JP6258716B2 - Soft capsule formulation containing hydrophobic gel - Google Patents

Description

  The present invention relates to a soft capsule formulation containing a hydrophobic gel, and more particularly to a soft capsule formulation containing a hydrophobic gel obtained by gelling a hydrophobic liquid with a gelling agent.

  Soft capsule preparations are used in many fields such as pharmaceuticals, quasi drugs, and foods. Since such soft capsule preparations are taken orally, aesthetics are regarded as important. Therefore, it is desired that the contents and film of the soft capsule preparation are excellent in transparency.

  Conventionally, various soft capsule preparations containing drugs and functional foods have been reported. As a film material in such a soft capsule formulation, gelatin (see Patent Document 1 and Patent Document 2), a mixture of agar and water-soluble polymer (see Patent Document 3), and alginate (see Patent Document 4 and Patent Document 5) Etc. are used.

  In general, water is used as a solvent for hydrophilic substances. However, when gelatin or a mixture of agar and water-soluble polymer is used as a coating material, a soft capsule formulation containing water-containing material can be manufactured. The soft capsule film is softened due to the compatibility of the coating liquid with water and the transfer of water after encapsulation. Therefore, the present situation is that a hydrophilic substance cannot be encapsulated in a soft capsule in a stable state.

  In soft capsules using gelatin as the film material, the film is hydrophilic, so if you include a water-containing material such as a food extract such as garlic extract, coffee extract, aloe vera extract, the film dissolves in water. There's a problem. Therefore, the encapsulated material must be powdered or suspended in hardened oil and encapsulated in a capsule.

  In a soft capsule using a mixture of agar and a water-soluble polymer as a film material, a film is formed from a mixed solution obtained by dissolving agar in water and adding a water-soluble polymer such as carrageenan. Since such a film is also hydrophilic, there is a problem that when a material containing water is encapsulated, the film is dissolved by water, which is used when encapsulating contents dissolved in fats and oils (see Patent Document 3).

  Furthermore, as a method for producing a soft capsule using an alginate as a coating material, for example, a desired material is dispersed or dissolved in an aqueous solution of sodium alginate, and this is dropped into an aqueous solution of a polyvalent metal salt. A method is known in which a water-insoluble film is formed on the outside of a droplet, and further solidified to the inside of the droplet to obtain a strong soft capsule (see Patent Document 4). Such a method requires complicated steps such as washing and drying in the production of the soft capsule preparation.

  On the other hand, regarding the encapsulation of a hydrophilic substance, a method has been proposed in which a hydrophilic substance is encapsulated by interposing a lower fatty acid ester of sucrose between the hydrophilic substance and a film (see Patent Document 5). However, a hydrophobic film made of a lower fatty acid ester of sucrose is an aggregate of low molecular weight compounds, so that there is a problem that hydrophilic substances are not effectively blocked.

  Further, a seamless capsule having a hydrophilic substance as a content and a capsule using a hydrophobic protective layer made of a hardened fat between the content and the capsule film has been proposed (see Patent Document 6). However, hardened fats and oils become cloudy when solidified, and the appearance of the product is impaired. Furthermore, when handling hardened fats and oils as a raw material, there has been a problem that the operation becomes complicated such as troublesome washing of the capsule manufacturing apparatus.

JP 59-139317 A JP 61-151127 A Japanese Patent Laid-Open No. 9-25228 Japanese Patent Laid-Open No. 3-68508 JP-A-3-52639 JP 2001-238611 A

  The present invention has been made in view of the conventional situation as described above, and it is an object to provide a soft capsule preparation excellent in transparency and a soft capsule preparation capable of stably holding a hydrophilic substance for a long period of time. To do.

  As a result of various studies to solve the above problems, the present inventors have found that when 12-hydroxystearic acid is added to a hydrophobic liquid, a transparent hydrophobic gel is obtained. Furthermore, when a soft capsule preparation in which water is encapsulated in such a hydrophobic gel is produced and stored for a long period of time, the encapsulated water is stably maintained, and it is found that there is no leakage of water from the hydrophobic gel, The present invention has been completed.

  That is, the present invention provides [1] a soft capsule formulation containing a hydrophobic gel obtained by gelling a hydrophobic liquid with a gelling agent, or [2] an aqueous solution encapsulated in the hydrophobic gel. The soft capsule formulation, [3] the soft capsule formulation of [1] or [2], wherein the hydrophobic gel is encapsulated with a hydrophilic film, and [4] the above-mentioned [1]- It is related with the soft capsule formulation in any one of [3].

  According to the present invention, it is possible to produce a soft capsule preparation excellent in transparency. In addition, by encapsulating the aqueous solution in the hydrophobic gel contained in the soft capsule preparation of the present invention, the aqueous solution can be stably maintained for a long period of time, and when encapsulated with a hydrophilic film, the film is softened. It becomes possible to prevent.

  The soft capsule preparation of the present invention is not particularly limited as long as it is a soft capsule preparation containing a hydrophobic gel obtained by gelling a hydrophobic liquid with a gelling agent, but an aqueous solution is preferably included in the hydrophobic gel.

  The hydrophobic liquid in the present invention is not particularly limited as long as the substance immiscible with water is a transparent liquid and can maintain transparency by gelation, and is immiscible with such water. Examples of the functional substance include various fats and oils, fatty acids, sugar fatty acid esters, aliphatic hydrocarbons, aromatic hydrocarbons, chain ethers, higher fatty acid esters, higher alcohols, and terpenes. Specifically, safflower oil, linseed oil, sesame oil, olive oil, mustard oil, sesame oil, corn oil, soybean oil, evening primrose oil, terpene oil, rapeseed oil, palm oil, palm kernel oil, jojoba oil, cottonseed oil, Examples include coconut oil, peanut oil, EPA, DHA, shark liver oil, cod liver oil, various animal and vegetable oils, synthetic oils, refined oils such as medium-chain fatty acid triglycerides (MCT) and diacylglycerols. Can do.

  The substance immiscible with water is preferably liquid at room temperature, and the melting point of the substance immiscible with water is 40 ° C. or less, preferably 25 ° C. or less, more preferably from the viewpoint of ease of work. 10 degrees C or less can be mentioned.

  In the hydrophobic liquid in the present invention, two or more kinds of substances immiscible with water may be combined. Moreover, as long as the immiscibility with water is not lost, the hydrophobic liquid in the present invention may further contain other substances.

  In the present invention, the gelling agent is not particularly limited as long as it is added to the hydrophobic liquid and gels the hydrophobic liquid. Specifically, organic compounds such as 12-hydroxystearic acid, monobenzylidene sorbitol, dibutylethylhexanoylglutamide, dibutyllauroylglutamide, amorphous synthetic silica, alumina, alumina hydrate Inorganic compounds such as calcium carbonate, magnesium carbonate and titanium dioxide can be mentioned, and 12-hydroxystearic acid can be preferably mentioned.

  The addition amount of the gelling agent is appropriately selected depending on the combination of the gelling agent and the hydrophobic liquid to be used, and is not particularly limited, but is 1% to 20%, preferably 2% to 12%, more preferably with respect to the hydrophobic liquid. 3 to 10%, particularly preferably 3 to 5%. If the addition amount of the gelling agent exceeds 20%, the sol-gel transition temperature becomes high and the heat-sensitive component cannot be encapsulated, and handling becomes difficult, and the gel tends to become cloudy. Further, when the addition amount of the gelling agent is less than 1%, the strength of the gel becomes too weak, and the stability of the capsule shape is liable to be impaired. In particular, when the aqueous solution is encapsulated, the stability of the aqueous solution is also impaired. It becomes easy.

  In the present invention, the hydrophobic gel is not particularly limited as long as it is a water-impermeable gel obtained by gelling a hydrophobic liquid with a gelling agent, and a method for producing such a hydrophobic gel includes a hydrophobic liquid. A method may be mentioned in which a gelling agent is added and dissolved by heating, and then cooled until the hydrophobic liquid gels. In addition, by combining a desired hydrophobic liquid and a desired gelling agent, the gelling temperature range of the hydrophobic liquid and the melting point of the hydrophobic gel can be appropriately adjusted. The melting point of the hydrophobic gel is 60 ° C. or lower, preferably 50 ° C. or lower, more preferably 48 ° C. or lower, more preferably 45 ° C. or lower, particularly preferably 40 ° C. or lower, from the viewpoint of ease of handling in the capsule manufacturing process. Can be mentioned.

  In the present invention, the aqueous solution is not particularly limited as long as it is water or a liquid substance in which a hydrophilic substance is dissolved in water, and a plurality of hydrophilic substances may be dissolved in water. As the hydrophilic substance in the present invention, a functional group that easily forms a bond with a water molecule such as a hydroxyl group, a carboxyl group, an amino group, a ketone group, or a sulfo group is part of the molecular structure and is soluble in water. If it is a new substance, it will not be restrict | limited, Drugs, quasi-drugs, foods, seasonings, fragrances, herbal medicines, cosmetics such as water-soluble vitamins, organic acids and salts thereof, sugars, nucleic acids, and other Chinese medicines In this field, substances used for various purposes can be mentioned.

  The aqueous solution may contain components other than hydrophilic substances and water, such as water extracts such as food extracts such as blueberry extract, lemon juice, garlic extract and shijimi extract, and pharmaceutical extracts such as carrot extract and toki extract. A liquid material having a content of 15 to 40% and low fluidity is also included. In addition, water-soluble polymers such as agar, gelatin, sodium carrageenan alginate, pullulan, glucomannan, gum arabic, fur celerane, yukema algae, gellan gum, hydroxypropyl methylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, starches, etc. Soft granules produced by dissolution are also included in the aqueous solution for convenience.

  The content of the aqueous solution may be 0.01 to 1000 parts by weight, preferably 0.01 to 500 parts by weight, and more preferably 0.01 to 200 parts by weight with respect to 100 parts by weight of the hydrophobic liquid.

  The content of water in the aqueous solution can be adjusted as appropriate according to the amount of the hydrophilic substance to be dissolved, but is preferably an amount capable of dissolving the hydrophilic substance to be dissolved.

  In the present invention, the aqueous solution is encapsulated in the hydrophobic gel is not particularly limited as long as the aqueous solution is covered with the hydrophobic gel and the aqueous solution is present inside the hydrophobic gel, and is encapsulated in the hydrophobic gel. The number of aqueous solutions may be one or two or more.

  In the present invention, examples of the method for producing a hydrophobic gel encapsulating an aqueous solution include a method in which an aqueous solution is added to a sol-state hydrophobic liquid containing a gelling agent and cooled until gelled. In such a method, after adding the aqueous solution, the hydrophobic liquid containing the gelling agent may be stirred. By stirring, the added aqueous solution is separated into a plurality of aqueous solutions, and the hydrophobic liquid containing the gelling agent is contained. If contained in a liquid, the aqueous solution is encapsulated in the hydrophobic gel after gelation.

  Moreover, in the hydrophobic gel in which the aqueous solution is encapsulated, a hydrophilic substance dissolved in the aqueous solution and a mixture contraindicated component can be contained. As a method for producing such a hydrophobic gel, a method of adding a powder mixture incompatible component together with an aqueous solution to a hydrophobic liquid containing a gelling agent and stirring, or a method of mixing a gelling agent and a powder incompatible component are included. Examples thereof include a method of preparing a hydrophobic liquid to be contained, adding an aqueous solution to the hydrophobic liquid, and stirring the solution.

  In addition, in the case where the mixed contraindication component is hydrophobic, a method of preparing a hydrophobic liquid containing a gelling agent and dissolving the mixed contraindication component, adding an aqueous solution to the hydrophobic liquid, and stirring the mixture is given. be able to.

  In the present invention, the film is not particularly limited, and may be a hydrophobic film or a hydrophilic film, but is preferably a hydrophilic film. When the aqueous solution is encapsulated in the hydrophobic gel, even if it is a hydrophilic film, since the hydrophobic gel exists between the aqueous solution and the hydrophilic film, the film is not softened.

  Examples of the hydrophilic film material include gelatin, carrageenan, agar, sodium alginate, pullulan, glucomannan, gum arabic, farseleran, yukema algae, gellan gum, hydroxypropylmethylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, and starches. A hydrophilic polymer can be exemplified, and gelatin can be preferably exemplified.

  When producing a film, the film material is made of a plasticizer such as glycerin, a pH adjuster such as sodium phosphate, a chelating agent such as trisodium citrate or sodium metaphosphate, or a gelation accelerator such as calcium lactate or potassium chloride. Further, surfactants such as polyglycerin fatty acid ester and lecithin, sweeteners, fragrances, preservatives, coloring agents and the like may be added.

  The capsule preparation of the present invention is manufactured using a known capsule preparation manufacturing method such as a flat plate method, a rotary die method, or a seamless method. In particular, the seamless method does not require major changes to existing capsule preparation apparatuses. Is preferable. The major axis of the capsule preparation is not particularly limited, but can be 1 to 50 mm, preferably 5 to 20 mm.

  Hereinafter, the present invention will be described in detail, but the present invention is not limited thereto.

(Manufacture of hydrophobic gel)
Add 3%, 5%, 7%, 10% of 12-hydroxystearic acid as a gelling agent to each hydrophobic liquid of MCT (Coconard MT, manufactured by Kao Corporation), canola oil, soybean white oil, and rice salad oil. The gelling agent was dissolved by heating at 80 ° C. for 1 hour. Then, it was allowed to cool at room temperature while measuring the temperature of the hydrophobic liquid, and the temperature at the time when the hydrophobic liquid gelled was defined as the gelation temperature. Furthermore, the obtained gel was gradually heated while measuring the temperature, and the temperature at which the gel became liquid was taken as the melting point of the gel. Table 1 shows the gelation temperatures and the melting points of the gels.

  Generally, hydrophobic substances such as wax and hardened oil are cloudy at room temperature, but gelling agents are added to each hydrophobic liquid of MCT, canola oil, soybean white oil, and rice salad oil shown in Table 1. As a result, the gels prepared by adding 3%, 5%, 7%, and 10% of 12-hydroxystearic acid were all transparent. Therefore, it has been clarified that a transparent gel suitable for a capsule preparation can be produced by adding 12-hydroxystearic acid to a hydrophobic liquid. In addition, since the difference between the gelation temperature of the hydrophobic liquid and the melting point of the hydrophobic gel is large, the hydrophobic liquid maintains a sol state at a low temperature during capsule production, and the hydrophobic gel is difficult to dissolve after capsule production. It was revealed that it was possible to maintain a gel state in which the shape was not easily broken.

(Water-filled capsule)
7% of 12-hydroxystearic acid was added to MCT (Coconard MT, manufactured by Kao Corporation) and dissolved by heating to prepare a solution for hydrophobic gel. The gelation temperature of the hydrophobic gel solution was 44 ° C., and the melting point of the gel was 57 ° C.

  Place the hydrophobic gel solution in a capsule mold, drop water at the center when in the sol state, cool at 25 ° C. for 30 minutes to gel the hydrophobic gel solution, and add the aqueous solution to the hydrophobic gel. Produced a soft capsule formulation.

  The resulting soft capsule formulation was transparent. In addition, even after the obtained soft capsule preparation is stored for 1 month or longer in an open atmosphere at 25 ° C. and for 1 year or longer in a sealed container at 25 ° C., the amount of water in the soft capsule preparation remains almost the same as that during the production of the soft capsule preparation. And maintained transparency.

(Water-encapsulated capsule encapsulated with a hydrophilic film)
To 90 parts by weight of water, 30 parts by weight of glycerin and 100 parts by weight of gelatin were added to swell and absorb water, and then heated and dissolved at 80 ° C. to obtain a capsule film solution. The water-encapsulated capsule obtained in Example 2 was encapsulated with the capsule film solution, and then dried at 25 ° C. for 20 hours to produce a water-encapsulated capsule encapsulated with a hydrophilic film.

  The obtained capsule preparation was transparent. In addition, even after the obtained soft capsule preparation is stored for 1 month or longer in an open atmosphere at 25 ° C. and for 1 year or longer in a sealed container at 25 ° C., the amount of water in the soft capsule preparation remains almost the same as that during the production of the soft capsule preparation. And maintained transparency. Furthermore, the film did not soften.

  As described above, according to the present invention, there is provided a soft capsule that is excellent in transparency and encapsulates a hydrophilic liquid such as water that cannot be encapsulated conventionally.

  The soft capsule preparation of the present invention can be used as a capsule preparation that can stably retain a hydrophilic substance for a long period of time in the fields of medicine, quasi-drug, food, and the like.

Claims (2)

A soft capsule preparation containing a hydrophobic gel obtained by gelling a hydrophobic liquid with a gelling agent , wherein the hydrophobic gel contains an aqueous solution, wherein the hydrophobic liquid is an oil, fatty acid, fatty acid of sugar At least one selected from esters, aliphatic hydrocarbons, aromatic hydrocarbons, chain ethers, higher fatty acid esters, higher alcohols and terpenes, and the gelling agent is 12-hydroxystearic acid, monobenzylidene sorbitol, A soft capsule preparation which is at least one selected from dibutylethylhexanoylglutamide and dibutyllauroylglutamide . Hydrophobic gel is encapsulated in a hydrophilic coating according to claim 1 Symbol placement of soft capsule formulation.