JP6605317B2 - Soft capsule film and soft capsule using the film - Google Patents

Description

  The present invention relates to a soft capsule film and a soft capsule using the film.

Capsules include soft capsules (soft capsules) and hard capsules. In the 16th revision Japanese Pharmacopoeia, these two types are distinguished as follows.
(I) Hard capsules are obtained by mixing an active ingredient with additives such as excipients and mixing them into a homogeneous capsule, or by using a suitable method to form granules or molded products as they are. Fill and make.
(Ii) A soft capsule is obtained by encapsulating an active ingredient with an additive into a certain shape with an appropriate capsule base such as gelatin with increased plasticity by adding glycerin or D-sorbitol. Make.

  Soft capsules are widely used in fields such as pharmaceuticals, cosmetics, and health foods. In the manufacture of soft capsules, filling of the filler and molding of the capsule film are performed simultaneously. In general, a rotary method and a seamless method are known as soft capsule manufacturing methods. Among these, in the rotary method, two coated sheets are inserted between rotating molders, and the sheets are pressure-molded while injecting the filler. Thereafter, the filled portion of the filling is punched out to form a soft capsule.

  A general soft capsule is based on gelatin, and a relatively large amount of a plasticizer is added to the capsule, which is rich in elasticity and flexibility. However, gelatin has an amino group, so if there are substances in the capsule filling that contain aldehyde groups such as reducing sugars or macrolide antibiotics, or substances that react with time to produce aldehydes. During storage, the amino group of gelatin and the aldehyde group in the packing are chemically bonded to cause discoloration or insolubilization of the film, resulting in a delayed release of the packing.

  By the way, a PVA copolymer (polyvinyl alcohol copolymer) is a copolymer having polyvinyl alcohol (PVA) as a structural unit, and as an example, a polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer is known. The copolymer is listed in the standard of pharmaceutical additives as a pharmaceutical additive under the name of “polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer”, and in Patent Document 1, the pharmaceutical coating agent of the copolymer is disclosed in Patent Document 1. Patent Document 2 suggests the use of the copolymer as a pharmaceutical binder, and Patent Document 3 suggests the use of the copolymer as a hard capsule base. However, there is no mention of using PVA copolymer as a soft capsule base.

  The biggest feature of soft capsules is that the filling is usually a liquid. On the other hand, the filling of hard capsules is usually a solid such as a powder, and when a liquid is filled, it is necessary to apply a band seal to prevent leakage. In addition, the combination of the type of liquid that can be filled and the capsule film base is very limited so that the filling liquid does not bleed through the hard capsule film or take away moisture in the film and crack.

  In the manufacture of soft capsules, filling of the filling liquid and molding of the capsule film are usually performed at the same time, and there are no seams such as seamless capsules, or the seams are sealed by pressure molding, so there is no risk of the filling liquid leaking. . In addition, the soft capsule film contains a plasticizer, and there is little fear of cracking due to deprivation of moisture. In addition, by selecting the type and amount of plasticizer, it is possible to fill not only lipophilic liquids that are not compatible with water but also liquids that are compatible with water, such as polyethylene glycol. The absorbability in the body of the component dissolved in a simple liquid can be increased. Since soft capsules are relatively easy to design, they are often used in the early stages of drug development and venture companies.

WO2005 / 019286 JP 2011-001376 A WO2002 / 017848 JP 2010-90080 A JP 2010-95449 A JP 2011-79786 A JP 2012-51945 A

  An object of the present invention is to provide a novel soft capsule film.

  The present inventors can prevent the capsule from being insolubilized by a substance containing an aldehyde group and can oxidize the filler if the soft capsule is a soft capsule film prepared using a specific PVA copolymer and a gelling agent. It has been found that it can be reduced, and further improvements have been made to complete the present invention.

That is, the present invention includes, for example, the subject matters described in the following sections.
Item 1.
(I) polyvinyl alcohol,
(Ii) at least one unsaturated carboxylic acid selected from the group consisting of acrylic acid, methacrylic acid, fumaric acid, and maleic acid, and (iii) formula [I]
^{_{H 2 C = C (R 1}} ) -COOR 2 [I]
(Wherein R ¹ represents a hydrogen atom or a methyl group, and R ² represents an alkyl group having 1 to 4 carbon atoms). At least one kind selected from the group consisting of compounds represented by A polyvinyl alcohol copolymer containing a saturated carboxylic acid ester as a structural unit, and
Soft capsule film containing gelling agent.
Item 2.
(Ii) The soft capsule film according to Item 1, wherein the unsaturated carboxylic acid is acrylic acid.
Item 3.
(Iii) The soft capsule film according to Item 1 or 2, wherein the unsaturated carboxylic acid ester is methyl methacrylate.
Item 4.
Item 4. The soft capsule film according to any one of Items 1 to 3, wherein the gelling agent is carrageenan.
Item 5.
Item 5. The soft capsule film according to any one of Items 1 to 4, wherein 40 to 90 parts by weight of the polyvinyl alcohol copolymer is contained with respect to 100 parts by weight of the soft capsule film.
Item 6.
Item 6. A soft capsule comprising the soft capsule film according to any one of Items 1 to 5.
Item 7.
Item 7. A soft capsule, wherein the soft capsule according to item 6 contains a substance containing at least an aldehyde group.

  Capsule insolubilization by a substance containing an aldehyde group can be prevented, and oxidation of the filler can be reduced. As a result, soft capsules with excellent long-term stability can be obtained by filling the soft capsules of the present invention with the fillers that could not be commercialized with gelatin soft capsules due to solubility and stability problems during long-term storage. It can be obtained and commercialized. Furthermore, according to the present invention, it is possible to provide a soft capsule that does not use any animal-derived raw material (for example, gelatin).

  One embodiment of the present invention relates to a soft capsule film containing a specific PVA copolymer (a copolymer containing polyvinyl alcohol as a constituent unit) and a gelling agent.

The specific PVA copolymer comprises (i) polyvinyl alcohol, (ii) at least one unsaturated carboxylic acid selected from the group consisting of acrylic acid, methacrylic acid, fumaric acid, and maleic acid, and (iii) formula [ I]
^{_{H 2 C = C (R 1}} ) -COOR 2 [I]
(Wherein R ¹ represents a hydrogen atom or a methyl group, and R ² represents an alkyl group having 1 to 4 carbon atoms). At least one kind selected from the group consisting of compounds represented by It is a copolymer containing a saturated carboxylic acid ester as a structural unit. A copolymer having these (i) to (iii) as structural units (that is, a copolymer containing only (i) to (iii) as structural units) is preferable. In addition, it is preferable that the said copolymer is a random copolymer. In addition, the structural unit here refers to the monomer before superposition | polymerization in a (co) polymer.

  (I) As polyvinyl alcohol (PVA), any of a completely saponified product, an intermediate saponified product, and a partially saponified product can be used. Examples of polyvinyl alcohol derivatives include amine-modified polyvinyl alcohol, ethylene-modified polyvinyl alcohol, carboxylic acid-modified polyvinyl alcohol, diacetone-modified polyvinyl alcohol, thiol-modified (particularly terminal thiol-modified) polyvinyl alcohol, and the like. Can be used.

Polyvinyl alcohol can be obtained by radical polymerization of vinyl acetate and appropriately saponifying the resulting vinyl acetate. Thus, usually, polyvinyl alcohol has a —OCOCH ₃ group derived from vinyl acetate. Polyvinyl alcohol is classified into a completely saponified product, an intermediate saponified product, a partially saponified product, etc., depending on the degree of saponification. The saponification degree of the polyvinyl alcohol used in the present invention is preferably about 75 mol% or more, more preferably about 80 mol% or more, and further preferably 85 mol% or more. Of these, a saponification degree of 78 to 96 mol% is preferable, and a saponification degree of 85 to 90 mol% is more preferable. As is known in the technical field relating to polyvinyl alcohol, a completely saponified product of polyvinyl alcohol is usually a polyvinyl alcohol having a saponification degree of 98 mol% or more, and is not necessarily 100 mol% saponified. Absent.

  Moreover, the derivative | guide_body of polyvinyl alcohol can be manufactured by a well-known method in the said field | area.

  In addition, polyvinyl alcohol and its derivative can also purchase and use a commercial item. For example, Gohsenol (registered trademark) EG05 (manufactured by Nippon Synthetic Chemical Industry), EG40 (manufactured by Nippon Synthetic Chemical Industry), PVA203 (manufactured by Kuraray), PVA204 (manufactured by Kuraray), PVA205 (manufactured by Kuraray), JP-04 (Nippon Vinegar / Poval), JP-05 (Nippon Vinegar / Poval) or the like can be used.

  Polyvinyl alcohol and derivatives thereof are known in various degrees of polymerization, but the average degree of polymerization is not particularly limited, and is preferably about 100 to 4000, more preferably about 200 to 3000, for example.

  Polyvinyl alcohol and its derivative can be used individually by 1 type or in combination of 2 or more types. For example, polyvinyl alcohol and various modified polyvinyl alcohols having different saponification degrees can be used singly or in combination of two or more. Further, for example, polyvinyl alcohols having different average degrees of polymerization can be used in combination. For example, polyvinyl alcohol having an average polymerization degree of 300 and polyvinyl alcohol having an average polymerization degree of 1500 can be mixed and used.

  (Ii) For unsaturated carboxylic acid, among at least one unsaturated carboxylic acid selected from the group consisting of acrylic acid, methacrylic acid, fumaric acid, and maleic acid, from the group consisting of acrylic acid and methacrylic acid At least one selected is preferable, and acrylic acid is more preferable.

  In addition, (iii) unsaturated carboxylic acid ester is specifically, methyl methacrylate, methyl acrylate, ethyl methacrylate, ethyl acrylate, propyl methacrylate, propyl acrylate, isopropyl methacrylate, isopropyl acrylate, methacryl At least one selected from the group consisting of butyl acrylate, butyl acrylate, isobutyl methacrylate, and isobutyl acrylate, preferably from the group consisting of methyl methacrylate, methyl acrylate, ethyl methacrylate, and ethyl acrylate At least one selected. More preferred is at least one selected from the group consisting of methyl methacrylate and methyl acrylate, and more preferred is methyl methacrylate. Moreover, the mass ratio of (ii) and (iii) contained in the copolymer is preferably (ii) 5 to 50 parts by mass, (iii) 50 to 95 parts by mass, and more preferably (ii) 10 to 10 parts. (Iii) 60-90 parts by mass with respect to 40 parts by mass, more preferably (iii) 70-90 parts by mass, and even more preferably (ii) 10-20 with respect to (ii) 10-30 parts by mass. It is (iii) 80-90 mass parts with respect to a mass part. Furthermore, the mass ratio of (ii) is preferably 5 to 50% by mass, more preferably 10 to 40% by mass, still more preferably 10 to 30% by mass, and more preferably 10 to 20%, based on the total amount of polymerizable vinyl monomers. The mass ratio of (iii) is preferably 50 to 95 mass%, more preferably 60 to 90 mass%, further preferably 70 to 90 mass%, and still more preferably 80 to 90 mass%. .

  In particular, when only acrylic acid is used as (ii) and only methyl methacrylate is used as (iii), the mass ratio of (i) :( ii) :( iii) is 60 to 90: 0.5. About 12: 7-38 is preferable, and about 70-90: 1-5: 10-25 is more preferable.

  A known method can be used as a copolymerization method. For example, (i) polyvinyl alcohol is added to water and dissolved by heating, and then (ii) an unsaturated carboxylic acid and (iii) an unsaturated carboxylic acid ester and a polymerization initiator are added and copolymerized to form a resin. Can be obtained. More specifically, for example, after (i) polyvinyl alcohol is dispersed in ion-exchanged water and completely dissolved at 90 to 100 ° C., (ii) unsaturated carboxylic acid and (iii) unsaturated carboxylic acid ester are added. Then, the reaction may be carried out for about 2 to 5 hours by substituting with nitrogen and adding a polymerization initiator. The mass ratio of (i), (ii), and (iii) in the above-mentioned copolymer is determined by the mass ratio of (i), (ii), and (iii) added to water. Therefore, the mass ratio of each component added to water is preferably the mass ratio of (i), (ii), and (iii) in the above-mentioned copolymer.

  As the polymerization initiator, those conventionally used can be used. For example, azo compounds such as 2,2′-azobis (2-amidinopropane) hydrochloride, AIBN (azoisobutyronitrile), persulfates such as potassium persulfate, sodium persulfate and ammonium persulfate, t-butyl hydro Organic peroxides such as peroxides, redox initiators such as hydrogen peroxide-tartaric acid, hydrogen peroxide-sodium tartrate, and the like can be used.

Although a limited interpretation is not desired, the reaction mechanism when the components (i), (ii), and (iii) are copolymerized in the present invention is considered as follows. That is, first, the hydrogen of the methyl group at the terminal of the —OCOCH ₃ group present in the polyvinyl alcohol is extracted by the polymerization initiator to generate radicals. The polymerizable vinyl monomer (ii) or (iii) is bonded to the radical, the double bond of the polymerizable vinyl monomer is cut, and a radical is generated again. A polymerizable vinyl monomer couple | bonds with the said radical, and reaction is repeated similarly.

In the present invention, the PVA copolymer has a structure in which at least one of (ii) or (iii), which is a polymerizable vinyl monomer, is graft-polymerized to —OCOCH ₃ groups existing as side chains of polyvinyl alcohol. In this graft polymerization, polyvinyl alcohols may be bonded to each other through “a polymer in which at least one polymerizable vinyl monomer is polymerized or copolymerized”. That is, polyvinyl alcohol and polyvinyl alcohol may be crosslinked by “a polymer in which at least one polymerizable vinyl monomer is polymerized or copolymerized”.

For example, when (ii) acrylic acid and (iii) methyl methacrylate are used, the PVA copolymer is a copolymer of acrylic acid and methyl methacrylate bound to polyvinyl alcohol via the -OCOCH ₃ group of polyvinyl alcohol. Has the structure. Specific examples of such a PVA copolymer (polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer) include POVACOAT (registered trademark) Type F and Type MP (manufactured by Daido Kasei Kogyo Co., Ltd.), and preferably in the present invention. Can be used. In addition, the gelling agent is not particularly limited as long as the effect of the present invention is exhibited. For example, from carrageenan (iota carrageenan, copper carrageenan, lambda carrageenan), gellan gum (native gellan gum, deacylated gellan gum), locust bean gum, agar, gum arabic, pectin, guar gum, alginic acid, pullulan, konjac gum, tara gum and glucomannan At least one selected from the group consisting of: Among soft capsules, such as seamless capsules, those produced using a capsule preparation solution having a relatively low viscosity are preferably copper carrageenan, and more preferably only copper carrageenan as a gelling agent. It is particularly preferable to use iota carrageenan alone or a combination of iota carrageenan and copper carrageenan for those which are required to be produced using a preparation solution having a relatively high viscosity, such as a rotary soft capsule.

  When carrageenan is used as a gelling agent, generally a metal salt (for example, potassium salt, sodium salt, calcium salt, magnesium salt, etc.) is required as a gelling aid, but when PVA copolymer is included, gelation There is an advantage that a film having a strength capable of being encapsulated can be formed without using an auxiliary agent. Further, when a gelling aid is used, a stronger film can be created.

  A general soft capsule contains a large amount of a plasticizer. However, since a PVA copolymer itself has plasticity, a soft capsule, particularly a seamless capsule, does not necessarily require a plasticizer. Of course, a small amount of plasticizer can also be added. A rotary soft capsule may not use a plasticizer, but it is preferable to use a plasticizer in order to give the film sufficient flexibility.

  Examples of plasticizers include triacetin, sorbitol, glycerin, triethyl citrate, propylene glycol, maltitol, polyethylene glycol, lactitol, xylitol, erythritol, polyalkylene glycol, diethylene glycol, corn syrup, monosaccharide, disaccharide, oligosaccharide, etc. it can. A plasticizer can be used individually by 1 type or in combination of 2 or more types. Of these, triacetin, sorbitol, glycerin or a mixture thereof is particularly preferable.

  The soft capsule film of the present invention includes pigments, food colors, dyes and other colorants, light-shielding agents such as titanium dioxide, surfactants such as sodium lauryl sulfate and fatty acid esters, flavoring agents, flavoring agents, preservatives, and fragrances. Etc. can be contained as needed.

  Moreover, the obtained film | membrane for soft capsules can be preferably used for a soft capsule. Moreover, it can be preferably used as a soft capsule in which a soft capsule is filled.

  The soft capsules may contain fats, waxes, fatty acids, vitamins, pharmaceuticals, foods, wetting agents, moisturizers, antioxidants, preservatives, astringents, whitening agents, organic acids, perfumes. However, there is no particular limitation as long as it can be included in a soft capsule and does not invade the capsule film. In particular, since the soft capsule can prevent the capsule from being insolubilized by the substance containing an aldehyde group and can reduce the oxidation of the filler, the substance containing the aldehyde group can also be contained as a filler. . For example, a filling liquid in which a component containing an aldehyde group or a component that easily undergoes an oxidation reaction is dissolved in a solution such as fatty acid triglyceride or polyethylene glycol is particularly preferable from the viewpoint of taking advantage of the soft capsule of the present invention. Examples of the component containing such an aldehyde group include various reducing sugars (eg, glucose, fructose, lactose, arabinose, maltose, etc.), citral, vanillin, benzaldehyde, glutaraldehyde, o-bromobenzaldehyde, butanal, chlorobutanal, Furfural, hydroxymethylfurfural, perillaldehyde, acrolein, aldosterone and the like can be mentioned.

  The content of the PVA copolymer in the soft capsule film of the present invention is not particularly limited as long as the effect of the present invention is obtained, but is preferably about 40 to 90 parts by weight with respect to 100 parts by weight of the soft capsule film, and 42.5 to 87. About 5 parts by weight is more preferable, and about 45 to 85 parts by weight is more preferable.

  The content of the gelling agent in the soft capsule film of the present invention is not particularly limited as long as the effect of the present invention can be obtained, but is preferably about 1 to 45 parts by weight with respect to 100 parts by weight of the soft capsule film, About 40 parts by weight is more preferable, and about 7.5 to 37.5 parts by weight is more preferable. Further, the content weight ratio of the PVA copolymer and the gelling agent in the soft capsule film of the present invention (PVA copolymer / gelling agent) is not particularly limited as long as the effect of the present invention is obtained, but is preferably about 0.5 to 10, About 1-8 is more preferable, and about 1.5-7 is further more preferable.

  Further, when a plasticizer is contained in the soft capsule film, the content of the plasticizer is not limited as long as the effects of the present invention are not impaired, and for example, preferably 3 to 100 parts by weight of the soft capsule film. About 35 parts by weight, more preferably about 3.5 to 30 parts by weight can be used.

  About a manufacturing method, a manufacturing method can be suitably selected depending on whether the target capsule is a seamless capsule or a soft capsule such as a rotary type. Each can be easily produced by a known method or from a known method. A soft capsule preparation liquid containing the copolymer and the gelling agent can be prepared first, and a soft capsule can be produced using the preparation liquid. The preparation liquid can be prepared, for example, by adding a PVA copolymer, a gelling agent, and, if necessary, other components (for example, a plasticizer) to a solvent (for example, water) and mixing them. Since the content weight ratio of various components such as PVA copolymer and gelling agent in the soft capsule film is the same as the content weight ratio of those components included in the preparation liquid, the content of various components included in the preparation liquid is determined. By adjusting, the content weight ratio of various components in the soft capsule film can be adjusted. In addition, in order to prepare a soft capsule (film) by removing moisture from the preparation liquid, the content of each component in the soft capsule (film) is adjusted by adjusting each component contained in the preparation liquid, The content of each component in the film) can be adjusted.

  For example, a seamless capsule can be produced by a dropping method. Using a concentric double nozzle, the capsule coating liquid is dropped from the outer nozzle and the filling liquid is dropped from the inner nozzle into the liquid in which the coating liquid gels simultaneously as double droplets. It is a production method in which a capsule film is formed by gelation to produce a seamless capsule with no seams. Sometimes called a submerged curing method or an orifice method. In some cases, multiple nozzles of triple or more are used.

  The soft capsule of the present invention is suitably used in the fields of medicine and food, but is not limited to this, and can be used in the field of daily necessities such as quasi-drugs, cosmetics, and cleaning products as well. .

  Hereinafter, the present invention will be described more specifically, but the present invention is not limited to the following examples. In the following examples, POVACOAT (registered trademark) Type F (produced by Daido Kasei Kogyo Co., Ltd., partially saponified polyvinyl alcohol / methyl methacrylate / acrylic acid copolymer) was used as the PVA copolymer.

Preparation of insolubilization test PVA copolymer film (film piece (1)) 20 g of PVA copolymer, κ (copper) carrageenan (MV110, manufactured by Mitsubishi Chemical Foods) 3.0 g, iota carrageenan (MV210, Mitsubishi Chemical Foods, Inc.) (Manufactured) 8.0 g, glycerin 8.0 g, and sorbitol 4.0 g were dissolved in 157 g of water to prepare a capsule film solution. Using this capsule film solution and an applicator for film preparation, the solution was applied to a uniform thickness on a glass plate and allowed to stand at room temperature overnight to dry. The prepared film was cut into a 1 cm square to obtain a test film piece (1).

Preparation of gelatin film (film piece (A)) 43 g of gelatin and 19 g of concentrated glycerin were dissolved in 38 g of purified water to prepare a capsule film solution.
Using this capsule film solution and an applicator for film preparation, the solution was applied to a uniform thickness on a glass plate and allowed to stand at room temperature overnight to dry. The prepared film was cut into a 1 cm square to obtain a test film piece (A).

0.40 g of cinnamon oil was mixed with 9.60 g of insolubilized test solution MCT (medium chain fatty acid triglyceride) to prepare an insolubilized test solution.

<Film Insolubility Test Method>
The prepared test film piece was immersed in an insolubilized test solution and stored at 40 ° C. for 1 week. Thereafter, a film piece was taken out of the liquid, and the liquid adhering to the surface was wiped off with a Kim towel and subjected to a disintegration test. The disintegration test was conducted according to the Japanese Pharmacopoeia 16th Disintegration Test Method. Moreover, the data which performed the disintegration test without immersing each film piece in the insolubilization test liquid were also acquired. The results are shown in Table 1.

The color of the film taken out from the insolubilizing test solution was hardly changed in the film piece (1) and was only slightly yellowish, but it was clearly brown in the film piece (A). As is apparent from Table 1, the disintegration test results show that the film piece (1) averaged 6.28 minutes and the film piece completely disintegrated, but the film piece (A) only swelled, and after 120 minutes. Was confirmed not to collapse. From this, it was found that when a PVA copolymer was used as a base, the cross-linking reaction due to the aldehyde group of cinnamon oil did not occur like gelatin, and thus it was not insolubilized.

Oxygen permeability test The gas permeability test of the film was conducted according to JIS K7126-1: 2006 "Plastic film and sheet-Gas permeation test method-Part 1: Differential pressure method".

Preparation of PVA copolymer film (film piece (2)) 40 g of PVA copolymer, 12.0 g of k-carrageenan and 2.0 g of triacetin were dissolved in 346 g of water to prepare a capsule coating solution. A film (film piece (2)) was prepared using the capsule coating solution and the applicator for film preparation, and a gas permeation test was performed.

Preparation of PVA copolymer film (film piece (3)) 40 g of PVA copolymer, 12.0 g of k-carrageenan and 4.0 g of sorbitol were dissolved in 344 g of water to prepare a capsule coating solution. A film (film piece (3)) was prepared using this capsule coating solution and the applicator for film preparation, and a gas permeation test was performed.

Preparation of PVA copolymer film (film piece (4)) 40 g of PVA copolymer and 10.0 g of k-carrageenan were dissolved in 350 g of water to prepare a capsule coating solution. A film (film piece (4)) was prepared using this capsule coating solution and an applicator for film preparation, and a gas permeation test was performed.

Preparation of gelatin film (film piece (B)) 62.1 g of gelatin, 6.30 g of glycerin, and 9.3 g of sorbitol were dissolved in 222.3 g of water to prepare a capsule coating solution. A film (film piece (B)) was prepared using this capsule coating solution and an applicator for film preparation, and a gas permeation test was performed.

The results are shown in Table 2.

As is clear from Table 2, it was confirmed that the film piece (B) using gelatin had a larger oxygen permeability than the film pieces (2) to (4) using PVA copolymer, and it was easy to pass oxygen. From this, it was found that by using the PVA copolymer as a soft capsule base, an effect of suppressing the oxidation of the filling component can be obtained, and that the effect is not lost even when a plasticizer is added.

<Seamless capsule solution>
Preparation of PVA copolymer film (film piece (5)) 6.5 g of PVA copolymer and 2.5 g of κ-carrageenan were dissolved in 91 g of water to prepare a capsule coating solution. A film (film piece (5)) was prepared using the capsule coating solution and the applicator for film preparation.

  For the film pieces (2) to (5) and (B), the film preparation solution composition, the viscosity of the preparation solution at 66 ° C., the gelled temperature, and the hardness of the film piece at 25 ° C. or one at 70 ° C. Table 3 shows the hardness at 25 ° C. after storage overnight.

  The viscosity was measured according to the Japanese Pharmacopoeia 16th Viscosity Measurement Method, Method 2, Rotational Viscometer Method. A Brookfield viscometer LVDV-II + was used as the viscometer. The hardness of the film piece was determined by the feel obtained by actually touching with a finger. The same applies to the following.

In general, the viscosity of the coating liquid for preparing a seamless capsule is preferably 500 mPa · s or less, and more preferably 250 mPa · s or less. The viscosity of the film solution of the film pieces (2) to (5) is 500 mPa · s or less. The film liquid rapidly changes to a temperature lower than the gelling temperature, and has a sufficient hardness as a seamless capsule film. A gel was formed. In particular, it was found that the film pieces (2), (3) and (5) have a low viscosity and have a low gelation temperature, which is easy to handle and is preferable because it forms a gel with sufficient hardness. In addition, compared with the film piece (B) assuming a gelatin seamless capsule preparation liquid, the film liquids of the film pieces (2) to (5) show a difference in gelation temperature. This is the temperature at the time of seamless capsule preparation. This can be handled by changing the conditions. Only the film piece (B) was poorly stable at 70 ° C., and most of the gelling ability was lost after overnight storage. From this, it was also found that the coating solution using the PVA copolymer and the gelling agent is excellent in storage stability.

<Soft capsule film solution>
A coating solution for a soft capsule for rotary type preparation was prepared as follows.

Preparation of PVA Copolymer Film (Film Piece (6)) 10 g of PVA copolymer aqueous solution, 1.5 g of κ-carrageenan and 4.0 g of ι-carrageenan were dissolved in 84.5 g of water to prepare a capsule coating solution. A film (film piece (6)) was prepared using the capsule coating solution and the applicator for film preparation.

Preparation of PVA copolymer film (film piece (7)) 12.5 g of PVA copolymer, 1.25 g of κ-carrageenan, 3.33 g of ι-carrageenan, 3.33 g of glycerin and 1.67 g of sorbitol were dissolved in 77.92 g of water, A capsule film solution was prepared. A film (film piece (7)) was prepared using this capsule film solution and the applicator for film preparation.

Preparation of PVA copolymer film (film piece (8)) 15 g of PVA copolymer, 1.5 g of κ-carrageenan, 4.0 g of ι-carrageenan, 4.0 g of glycerin and 2.0 g of sorbitol were dissolved in 73.5 g of water to form a capsule film. A liquid was prepared. A film (film piece (8)) was prepared using the capsule coating solution and the applicator for film preparation.

Preparation of PVA copolymer film (film piece (9)) 20 g of PVA copolymer, 3.0 g of κ-carrageenan, and 8.8 g of glycerin were dissolved in 68.2 g of water to prepare a capsule coating solution. A film (film piece (9)) was prepared using this capsule coating solution and the applicator for film preparation.

Preparation of PVA copolymer film (film piece (10)) 22 g of PVA copolymer, 1.1 g of κ-carrageenan and 2.93 g of ι-carrageenan were dissolved in 73.97 g of water to prepare a capsule coating solution. A film (film piece (10)) was prepared using this capsule film solution and the applicator for film preparation.

For the film pieces (6) to (10) and (1) and (B), the film preparation liquid composition, the viscosity of the preparation liquid at 66 ° C., the gelled temperature, and the hardness of the film piece at 25 ° C. or 70 Table 4 shows the hardness at 25 ° C. after storage at 0 ° C. overnight.

In general, the viscosity of the coating liquid for preparing soft capsules is preferably about 2000 to 25000 mPa · s. If the viscosity is higher than this, defoaming becomes difficult. The coating liquids of the film pieces (6) to (10) and (1) had an appropriate viscosity and formed an elastic gel having sufficient hardness as a soft capsule film. In particular, it was found that the film solutions of film pieces (6), (7) and (1) are preferable because they have a low viscosity at the time of dissolution and form a gel having sufficient hardness as a soft capsule film. The film solution for the film piece (B) was assumed to be a gelatin soft capsule preparation solution, and only this solution had poor storage stability at 70 ° C.

  From the above results, it was found that by using PVA copolymer as a capsule base, discoloration or insolubilization due to aldehyde groups does not occur, oxidation can be prevented, and a capsule film having the same hardness as gelatin can be produced. .

Claims (6)

(I) polyvinyl alcohol,
(Ii) at least one unsaturated carboxylic acid selected from the group consisting of acrylic acid, methacrylic acid, fumaric acid, and maleic acid, and (iii) formula [I]
^{_{H 2 C = C (R 1}} ) -COOR 2 [I]
(Wherein R ¹ represents a hydrogen atom or a methyl group, and R ² represents an alkyl group having 1 to 4 carbon atoms). At least one kind selected from the group consisting of compounds represented by A polyvinyl alcohol copolymer containing a saturated carboxylic acid ester as a structural unit, and
The gelling agent is contained in an amount of 7.5 to 37.5 parts by weight with respect to 100 parts by weight of the soft capsule film.
Seamless soft capsule film. (Ii) The seamless soft capsule film according to claim 1, wherein the unsaturated carboxylic acid is acrylic acid. (Iii) The seamless soft capsule film according to claim 1 or 2, wherein the unsaturated carboxylic acid ester is methyl methacrylate. The seamless soft capsule film according to any one of claims 1 to 3, wherein the gelling agent is carrageenan. The seamless soft capsule film according to any one of claims 1 to 4, wherein the polyvinyl alcohol copolymer is contained in an amount of 40 to 90 parts by weight with respect to 100 parts by weight of the soft capsule film. The seamless soft capsule which consists of a soft capsule membrane | film | coat in any one of Claims 1-5.