and sorbitan monolaurate.

[0040] The film can be formed as follows: i. First, a film-forming polymer is added to water to obtain a dispersion. The water temperature for obtaining the dispersion is preferably 80°C or higher. ii. A whitening agent, i.e., a surfactant, a salt, and any optional ingredients, are added to the dispersion and then mixed. iii. This mixed dispersion is formed into a film, which is then dried, preferably at a temperature of 55°C or lower.

[0041] Drying conditions for the coating or capsule include drying at a temperature of 55°C or less, such as drying at room temperature (RT). Drying can also be carried out in the absence of wind. The drying temperature can be 50°C or less, 45°C or less, 40°C or less, 35°C or less, 30°C or less, or room temperature (RT). In the present invention, room temperature is defined as 25°C.

[0042] In the sense of the present invention, the expressions "parts by weight" and "% by weight" are used synonymously. For example, "2% by weight of whitening agent based on the weight of the film-forming polymer" has the same meaning as "2 parts by weight of whitening agent based on 100 parts by weight of the film-forming polymer." In the sense of the present invention, "molding" and "forming" are terms that generally mean giving something a specific shape. Molding includes not only molding without a mold, such as film forming, but also molding with a mold, such as dip molding.

[0043] According to the present invention, a coating film with high mechanical strength, for example, a white coating film in the form of a coating film or a hard capsule shell, can be obtained using ingredients that are harmless to health, namely, a surfactant and a salt containing sodium sulfate, which have been conventionally used in the pharmaceutical and food industries, without using titanium oxide, which is a concern for its carcinogenicity. Therefore, the present invention can be suitably used not only for ordinary coloring but also for the formulation of pharmaceuticals and foods that are unstable to light.

[0044] Therefore, particularly for the health food market, by combining it with a natural pigment such as gardenia, it is possible to provide a safe, beautifully colored light-blocking capsule with high mechanical strength, preferably a hard capsule shell or membrane, with a membrane that has high mechanical strength.

[0045] FIG. 1 shows a capsule produced by the method of the present invention and a TiO2 solution in which 6 parts by weight of calcium carbonate are dispersed in 100 parts by weight of HPMC. ２ 1 shows the results of measuring the transmittance of light at each wavelength for an HPMC hard capsule shell that does not contain PEG-10.

[0046] [Test Examples and Examples] 1. Investigation of gelling conditions and whitening agent composition Test samples (6 cm x 15 cm square films) containing cellulose derivatives, surfactants, and various salts were prepared, and the temperature conditions during film formation, film strength, and degree of whitening were evaluated.

[0047] The guidelines for visually judging the whiteness ratio and whiteness intensity are as follows: "Whiteness ratio" indicates the percentage of the area of ​​the whitened portion, regardless of "whiteness intensity," while "whiteness intensity" indicates the color intensity of the portion that appears white. Whiteness ratio: ◎ 100-90%, 〇 90-80%, △ 80-70%, □ 70% or less ● 0% Whiteness intensity: ◎ Pure white, 〇 White, △ Translucent, □ Dim white ● For the strength of the transparent film, the test sample was folded 180 degrees so that it was folded in half, and an evaluation was made as to whether it would crack or not, and the evaluation was made as follows: × Cracks 〇 Does not crack

[0048] The coatings of Formulations 1 to 11 were prepared by the following method. Formulation 1 (Comparative Example): Hydroxypropyl methylcellulose was dispersed in water at approximately 90°C, and an aqueous solution containing 2.5 parts by weight of sodium malate and 2.5 parts by weight of sucrose monolaurate (SE) was added to 100 parts by weight of hydroxypropyl methylcellulose, followed by heating to approximately 60°C to prepare a mixture. This solution was poured onto a glass plate at approximately 70°C and dried at 60°C for 15 minutes. Formulation 2 (Comparative Example): To 100 parts by weight of hydroxypropyl methylcellulose, 0.2 parts by weight of potassium chloride, 0.5 parts by weight of gellan gum, and hydroxypropyl methylcellulose were added. This mixture was heated at 90°C for 30 minutes and then stored at 80°C for 20 to 30 minutes. An aqueous solution containing 2.5 parts by weight of sodium malate and 2.5 parts by weight of SE was added to 100 parts by weight of hydroxypropyl methylcellulose to prepare a mixture heated to approximately 60°C. This solution was poured onto a glass plate and dried at room temperature. Formulation 3 (Comparative Example) Hydroxypropyl methylcellulose was dispersed in water at approximately 90°C, and an aqueous solution containing 2.5 parts by weight of sodium malate and 2.5 parts by weight of sorbitan monolaurate (SML) per 100 parts by weight of hydroxypropyl methylcellulose was added, followed by heating to approximately 60°C to prepare a mixed solution. This solution was poured onto a glass plate at approximately 70°C and dried at 60°C for 15 minutes. Formulation 4 (Comparative Example) Hydroxypropyl methylcellulose was dispersed in water at approximately 90°C, and an aqueous solution containing 2.5 parts by weight of sodium bicarbonate and 2.5 parts by weight of SML per 100 parts by weight of hydroxypropyl methylcellulose was added, followed by heating to approximately 60°C to prepare a mixed solution. This solution was poured onto a glass plate and dried at room temperature. Formulation 5 (Comparative Example) Hydroxypropyl methylcellulose was dispersed in water at approximately 90°C, and an aqueous solution containing 2.5 parts by weight of sodium pyrophosphate and 2.5 parts by weight of SML per 100 parts by weight of hydroxypropyl methylcellulose was added, followed by heating to approximately 60°C to prepare a mixed solution. This solution was poured onto a glass plate and dried at room temperature.Formulation 6 (Comparative Example) Hydroxypropyl methylcellulose was dispersed in water at approximately 90°C, and an aqueous solution containing 2.5 parts by weight of sodium carbonate and 2.5 parts by weight of SML was added to 100 parts by weight of hydroxypropyl methylcellulose, and the temperature was then adjusted to approximately 60°C. This solution was poured onto a glass plate and dried at room temperature. Formulation 7 (Example) Hydroxypropyl methylcellulose was dispersed in water at approximately 90°C, and an aqueous solution containing 2.5 parts by weight of sodium sulfate and 2.5 parts by weight of SML was added to 100 parts by weight of hydroxypropyl methylcellulose, and the temperature was then adjusted to approximately 60°C. This solution was poured onto a glass plate and dried at room temperature. Formulation 8 (Example) 0.2 parts by weight of potassium chloride, 0.5 parts by weight of carrageenan, and hydroxypropyl methylcellulose were added to 100 parts by weight of hydroxypropyl methylcellulose in water at approximately 90°C. The mixture was heated at 90°C for 30 minutes and then stored at 80°C for 20-30 minutes. An aqueous solution containing 3.5 parts by weight of sodium sulfate and 1.5 parts by weight of SML was added to 100 parts by weight of hydroxypropyl methylcellulose, and the temperature was adjusted to approximately 60°C. This solution was poured onto a glass plate and dried at room temperature. Formulation 9 (Example) 0.2 parts by weight of potassium chloride, 0.5 parts by weight of gellan gum, and hydroxypropyl methylcellulose were added to 100 parts by weight of hydroxypropyl methylcellulose in water at approximately 90°C. The mixture was heated at 90°C for 30 minutes and then stored at 80°C for 20-30 minutes. An aqueous solution containing 2.5 parts by weight of sodium sulfate and 2.5 parts by weight of SML was added to 100 parts by weight of hydroxypropyl methylcellulose, and the temperature was adjusted to approximately 60°C. This solution was poured onto a glass plate and dried at room temperature. Formulation 10 (Comparative Example: Example in which no surfactant is used) 0.2 parts by weight of potassium chloride, 0.5 parts by weight of gellan gum and hydroxypropyl methylcellulose were added to 100 parts by weight of hydroxypropyl methylcellulose in water at approximately 90°C, and the mixture was heated at 90°C for 30 minutes and then stored at 80°C for 20 to 30 minutes. An aqueous solution containing 2.5 parts by weight of sodium sulfate per 100 parts by weight of hydroxypropyl methylcellulose was added, and the temperature was adjusted to approximately 60°C to prepare an aqueous solution. This solution was poured onto a glass plate and dried at room temperature.Formulation 11 (Comparative Example: Example in which sodium sulfate was not used) Hydroxypropyl methylcellulose was dispersed in water at approximately 90°C, and an aqueous solution containing 2.5 parts by weight of SE per 100 parts by weight of hydroxypropyl methylcellulose was added, followed by heating to approximately 60°C to prepare an aqueous solution. This solution was poured onto a glass plate and dried at room temperature. The evaluation of each formulation is shown in Table 1.

[0049]

[0050] When a film-forming composition using sodium malate and a surfactant as whitening agents was gelled and then dried at 60°C, a film with good whiteness and whiteness intensity was obtained, but only with poor film strength (Formulations 1 and 3). Drying this film-forming composition at room temperature without heating improved film strength but reduced whiteness (Formulation 2). Furthermore, film-forming compositions using sodium bicarbonate, sodium pyrophosphate, and sodium carbonate as water-soluble salts also improved film strength by drying at room temperature, but did not produce films with high whiteness (Formulations 4-6). On the other hand, when a film-forming composition using sodium sulfate and a surfactant as whitening agents was dried at room temperature, films with excellent whiteness and film strength were obtained (Formulations 7-9). It was also found that the use of gelling agents (gellan gum, carrageenan) and gelling aids (potassium chloride) did not affect film whiteness or strength (Formulations 7-9). Since the absence of either sodium sulfate or a surfactant reduced whiteness (Formulations 10 and 11), it was necessary to use both in combination.

[0051] 2. Study of sodium sulfate and surfactant concentrations: Hydroxypropyl methylcellulose was dispersed in water at approximately 90°C, and then an aqueous solution containing sodium sulfate and sorbitan monolaurate (SML) in the proportions shown in Table 2 was added to 100 parts by weight of hydroxypropyl methylcellulose, followed by heating to approximately 60°C. This solution was poured onto a glass plate and dried at room temperature. The resulting film was evaluated for the degree of whitening and film strength. The results are shown in Table 2.

[0052]

[0053] From the results of formulations 7 to 9 in Table 1 and formulations 12 to 20 in Table 2, the range of sodium sulfate used was 0.25 to 13 parts by weight relative to 100 parts by weight of HPMC, whereby the white color ratio was good, and in the range of 1 to 10 parts by weight, whereby both the white color ratio and the white color concentration were good. Furthermore, the range of surfactant used in combination with sodium sulfate was 0.25 to 15 parts by weight relative to 100 parts by weight of HPMC, whereby the white color ratio and the white color concentration were good.

[0054] 3. Preparation of Calcium Carbonate-Containing Films: Films were prepared according to the following recipes, and evaluations of whiteness ratio and whiteness intensity, as well as film bending tests, were performed. The results are shown in Table 4. Recipe 21: Hydroxypropyl methylcellulose was dispersed in water at approximately 90°C, and an aqueous solution containing 0.25 parts by weight of sodium sulfate, 0.25 parts by weight of SML, and 1 part by weight of calcium carbonate was added to 100 parts by weight of hydroxypropyl methylcellulose. The solution was then heated to approximately 60°C. This solution was poured onto a glass plate and dried at room temperature. Recipe 22: Hydroxypropyl methylcellulose was dispersed in water at approximately 90°C, and an aqueous solution containing 0.25 parts by weight of sodium sulfate, 0.25 parts by weight of SML, and 15 parts by weight of calcium carbonate was added to 100 parts by weight of hydroxypropyl methylcellulose. The solution was then heated to approximately 60°C. This solution was poured onto a glass plate and dried at room temperature.

[0055] Formulations 21 and 22 are formulations in which 1 part by weight and 15 parts by weight of calcium carbonate have been added to formulation 12. In both cases, it can be seen that the use of calcium carbonate improves the depth of whiteness and maintains the film strength.

[0056] 4. Capsule Production: 100 parts by weight of hydroxypropyl methylcellulose, 0.2 parts by weight of KCl per 100 parts by weight of hydroxypropyl methylcellulose, and 0.5 parts by weight of gellan gum were added to water at 80°C or higher to prepare a dispersion at approximately 65°C. To this solution, an aqueous solution containing 1.5 parts by weight of sodium sulfate and 0.5 parts by weight of sorbitan monolaurate (SML) per 100 parts by weight of hydroxypropyl methylcellulose was added, mixed, and cooled to approximately 60°C. A body mold and a cap mold at 25°C were immersed in this aqueous solution and dried at 25°C for 30 minutes. The coating formed on the mold was removed from the mold, and the unnecessary portion of the coating was cut off. The body and cap were then mated to obtain a capsule shell.

[0057] The capsules produced by the method of the present invention were white and had excellent light-shielding properties, and had excellent film strength and mechanical strength. ２ The transmittance of light by wavelength was compared with that of an HPMC capsule containing no TiO (Figure 1). ２ The HPMC capsules exhibit better light-blocking properties than those containing no HPMC.

[0058] The film-forming composition of the present invention, which contains a film-forming polymer dispersed in water and a whitening agent containing a surfactant and a salt containing sodium sulfate, enables the whitening and / or opacification of films and provides light-blocking properties without using titanium oxide, which has been reported to be carcinogenic. Furthermore, adding a pigment to the film-forming composition can produce an opaque, colored film. This film-forming composition can be gelled by drying at 55°C or below to produce a film with excellent mechanical strength. Therefore, it is particularly useful as a capsule material for filling contents such as pharmaceuticals, veterinary drugs, cosmetics, and health foods, as a coating material for tablets and granules, as an edible film, and as a food ink.

Claims

1. A coating comprising a film-forming polymer and a whitening agent, wherein the film-forming polymer is selected from the group consisting of cellulose derivatives, gelatin, and pullulan, the whitening agent comprises a salt and a surfactant, the salt being sodium sulfate or a combination of sodium sulfate and a white pigment other than titanium oxide, and the coating does not contain titanium oxide.

2. The film according to claim 1, wherein the film is obtained by forming the film and then drying it at 55°C or less, preferably by forming a film-forming composition containing the film-forming polymer, the whitening agent, and water into a film, and then drying it at 55°C or less after the forming.

3. The coating of claim 1 or 2, wherein the cellulose derivative is hydroxypropyl methylcellulose, preferably the cellulose derivative is selected from the group of HPMC2910, HPMC2906, HPMC2208, and combinations thereof.

4. The coating of any one of claims 1 to 3, comprising salt in an amount of 0.1 to 20% by weight, the weight percentage being based on the weight of the film-forming polymer.

5. A coating according to any one of claims 1 to 4, wherein the surfactant is selected from the group consisting of fatty acid esters of polyhydric alcohols, polyethylene glycol, polypropylene glycol, polyalkylene oxide derivatives, and alkyl sulfate salts, preferably selected from the group consisting of sucrose fatty acid esters, sorbitan fatty acid esters, glycerin fatty acid esters, polyoxysorbitan fatty acid esters, polyethylene glycol 4000, polyoxyethylene polyoxypropylene glycol, polyoxyethylene alkyl ethers, polyoxyethylene fatty acid esters, and sodium lauryl sulfate, more preferably selected from the group consisting of sucrose monolaurate, sucrose palmitate, sorbitan monolaurate, polysorbate 80, macrogol 4000, polyoxyethylene (105) polyoxypropylene (5) glycol, and polyoxyethylene (160) polyoxypropylene (30) glycol, and even more preferably the surfactant is sucrose monolaurate or sorbitan monolaurate.

6. A coating according to any one of claims 1 to 5, comprising 0.1 to 20 wt% of a surfactant, said wt% being based on the weight of the film-forming polymer.

7. A coating according to any one of claims 1 to 6, comprising a gelling agent or a combination of a gelling agent and a gelling aid.

8. A coating according to any one of claims 1 to 7, wherein the gelling agent is selected from the group consisting of carrageenan, gellan gum, agar, pectin, gelatin, xanthan gum, locust bean gum, curdlan, alginic acid, sodium alginate, guar gum, gum arabic, glucomannan, tamarind seed gum, furcellaran, tara gum, and karaya gum, preferably the gelling agent is gellan gum or carrageenan.

9. The coating according to claim 7 or 8, wherein the gelling aid is K ＋ and / or Ca ２＋ The coating is a salt comprising the formula (I), preferably a water-soluble salt, more preferably potassium chloride or calcium chloride.

10. The coating of any one of claims 1 to 9, wherein the white pigment is selected from the group consisting of calcium carbonate, magnesium carbonate, magnesium oxide, tricalcium phosphate, calcium stearate, magnesium stearate, and combinations thereof.

11. The coating of claim 10, wherein the white pigment is calcium carbonate.

12. A film according to any one of claims 1 to 11, wherein the film-forming polymer is a cellulose derivative.

13. A coating according to any one of claims 1 to 12, which is coloured a colour other than white by the addition of a non-white dye or pigment.

14. A capsule suitable for oral administration comprising a coating according to any one of claims 1 to 12, the capsule preferably being a hard capsule shell.

15. A capsule according to claim 14, said capsule being coloured a colour other than white by the addition of a non-white dye or pigment.

16. A film-forming composition for forming the film or capsule according to any one of claims 1 to 15, comprising a film-forming polymer, a whitening agent and water.

17. A method for producing a film according to any one of claims 1 to 13 using the film-forming composition according to claim 16, said method comprising the following steps: i. adding a film-forming polymer to water to obtain a dispersion. The water temperature for obtaining the dispersion is preferably 80°C or higher; ii. adding an aqueous solution containing a whitening agent, adding optional ingredients to the dispersion, and mixing the obtained mixture; iii. forming the obtained mixture into a film and drying at 55°C or lower.

18. A method for producing a hard capsule shell body and cap suitable for joining together to provide a capsule according to claim 14 or 15 by dip-molding with the film-forming composition according to claim 16, said method comprising the steps of: i. Adding a film-forming polymer to water to obtain a dispersion. The water temperature for obtaining the dispersion is preferably 80°C or higher; ii. Add a whitening agent and any optional ingredients to the dispersion, and mix the resulting mixture; iii. Immerse the capsule body mold and cap mold into the mixture in parallel or succession, remove each mold from the mixture to obtain each mold whose surface is covered with the mixture, and then dry the mixture covering the surface of the mold at 55°C or less; iv. Pull the body and cap out of each mold, and cut off any unnecessary parts of the cap and body that may have formed during dip molding.

19. The method of claim 18, characterized in that in an additional subsequent step, the cap and body are fitted together to form a capsule shell.

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