WO2009125483A1 - Hard capsule - Google Patents

Abstract

A hard capsule made by using a polyvinyl alcohol copolymer as the film component, which is improved in the breaking extension of capsule film with the maximum stress of the film kept at a prescribed level and is thereby enhanced in fracture resistance and impact resistance. The hard capsule is characterized by being made of a capsule film prepared from a combination of a polyvinyl alcohol copolymer with polyvinyl alcohol.

Description

Hard capsule

This invention relates to the improvement of the hard capsule which uses a polyvinyl alcohol copolymer as a capsule film component. More specifically, the present invention relates to a hard capsule having improved crack resistance and impact resistance by improving the elongation at break of the capsule film (film) of the hard capsule, and a method for preparing the same. Furthermore, the present invention relates to a hard capsule obtained by filling the hard capsule with contents such as pharmaceuticals and foods, and a method for preparing the same.

There is a hard capsule as one of solid preparations such as pharmaceuticals and foods. This is usually filled with a powder, granule, or liquid (oil) pharmaceutical ingredient or food ingredient in a cap-like container, which is usually formed of a gelatin film, and open at one end. And completed. Such hard gelatin capsules are widely used because they are easy to formulate and easy to take due to the taste-masking and / or taste-masking action of pharmaceutical ingredients and food ingredients.

However, the gelatin film (coating) used in the hard gelatin capsule has a drawback that its mechanical strength is extremely lowered when the moisture contained therein is reduced. Specifically, hard gelatin capsules usually contain about 13 to 15% of moisture in the film, but if this is less than 10%, the film becomes less flexible and extremely brittle. For this reason, when filled with contents that require a low moisture environment as storage conditions, such as water-absorbing or water-reactive drugs and foods, the capsule film (film) will be cracked, cracked or chipped. May cause damage. As a measure for solving this problem, a capsule (Patent Document 1) using a water-soluble cellulose derivative, particularly hydroxypropylmethylcellulose (hereinafter referred to as “HPMC”) as a base material has been proposed. However, when HPMC is filled with low molecular weight polyethylene glycol having an average molecular weight of 200 to 600 (hereinafter referred to as “low molecular weight PEG”), it is observed that the low molecular weight PEG leaks through the capsule film (film). It is pointed out (see Patent Document 2), and low molecular weight PEG and compositions containing the same cannot be applied as contents. Moreover, since the capsule film using HPMC is easy to permeate | transmit water vapor | steam and oxygen, it has also been pointed out that a content deteriorates (refer patent document 2).

Therefore, good film strength can be reliably maintained even under low moisture, and low molecular weight PEG and its fats and oils such as glycerin fatty acid ester and medium chain fatty acid triglyceride can be filled without inconvenience. Polyvinyl alcohol and copolymers thereof have been proposed as hard capsules that can be suitably applied to filling water-reactive substances and oxidizable substances without permeation of oxygen (see Patent Documents 2 to 4, etc.). ).
JP-A-3-279325 JP 2001-170137 A US Patent Gazette (US7045184B2) International Publication (WO02 / 017848)

In the present invention, for a hard capsule having such a polyvinyl alcohol copolymer as a film component, the crack elongation and the impact resistance are enhanced by improving the elongation at break while maintaining a predetermined maximum stress of the capsule film (film). It is an object to provide a hard capsule.

The inventors of the present invention have been diligently studying day and night to achieve the above object, and as a film component of the capsule, polyvinyl alcohol copolymer (hereinafter referred to as “PVA copolymer”) and polyvinyl alcohol (hereinafter referred to as “ PVA ") and a combination of an organic acid such as acetic acid and tartaric acid or a salt thereof, while maintaining the predetermined maximum stress required for hard capsules, the capsule film breaks. It was found that the elongation was improved, and as a result, it was confirmed that it was possible to prepare a hard capsule that was more resistant to breakage and resistant to impact.

The present invention has been completed based on such knowledge and includes the following aspects.

(I) Hard capsule and manufacturing method thereof (I-1) A hard capsule comprising a film containing a PVA copolymer and PVA.

(I-2) The hard capsule according to (I-1), wherein the weight ratio of the PVA copolymer and PVA contained in the film is 100: 1 to 1: 100, preferably 99: 1 to 1:99 .

(I-3) The hard capsule according to (I-1), wherein the weight ratio of the PVA copolymer and PVA contained in the film is 90:10 to 1: 100, preferably 90:10 to 1:99 .

(I-4) The hard capsule according to (I-1), wherein the weight ratio of the PVA copolymer and PVA contained in the film is 50:50 to 1: 100, preferably 50:50 to 1:99 .

(I-5) The hard capsule according to any one of (I-1) to (I-4), which further contains at least one selected from the group consisting of organic acids and salts thereof as a component of the capsule film .

(I-6) The hard capsule according to (I-5), wherein the organic acid is acetic acid or tartaric acid.

(I-7) The hard capsule described in (I-5) or (I-6), wherein the organic acid salt is an alkali metal salt of an organic acid.

(I-8) The hard capsule according to any one of (I-1) to (I-8), which further contains a gelling agent in addition to the PVA copolymer and PVA.

(I-9) The hard capsule described in (I-8), which further contains a gelling aid.

(I-10) The hard capsule according to any one of (I-1) to (I-9), wherein the film has a moisture content of 3 to 5% and an elongation at break of 5 to 20 mm.

(I-11) Capsule molding pin is dipped in a capsule preparation liquid containing PVA copolymer and PVA, and the capsule preparation liquid attached to the molding pin is gelled and dried, and then molded. The method for producing a hard capsule according to any one of (I-1) to (I-10), wherein the hard capsule is obtained by desorbing and collecting from a pin.

(II) Hard capsule (II-1) A hard capsule comprising the hard capsule described in any one of (I-1) to (I-10) filled with polyethylene glycol or a composition containing polyethylene glycol .

(II-2) The hard capsule according to (II-1), wherein the polyethylene glycol is a low molecular weight polyethylene glycol having an average molecular weight of 200 to 600.

(II-3) The fitting part of the body part and the cap part is sealed with a band seal containing PVA copolymer, PVA or a mixture thereof, (II-1) or (II -2) Hard capsule described in the above.

(II-4) The hard capsule described in (II-3), wherein the band seal further contains sorbitol.

(II-5) After filling the hard capsule according to any one of (I-1) to (I-10), the cap part and the body part are fitted, and the formed fitting part is A method for preparing a hard capsule, which comprises applying a band seal preparation solution containing PVA copolymer, PVA or a mixture thereof, drying and sealing.

(II-6) The preparation method according to (II-5), wherein the band seal preparation solution further contains sorbitol.

(II-7) The preparation method according to (II-5) or (II-6), wherein the content is polyethylene glycol or a composition containing polyethylene glycol.

(III) Capsule film break elongation improvement method (III-1) Capsule film break elongation improvement method containing a PVA copolymer, characterized in that a PVA copolymer and PVA are used in combination as film components. how to.

(III-2) The weight ratio of the PVA copolymer to PVA blended in the capsule film is 100: 1 to 1: 100, preferably 99: 1 to 1:99, (III-1) A method for improving the breaking elongation of a capsule film to be described.

(III-3) The weight ratio of the PVA copolymer to PVA blended in the capsule film is 90:10 to 1: 100, preferably 90:10 to 1:99. A method for improving the breaking elongation of a capsule film to be described.

(III-4) The weight ratio of the PVA copolymer to PVA blended in the capsule film is 50:50 to 1: 100, preferably 50:50 to 1:99. A method for improving the breaking elongation of a capsule film to be described.

(III-5) The film component further includes at least one selected from the group consisting of an organic acid and a salt thereof, and is described in any one of (III-1) to (III-4) Method for improving elongation at break of capsule film.

(III-6) The hard capsule according to (III-5), wherein the organic acid is acetic acid or tartaric acid.

(III-7) The hard capsule described in (III-5) or (III-6), wherein the salt of the organic acid is an alkali metal salt of an organic acid.

The hard capsule of the present invention has almost the same maximum as a capsule film (coating) prepared by using a PVA copolymer without using PVA by using a PVA copolymer and PVA together as a film component. Although it is provided with stress, the elongation at break is improved, and as a result, it is a hard capsule in which cracks and cracks are less likely to occur even under low moisture (improved crack resistance). Improved cracking resistance improves (1) the production of defective products such as cracks and chips during capsule production, and improves production efficiency. (2) Physical properties such as shock and vibration during transport of capsules. There are advantages in that capsule breakage due to mechanical load is reduced, and (3) capsule breakage due to physical load caused by formulation machines such as filling machines and visual inspection machines is reduced. In addition, capsules filled with the contents also reduce (i) capsule breakage due to physical loads such as impact and vibration during transportation. (Ii) Extrude PTP-packed capsules with fingers. There is an advantage that the breakage of the capsule due to the physical load at the time of taking out is reduced.

In addition, the hard capsule of the present invention is a low-molecular-weight PEG, a glycerin fatty acid ester, a medium-chain fatty acid triglyceride, and the like, similar to a hard capsule prepared using a conventional PVA or PVA copolymer (see Patent Documents 2 to 4). Oils and fats can be filled without any inconvenience, and there is no permeation of water vapor or oxygen, and the water-reactive substance can be suitably applied to the filling of the oxidizable substance.

I. Hard capsule and method for preparing the same The hard capsule of the present invention is characterized in that polyvinyl alcohol (PVA) and polyvinyl alcohol copolymer (PVA copolymer) are used in combination as components for forming a hard capsule film (capsule film). To do.

PVA is a polymer obtained by saponifying polyvinyl acetate. Usually, the saponification degree is 97 mol% or more and a complete saponification product represented by the following formula (1), the saponification degree is 78 to 96 mol%, and the following formula: There is a partially saponified product represented by (2). In the present invention, any of the above-mentioned completely saponified product and partially saponified product can be used, and is not particularly limited. However, a partially saponified product having a saponification degree of 78 to 96 mol%, particularly about 86 to 90 mol% is preferably used. It is done.

The degree of polymerization (n) of PVA is not particularly limited as long as it is within a range where film forming ability can be exhibited, but it is usually preferably about 400 to 3300, particularly about 400 to 2000. The weight average molecular weight of the PVA is calculated from the degree of polymerization and the degree of saponification to be about 18000 to about 175000, but is not particularly limited thereto.

Examples of the PVA copolymer include a PVA copolymer obtained by copolymerizing a polymerizable vinyl monomer with the aforementioned PVA or a derivative thereof. Here, examples of PVA derivatives include known PVA derivatives such as amine-modified PVA, ethylene-modified PVA, and PVA having a thiol group at the terminal (terminal thiol-modified PVA). Terminal thiol-modified PVA is preferred.

Examples of the polymerizable vinyl monomer include (1) acrylic acid, methacrylic acid, fumaric acid, maleic acid, itaconic acid; (2) sodium salt, potassium salt, ammonium salt or alkylamine salt of the compound described in (1) above. (3) methyl methacrylate, methyl acrylate, ethyl methacrylate, ethyl acrylate, butyl methacrylate, butyl acrylate, isobutyl methacrylate, isobutyl acrylate, cyclohexyl methacrylate, cyclohexyl acrylate, 2-ethylhexyl methacrylate, 2-ethylhexyl acrylate, acrylonitrile, acrylamide, Dimethylacrylamide, styrene, vinyl acetate, hydroxyethyl methacrylate, hydroxyethyl acrylate, polyethylene glycol and methacrylic acid Ester, esters of polyethylene glycol and acrylic acid, esters of polypropylene glycol and methacrylic acid, esters of polypropylene glycol and acrylic acid, N- vinyl pyrrolidone or acryloyl morpholine; (4) a compound represented by the following formula:

Can be mentioned. The polymerizable vinyl monomer is preferably a combination of at least one compound selected from the group consisting of (1) and (2) and at least one compound selected from the group consisting of (3). used. Particularly preferred is a combination use of acrylic acid or methacrylic acid and methyl methacrylate.

The PVA copolymer is preferably a polymer copolymer obtained by copolymerizing acrylic acid and methyl methacrylate with the above-described partially saponified PVA as a skeleton. Specific examples of such polymer copolymers include POVACOAT (POVACOAT (registered trademark) Type F, Type R, and Type L (manufactured by Daido Kasei Co., Ltd.)) used in the experimental examples and examples described below. it can.

The blending ratio of the PVA copolymer and PVA in the hard capsule of the present invention is usually PVA copolymer: PVA = 100: 1 to 1: 100 (weight ratio, hereinafter the same). The ratio is preferably 99: 1 to 1:99, more preferably 90:10 to 1:99, and still more preferably 80:20 to 1:99. Further, as shown in Experimental Examples 2 and 3, when the ratio of the PVA copolymer to PVA is 50:50 to 1: 100, preferably 50:50 to 1:99, the viscosity of the capsule preparation liquid (52 ° C. ) Is about 1500 Pa · s or less, and the ratio of PVA copolymer to PVA is 40:60 to 1: 100, preferably 40:60 to 1:99, the viscosity of the capsule preparation liquid (52 ° C.) Is reduced to about 1350 Pa · s or less, and accordingly, the production yield (%) of the hard capsule is also improved to 90% or more.

The ratio of the PVA copolymer and PVA (total amount) contained in the hard capsule (capsule film) used in the present invention is not particularly limited, but when the weight of the capsule film excluding moisture is 100% by weight, The ratio can be 70 to 99.9% by weight, preferably 80 to 99.7% by weight, and more preferably 90 to 99.5% by weight.

In the hard capsule (capsule film) of the present invention, in addition to the PVA copolymer and PVA, at least one selected from the group consisting of organic acids and salts thereof may be blended. Examples of the organic acid salt include, but are not limited to, edible organic acids such as acetic acid, tartaric acid, lactic acid, malic acid, succinic acid and succinic acid, or alkali metal salts thereof, particularly sodium salt and potassium salt. . Acetic acid and tartaric acid or sodium and potassium salts thereof are preferred, and sodium acetate and sodium tartrate are more preferred. These may be used alone or in any combination of two or more.

These organic acids and / or salts thereof are not limited, but usually, the organic acid and / or PVA copolymer and PVA contained in the hard capsule and the organic acid and / or salt thereof in a total amount of 100% by weight. The salt (total amount) is used in such a proportion that it is contained in an amount of 0.1 to 19% by weight, preferably 0.15 to 8% by weight in terms of the proportion of the organic acid. The proportion is more preferably 0.2 to 3% by weight, particularly preferably 0.5 to 1% by weight.

In addition to the above components, a gelling agent can also be blended in the hard capsule (capsule film) used in the present invention. Examples of the gelling agent used here include carrageenan, tamarind seed polysaccharide, pectin, xanthan gum, locust bean gum, curdlan, gelatin, fur celerane, agar, and gellan gum. These may be used alone or in any combination of two or more.

Among the above gelling agents, carrageenan is an optimal gelling agent because of its high gel strength and excellent gelling properties when used in a small amount in the presence of specific ions. In general, three types of carrageenan are known: kappa-carrageenan, iota-carrageenan, and lambda-carrageenan. In the present invention, kappa and iota-carrageenan having gelling ability can be preferably used. Pectin can be classified into LM pectin and HM pectin depending on the degree of esterification, and gellan gum can be classified into acylated gellan gum (native gellan gum) and deacylated gellan gum according to the presence or absence of acylation. Can also be used without distinction.

In the hard capsule (capsule film) of the present invention, a gelling aid can be used depending on the type of gelling agent used. As a gelling aid that can be used in combination when carrageenan is used as a gelling agent, kappa-carrageenan can give one or more of potassium ion, ammonium ion and calcium ion in water. There may be mentioned compounds such as potassium chloride, potassium phosphate, ammonium chloride, ammonium acetate, calcium chloride. As for iota-carrageenan, calcium ion can be given in water, for example, calcium chloride. Moreover, as a gelling adjuvant that can be used in combination when gellan gum is used as a gelling agent, a compound that can give one or more of sodium ions, potassium ions, calcium ions, and magnesium ions in water. Examples include sodium chloride, potassium chloride, calcium chloride, and magnesium sulfate.

As the gelling agent used in combination, carrageenan, tamarind seed polysaccharide, xanthan gum, locust bean gum, and gellan gum are preferable, and carrageenan is particularly preferable. Moreover, potassium chloride can be illustrated suitably as a gelatinization adjuvant which uses this together.

When the hard capsule (capsule film) used in the present invention contains the gelling agent, the content is 0.05 to 10% by weight when the weight of the capsule film excluding moisture is 100% by weight. Preferably, 0.1 to 5% by weight, more preferably 0.2 to 2.5% by weight, and still more preferably 0.3 to 2% by weight. Further, when a gelling aid such as potassium chloride is included, the content thereof is in the range of 2.2% by weight or less, preferably 0.1 to 1.5% by weight, more preferably 0.2 to 1% by weight, Preferably, 0.3 to 0.8% by weight can be mentioned.

In addition to the above components (PVA copolymer and polyvinyl alcohol, if necessary, organic acid and / or salt thereof, and gelling agent or gelling aid), the hard capsule (capsule film) needs Depending on the case, a plasticizer, a metal sequestering agent, an opacifying agent, a coloring agent or a fragrance can be blended.

Here, the plasticizer is not particularly limited as long as it can be used for pharmaceuticals or foods. For example, dioctyl adipate, polyester adipate, epoxidized soybean oil, epoxyhexahydrophthalic acid diester, kaolin, triethyl citrate, Glycerin, glycerin fatty acid ester, sesame oil, dimethylpolysiloxane / silicon dioxide mixture, D-sorbitol, medium chain fatty acid triglyceride, corn starch-derived sugar alcohol solution, triacetin, concentrated glycerin, castor oil, phytosterol, diethyl phthalate, dioctyl phthalate, Dibutyl phthalate, butyl phthalyl butyl glycolate, propylene glycol, polyoxyethylene (105) polyoxypropylene (5) glycol, polysorbate 80, polyethylene Recall 1500, polyethylene glycol 400, polyethylene glycol 4000, polyethylene glycol 600, polyethylene glycol 6000, isopropyl myristate, cottonseed oil, soybean oil mixture, glyceryl monostearate, and the like linoleic acid isopropyl. When a plasticizer is used, the content in the hard capsule (capsule film) used in the present invention is usually 15% by weight or less when the weight of the capsule film excluding moisture is 100% by weight. Can do. Preferably it is 13 weight% or less, More preferably, it is 11 weight% or less, More preferably, it is the range of 8 weight% or less.

As a sequestering agent, ethylenediaminetetraacetic acid, acetic acid, boric acid, citric acid, gluconic acid, lactic acid, phosphoric acid, tartaric acid, or salts thereof, metaphosphate, dihydroxyethylglycine, lecithin, β-cyclodextrin, or these Combinations can be mentioned.

Further, the opacifying agent and the fragrance are not particularly limited as long as they can be used for pharmaceuticals or foods.

The hard capsule used in the present invention can be produced by using a conventional dipping method. Specifically, an aqueous solution containing the above-described components (hereinafter referred to as “capsule preparation solution”) is used as the dipping solution. The capsule molding pin can be immersed in this, and then pulled up to cool and gel the film made of the capsule preparation liquid formed on the outer surface of the capsule molding pin, and then dried.

The concentration of each component contained in the capsule preparation liquid can be appropriately adjusted according to the ratio of each component in the capsule film described above. Specifically, the total amount of the PVA copolymer and PVA can be 5 to 30% by weight, preferably 10 to 28% by weight, more preferably 16 to 24% by weight. The organic acid and / or salt thereof is 0.02 to 3.8% by weight, preferably 0.04 to 1.6% by weight, more preferably 0.04 to 0% in terms of the ratio of the organic acid. 2% by weight can be mentioned.

When a gelling agent is used, the concentration in the capsule preparation liquid is 0.01 to 2% by weight, preferably 0.02 to 1% by weight, more preferably 0.03 to 0.5% by weight. it can. When a gelling aid is used, the concentration in the capsule preparation liquid is 0.01 to 0.5% by weight, preferably 0.02 to 0.3% by weight, more preferably 0.03 to 0.3%. 2% by weight can be mentioned.

The amount of the solvent (water) contained in the capsule preparation liquid is not limited, but is a temperature (immersion liquid temperature) condition (30 to 80 ° C., preferably 40 to 60 ° C.) employed when the capsule molding pin is immersed. ), The ratio of the viscosity of the capsule preparation liquid is 100 to 20000 mPa · s, preferably 300 to 10000 mPa · s. Preferably, the viscosity of the capsule preparation liquid at a temperature condition of 52 ° C. is 300 to 3600 mPa · s, more preferably 500 to 3100 mPa · s, still more preferably 500 to 2600 mPa · s, and still more preferably 500 to 2000 mPa · s. The ratio is particularly preferably 500 to 1500 mPa · s.

The viscosity specified in the present invention is a B-type rotational viscometer. When the viscosity is less than 500 mPa · s, the rotor number is 2, and when the viscosity is 500 mPa · s or more and less than 2000 mPa · s, the rotor number is 3 and the viscosity is 2000 mPa · s or more. In the case of (4), the viscosity is measured when the rotor number 4 is used and measured at a predetermined temperature under the conditions of a rotation speed of 60 rpm and a measurement time of 1 minute (hereinafter the same).

Usually, the solvent content is 60 to 90% by weight, preferably 70 to 85% by weight.

In the preparation of the capsule preparation liquid (immersion liquid), the dissolution order of the above-mentioned components is not limited, and the gelling agent and the gelling auxiliary agent may be prepared by dissolving the essential components (PVA and PVA copolymer) first. Or may be dissolved simultaneously. Moreover, although it is preferable from the solubility of each component that the melting temperature is usually 60 ° C. or higher, it is not particularly limited. The capsule preparation liquid is preferably subjected to capsule molding by the dipping method in a state where fine bubbles are removed by vacuum degassing, ultrasonic defoaming or standing, and the temperature is kept at 50 to 60 ° C.

The hard capsule of the present invention was soaked in the capsule preparation liquid (immersion liquid) thus prepared, and then pulled up to gel the solution adhering to the capsule molding pin, and then gelled. The film is produced by drying at a temperature of about 20 to 80 ° C. Specifically, the hard capsule used in the present invention can be produced through the following steps.

(1) Capsule molding pin in a capsule preparation liquid (immersion liquid) containing a PVA copolymer and PVA (or an organic acid and / or a salt thereof, or a gelling agent or a gelling aid, if necessary) The step of immersing (immersion step),
(2) A step of pulling up the capsule molding pin from the capsule preparation solution (immersion solution) to gel the capsule preparation solution adhering to the outer surface of the pin (gelation step),
(3) A step of drying the gelled capsule film (gelated film) formed on the outer surface of the capsule molding pin (drying step),
(4) A step of detaching the dried capsule film (film) from the capsule molding pin (detachment step).

In addition, said (2) gelatinization process can be performed by heating or cooling according to the characteristic of the gelatinizer to be used. For example, when a solution containing carrageenan as a gelling agent is used as a capsule preparation liquid (immersion liquid), the temperature around the capsule manufacturing machine is adjusted by utilizing that the solution gels at a temperature of 50 ° C. or less. Usually, the gelation step (2) is carried out by allowing the capsule preparation solution adhering to the outer surface of the capsule molding pin to stand to cool at 35 ° C. or lower, preferably 30 ° C. or lower, preferably at room temperature. Yes (cold gel method). Specifically, in the dipping step (1), the capsule preparation solution (immersion liquid) adjusted to a constant temperature of 35 to 60 ° C., preferably 40 to 60 ° C., is preferably 10 to 30 ° C., preferably according to the liquid temperature. Is immersed in a capsule molding pin adjusted to 13 to 28 ° C., more preferably 15 to 25 ° C., and then in the gelation step (2), the capsule molding pin is pulled up from the capsule preparation solution (immersion liquid) The capsule preparation solution attached to the outer surface of the pin is gelled.

The drying step (3) can be performed at a temperature of about 20 to 80 ° C. Preferably, it is performed by blowing air at 60 ° C. The detachment step (4) is performed by extracting the dry capsule film formed on the surface of the capsule molding pin from the capsule molding pin.

The capsule film thus prepared can be provided as a hard capsule in a state where the body part and the cap part are fitted together or not fitted after being cut and adjusted to a predetermined length. In addition, by applying edible oil or the like as a release agent to the molding pin in advance, the release properties of the obtained capsule (body part and cap part) are improved, and the obtained hard capsule can be easily peeled and collected. can do.

The hard capsule of the present invention thus obtained is characterized by having a large elongation at break as compared with a hard capsule prepared without using PVA and a PVA copolymer in combination. As a hard capsule, a breaking elongation in the range of 5 to 20 mm is usually required, and the breaking elongation is preferably as large as possible with a maximum stress in the range of 70 to 130 N. The thickness is preferably 8 to 20 mm, more preferably 8.5 to 20 mm, still more preferably 9 to 20 mm, and still more preferably 9.5 to 20 mm. The maximum stress is not particularly limited as long as it is within the above range, but is preferably 75 to 130N, more preferably 80 to 130N.

In the present invention, the maximum stress (N) and elongation at break (mm) were measured using an autograph AGS-J (manufactured by Shimadzu Corporation), a tensile speed of 150 mm / min, a distance between chucks of 20 mm, a tensile distance of 20 mm, 23 ° C. It can be determined by a tensile test performed in an environment with a relative humidity of 40%. The maximum stress means the maximum value of the stress measured by such a method, and the elongation at break means the tensile stroke at 1/3 of the maximum stress (see FIG. 1).

Regarding the maximum stress and elongation at break of the hard capsule (capsule film) defined in the present invention, the target capsule (capsule film) was dried at 60 ° C. for 2 hours and then stored at 23 ° C. in an environment of 40% relative humidity for 1 week. Later, a tensile test was performed using the above conditions (Autograph AGS-J (manufactured by Shimadzu Corporation) under the environment of a tensile speed of 150 mm / min, a distance between chucks of 20 mm, a tensile distance of 20 mm, 23 ° C., and a relative humidity of 40%). Is the value obtained.

II. Hard capsule and its preparation method The body part and the cap part of the hard capsule thus prepared are filled with the above-mentioned contents, and then the body part is covered with the cap part to fit them together. Can be provided as a hard capsule.

The hard capsule of the present invention includes those obtained by attaching a band seal to the fitting part of the body part and the cap part of the hard capsule prepared above. Such a hard capsule, after fitting and joining the body part and the cap part, around the end edge part of the cap part, on the surface of the body part and the surface of the cap part with a constant width so as to straddle it, It can be prepared by applying the band seal preparation solution once to a plurality of times, preferably once or twice in the circumferential direction and sealing the fitting portion.

When fitting both the body part and the cap part of the hard capsule, the fitting width where the outer circumference of the body part and the inner circumference of the cap part overlap is the distance in the axial direction of the capsule. About 4 to 6 mm is generally preferred for 4.5-6.5 mm, No. 4 capsules. The sealing width is generally about 1.5 to 3 mm for the No. 3 capsule and about 1.5 to 2.8 mm for the No. 4 capsule.

The band seal formation of the hard capsule of the present invention is not limited as long as it has at least band sealability, but preferably PVA copolymer, PVA, or PVA copolymer having the same composition as the hard capsule described above. A band seal preparation solution containing a polymer and PVA (also used in combination with an organic acid and / or a salt thereof, or a gelling agent or a gelling aid as required) is used.

In addition to the PVA copolymer, PVA or a mixture thereof, sorbitol can also be blended in the band seal preparation liquid as a plasticizer. By blending such a plasticizer (sorbitol), an effect of increasing flexibility can be obtained. The blending ratio of sorbitol in the band seal is not particularly limited as long as it does not impair the band sealability of the PVA or / PVA copolymer, but in terms of the above effects, the band seal (in terms of dry weight: 100% by weight) ) In the range of 0.01 to 70% by weight, preferably 0.01 to 35% by weight, more preferably 0.01 to 30% by weight, and particularly preferably 1 to 30% by weight.

In the present invention, “band sealability” means that a film for sealing (sealing) the body part and the cap part of a hard capsule can be formed (film forming ability), and the body is sealed by sealing with this film. It means the property of the band seal that can prevent the contents from leaking out from the fitting portion between the cap portion and the cap portion (leakage prevention capability).

The presence or absence of the “band sealability” is determined by sealing the cap part of the capsule filled with polyethylene glycol (PEG400) with an average molecular weight of 400 (PEG400) and the fitting part of the body part using the target band seal preparation solution (band seal) When this is left on a white copy paper for 12 hours in an environment of 25 ° C. and a relative humidity of 40%, it can be evaluated by whether or not the contents leak from the band seal portion.

In addition, the presence or absence of leakage of the contents can be determined from the following criteria as shown in Experimental Example 5:
(a) Whether the contents (PEG400) are attached to the surface of the white copy paper that has been in contact with the sealed hard capsule after standing for 12 hours.
(b) Whether the contents (PEG400) adhere to the white copy paper surface when the sealed hard capsule is rolled on the white copy paper after being left for 12 hours.

In this case, in both cases (a) and (b), the case where there is no adhesion of the content to the white copy paper, that is, no leakage of the content is recognized, is `` with band sealability '', (a) In any of the cases (b), it can be determined that there is no band-sealability when content leakage is observed.

In addition, as a capsule used for the said band seal property evaluation test, the hard capsule which uses the PVA copolymer as a base material described in Experimental Example 5 mentioned later, or the hard capsule which uses PVA as a base material can be mentioned. The amount of PEG 400 filled therein may be 600 μL when the hard capsule is a size 0 capsule defined by the Japanese Pharmacopoeia, and 470 μL when the hard capsule is a size 1 capsule.

In addition to the above components, the band seal is optionally colored (for example, titanium oxide, bengara, tar colorant, etc.), opaque, as long as the effect of the present invention, ie, the band sealability is not hindered. Additives usually used in the preparation of hard capsules such as agents or fragrances can also be blended. The blending ratio of these additives to the band seal can be appropriately selected from the range of usually 0.1 to 7% by weight in consideration of the band sealing property.

When forming a band seal in a hard capsule, a band seal preparation solution is usually used. The band seal preparation solution is prepared by dissolving the above band seal component in water, a hydrophilic solvent, or a mixture of water and a hydrophilic solvent at room temperature or under heating (about 30 to 60 ° C.). can do. Preferably, a mixed solution of water and a hydrophilic solvent is used. Here, examples of the hydrophilic solvent include organic solvents compatible with water, and specific examples include lower alcohols such as ethanol and isopropanol. Ethanol is preferable. When a mixed liquid of water and a hydrophilic solvent is used for preparing the band seal preparation liquid, the ratio of the hydrophilic solvent in 100% by weight of the mixed liquid is 5 to 80% by weight, preferably 8 to 65% by weight, more preferably May be 10 to 50% by weight.

The band seal preparation liquid is adjusted so that the final viscosity of the preparation liquid is usually in the range of 100 to 5000 mPa · s under the condition of 23 ° C. The viscosity is a B-type rotational viscometer. When the viscosity is less than 500 mPa · s, the rotor number is 2, when the viscosity is 500 mPa · s or more and less than 2000 mPa · s, the rotor number is 3, and when the viscosity is 2000 mPa · s or more, the rotor is The number 4 is used to mean the viscosity when measured under the conditions of 23 ° C., rotation speed 60 rpm, and measurement time 1 minute.

According to the band seal preparation liquid in the range where the viscosity is applied, a strong band seal with a large sealing force (sealing force) can be formed in the fitting part of the hard capsule body and cap part, and at the time of manufacture There is no stringing and the handling in production is easy. If the viscosity of the band seal preparation liquid is significantly lower than the above range (100 to 5000 mPa · s, 23 ° C.), the band seal preparation liquid may be applied without dripping onto the fitting surface of the hard capsule. It may be difficult to form a band seal excellent in sealing power. On the other hand, when the viscosity of the band seal preparation liquid is significantly higher than the above range (100 to 5000 mPa · s, 23 ° C.), the viscosity may be too high to form a band seal with a machine. The preferred viscosity of the band seal preparation liquid is 125 to 4700 mPa · s, more preferably 150 to 4500 mPa · s, at 23 ° C.

The viscosity of the band seal preparation liquid can be easily adjusted by adjusting the concentration of the PVA copolymer, PVA or a mixture thereof mixed in the band seal preparation liquid, or the mixing ratio of both. Specifically, the viscosity tends to decrease as the proportion of PVA used in combination with the PVA copolymer is increased. The concentration of PVA in the band seal preparation liquid is usually 4 to 31% by weight, preferably 5 to 30% by weight, more preferably 6%, although it depends on the type of PVA copolymer and PVA to be blended and the degree of polymerization. The concentration of PVA copolymer is usually from 5 to 27% by weight, preferably from 6 to 26% by weight, more preferably from 7 to 25% by weight. When PVA and a PVA copolymer are used in combination, the viscosity can be adjusted in consideration of the viscosity (100 to 5000 mPa · s, 23 ° C.) on the basis of the ratio of each component.

Further, when sorbitol is blended in the band seal, the concentration in the band seal preparation liquid can be determined according to the blending ratio of sorbitol in the band seal described above. Specifically, the sorbitol concentration in the band seal (100 wt%) is 0.01 to 70 wt%, preferably while considering that the viscosity of the band seal preparation solution is in the range of 100 to 5000 mPa · s. It is preferable to adjust the band seal preparation solution so as to be 0.01 to 35% by weight, more preferably 0.01 to 30% by weight, and particularly preferably 1 to 30% by weight.

Such a band seal is suitable as a band seal of a hard capsule in which the hard capsule of the present invention is filled with polyethylene glycol (PEG) or a composition containing the same.

Here, the PEG is not particularly limited, and the PEG having an average molecular weight of about 20000 or less, specifically, the average molecular weight is 200, 300, 400, 600, 800, 1000, 1500, 2000, 3000, 4000, Mention may be made of 6000, 8000 or 20000 PEG. In addition, PEG having each of these average molecular weights can be obtained from each manufacturer according to Japanese Pharmacopoeia and pharmaceutical additive standards (see “Japanese Pharmacopoeia” and “Pharmaceutical Additives Standards”). And XX indicates the approximate average molecular weight of the above-mentioned PEG). Such PEG can be used individually by 1 type or in combination of 2 or more types. Among them, low molecular weight PEG such as PEG having an average molecular weight of 200 to 600 (also referred to as “PEG 200 to 600”) is a PEG that is suitably used as a filling component of a hard capsule in the use of the band seal of the present invention. That is, according to the band seal of the present invention, there is no problem of bleeding even when PEG 200 to 600 is filled, and the effect of the present invention can be enjoyed more effectively.

In addition, the average molecular weight of PEG can be measured according to the following test according to the standards defined in “Japanese Pharmacopoeia” and “Pharmaceutical Additives Standard”.

(Average molecular weight test)
Take 42 g of phthalic anhydride, add to a 1 L light-shielded stoppered bottle containing exactly 300 mL of freshly distilled pyridine, stir vigorously and let stand for at least 16 hours. Weigh accurately 25 mL of this solution, put it in an approximately 200 mL pressure-resistant stopper bottle, add approximately 0.8 to 15 g of the PEG sample to be measured to it, seal tightly, wrap it in a sturdy cloth, Place in a water bath heated to 2 ° C. At this time, the liquid in the bottle is immersed in the liquid in the water bath. After maintaining at 98 ± 2 ° C for 30 minutes, remove the bottle from the water bath and let it cool in air until it reaches room temperature. Next, add exactly 50 mL of 0.5 mol / L sodium hydroxide solution, add 5 drops of pyridine solution of phenolphthalein (1 → 100), and titrate this solution with 0.5 mol / L sodium hydroxide solution. However, the end point of titration is when the liquid shows a light red color lasting 15 seconds. A blank test is performed in the same manner.

When tested by such test methods, PEG 200 has an average molecular weight in the range of about 190-210, PEG 300 has an average molecular weight in the range of about 285-315, PEG 400 has an average molecular weight in the range of about 380-420, and PEG 600 has an average molecular weight of about It can be determined as being in the range of 570 to 630.

The content of the hard capsule may be PEG or a composition containing at least PEG as described above, and as such a composition, human or animal pharmaceuticals, quasi drugs, cosmetics, and foods containing PEG are included. Can be mentioned without limitation. The proportion of PEG contained in such a composition is not particularly limited, but is usually 0.1 to 99.9% by weight, preferably 1 to 99.9% by weight, more preferably 10 to 99.9% by weight, still more preferably. 50 to 99.9% by weight can be mentioned.

The shape of the contents is not particularly limited. For example, it may be a liquid, gel, powder, granule, tablet, pellet, or a mixed form (hybrid) thereof.

As the contents of hard capsules, in the case of pharmaceuticals, for example, nourishing tonics, antipyretic analgesics, antipsychotics, anxiolytics, antidepressants, hypnotic sedatives, antispasmodics, central nervous system drugs, brain Metabolic improver, cerebral circulation modifier, antiepileptic agent, sympathomimetic agent, gastrointestinal agent, antacid, antiulcer agent, antitussive expectorant, antiemetic agent, respiratory accelerator, bronchodilator, allergic agent, dental oral cavity Drugs, antihistamines, cardiotonic drugs, arrhythmia drugs, diuretics. Antihypertensive, Vasoconstrictor, Coronary vasodilator, Peripheral vasodilator, Antihyperlipidemic agent, Biliate, Antibiotic, Chemotherapeutic agent, Antidiabetic agent, Osteoporosis agent, Antirheumatic agent, Skeleton Mention may be made of one or more drug components selected from muscle relaxants, antispasmodic agents, hormone agents, alkaloid narcotics, sulfa drugs, anti-gout agents, blood coagulation inhibitors, antineoplastic agents and the like. These medicinal ingredients are not particularly limited and can include a wide range of known ingredients. Specifically, each ingredient described in paragraphs [0055] to [0060] of WO2006 / 070578 Can be given as examples.

In the case of food, for example, docosahexaenoic acid, eicosapentaenoic acid, α-lipoic acid, royal jelly, isoflavone, agaricus, acerola, aloe, aloe vera, turmeric, ercarnitine, oligosaccharide, cacao, catechin, capsaicin, chamomile, agar, Tocopherol, linolenic acid, xylitol, chitosan, GABA, citric acid, chlorella, glucosamine, ginseng, coenzyme Q10, brown sugar, collagen, chondroitin, sorghum, squalene, stevia, ceramide, taurine, saponin, lecithin, dextrin, dodomi, niacin, Natto, bittern, lactic acid bacteria, saw palmetto, honey, hatomugi, plum extract, pantothenic acid, hyaluronic acid, vitamin A, vitamin K, vitamin C, vitamin D, vitamin B1, bi Examples include functional components such as Tamine B2, Vitamin B6, Vitamin B12, Quercetin, Protein, Propolis, Morohaya, Folic Acid, Lycopene, Linoleic Acid, Rutin, Ganoderma. However, it is not limited to these.

Filling of the contents into the hard capsule may be performed by a capsule filling machine known per se, for example, a fully automatic capsule filling machine (model name: LIQFILsuper 80/150, manufactured by Qualicaps), a capsule filling / sealing machine (model name: LIQFILsuperFS, Qualicaps Co., Ltd.) can be used. Moreover, sealing of hard capsules can be carried out using a capsule filling and sealing machine known per se, such as the capsule filling and sealing machine or capsule sealing machine (model name: HICAPSEALＳＥ40 / 100, manufactured by Qualicaps Co., Ltd.). .

緘 At the time of encapsulation, the band seal preparation liquid can be generally used at room temperature or under heating. From the viewpoint of preventing liquid leakage of the hard capsule, it is desirable to use a seal preparation liquid preferably within a temperature range of about 23 to 45 ° C, more preferably about 23 to 35 ° C, and most preferably about 25 to 35 ° C. The temperature adjustment of the seal preparation liquid can be carried out by a method known per se such as a panel heater and a hot water heater. For example, a circulating hot water heater or a seal pan unit of the integrated capsule filling and sealing machine is circulated. It is preferable to adjust with a hot water heater type modified because the temperature range can be finely adjusted. In addition, since alcohol, for example, ethanol in the seal preparation liquid may volatilize depending on temperature conditions, it is preferable to appropriately replenish the component composition of the seal preparation liquid.

The thus obtained hard capsule of the present invention is excellent in operability without leaching even when PEG, particularly low molecular weight PEG having an average molecular weight of 200 to 600 is filled therein. Has advantages. In addition, since the film does not become brittle even when glycerin fatty acid ester or medium chain fatty acid triglyceride of low molecular weight PEG is filled, these low molecular weight PEG, its glycerin fatty acid ester and medium chain fatty acid triglyceride are used as excipients. It can be applied well to drugs that contain it. In addition, good strength can be maintained even when the water content in the film is reduced, and there is no inconvenience such as cracking. Therefore, it is also suitable for use in drugs that have water absorption or recommended to be stored under low moisture. Furthermore, since water vapor and oxygen hardly permeate, it is preferably used for water-reactive substances and oxidizable substances.

III. Method for improving elongation at break of capsule film The present invention provides a method for improving the elongation at break for a capsule film (film) containing a PVA copolymer.

In this method, as a component of a capsule film (film), a PVA copolymer and PVA are used in combination, and at least one selected from PVA copolymer, PVA, and an organic acid and a salt thereof. It can carry out by using together.

As the types of PVA and PVA copolymer used here, those described in I above can be cited. Here, the ratio of the PVA and the PVA copolymer is not particularly limited, but is usually PVA copolymer: PVA = 100: 1 to 1: 100 (weight ratio, the same applies hereinafter), preferably 99: 1 to 1:99. . More preferably, it is 90:10 to 1: 100 (particularly preferably 90:10 to 1:99), still more preferably 80 to 20: 1: 100 (particularly preferably 80:20 to 1:99), More preferably, it is 50:50 to 1: 100 (particularly preferably 50:50 to 1:99), particularly preferably 40:60 to 1: 100 (particularly preferably 40:60 to 1:99). .

Also, the types of organic acids and / or their salts used in combination therewith can be the same as those described in I. Here, the ratio of the organic acid and / or salt thereof used in combination with PVA and the PVA copolymer is not particularly limited. Preferably, the ratio of the organic acid and / or salt (total amount) contained in 100% by weight of the total amount of the PVA and PVA copolymer and organic acid and / or salt thereof is 0 in terms of the amount of organic acid. The ratio can be raised to 0.1 to 19% by weight, preferably 0.15 to 8% by weight, more preferably 0.2 to 3% by weight, and particularly preferably 0.5 to 1% by weight.

In addition to PVA copolymer and PVA (or in addition to PVA copolymer, PVA, and organic acid and / or salt thereof), the capsule film contains a gelling agent as described in I. It is also possible to add a gelling aid as necessary. Those types and blending ratios can also be the same as those described in I above.

In addition, the above components (PVA copolymer and PVA, or PVA copolymer and PVA and organic acid and / or salt thereof, and a gelling agent as needed) may be included in the capsule film as long as the effects of the present invention are not impaired. And a gelling aid), if necessary, a plasticizer, a metal sequestering agent, an opacifying agent, a coloring agent or a fragrance can be blended.

Hard capsules obtained by applying the method for improving elongation at break of the present invention are hard capsules prepared without using PVA (hard capsules prepared by the same formulation and manufacturing method except that PVA is not used, hereinafter referred to as “control capsule”. Since the elongation at break is larger than that of the other), cracks and cracks are less likely to occur even under low moisture, and it is excellent in crack resistance and impact resistance. As described above, the hard capsule is usually required to have a breaking elongation in the range of 5 mm to 20 mm. The breaking elongation is preferably as large as possible with the maximum stress in the range of 70 to 130 N.

According to the method of the present invention, it is possible to achieve higher elongation at break than the control capsule while maintaining the maximum stress in the above range. The breaking elongation is preferably 8 to 20 mm, more preferably 8.5 to 20 mm, still more preferably 9 to 20 mm, and still more preferably 9.5 to 20 mm.

In the above, “under low moisture” means that the moisture content (%) of the capsule film is usually 5% or less, preferably 3 to 5%, more preferably 3 to 4%. The moisture content (%) of the capsule film can be measured according to the method described in Experimental Example 2 (2).

Hereinafter, the present invention will be described with reference to experimental examples and examples, but the present invention is not limited to such examples. Unless otherwise specified, “%” in the following means weight%.

Experimental Example 1 Measurement of Maximum Stress and Breaking Elongation Polyvinyl alcohol copolymer (hereinafter referred to as “PVA copolymer”) (POVACOAT Type L: manufactured by Daido Kasei Co., Ltd., 5% aqueous solution viscosity at 25 ° C. 20 mPa · s) 2%, polyvinyl alcohol (hereinafter referred to as “PVA”) (partially saponified PVA, polymerization degree 1,000, saponification degree 86-90 mol%, manufactured by Wako Pure Chemical Industries, Ltd.) 10.8%, kappa carrageenan (gelling agent) 0 A capsule preparation solution containing 144% and potassium chloride (gelling aid) 0.072% was prepared, and this was applied to a glass plate using a film making applicator so that the dry thickness was 0.1 mm. Casting. This was dried at 60 ° C. for 2 hours and stored for one week in an environment of 23 ° C. and relative humidity of 40%, and then cut into a film having a length of 70 mm and a width of 10 mm to obtain a test film.

The tensile test was performed using an autograph AGS-J (manufactured by Shimadzu Corporation) in an environment where the tensile speed was 150 mm / min, the distance between chucks was 20 mm, the tensile distance was 20 mm, 23 ° C., and the relative humidity was 40%. The maximum stress (N) and elongation at break (mm) were measured. FIG. 1 shows a stress-strain curve obtained in this tensile test. The maximum value of the stress (N) thus obtained corresponds to the “maximum stress” in the present invention, and the tensile stroke (tensile distance) at 1/3 of the maximum stress corresponds to the “breaking elongation” in the present invention. Equivalent to. Here, when the stress at a tensile distance of 20 mm was 1/3 or more of the maximum stress, the elongation at break was 20 mm.

Experimental Example 2 Preparation of Capsule Film A capsule film was prepared so that the ratios of PVA copolymer, PVA, and organic acid salt were in the ratios shown in Table 2. Specifically, first, a capsule preparation solution at 52 ° C. was prepared according to the formulation described in Table 1. Next, this capsule preparation solution was cast on a glass plate using a film-forming applicator so that the dry thickness was 0.1 mm. After drying at 60 ° C for 2 hours and storing for 1 week in an environment of 23 ° C and relative humidity of 40%, it is cut into a film with a length of 70 mm and a width of 10 mm, and a capsule film (sample numbers 1 to 22) Prepared.

The viscosity (mPa · s) at 52 ° C. of the capsule preparation liquid, the water content (%), the maximum stress (N), and the elongation at break (mm) of the prepared capsule film were measured according to the following methods.

(1) Viscosity (mPa · s) of capsule preparation liquid (52 ° C)
The viscosity was measured using a B-type rotational viscometer (rotor number 3) under the conditions of 52 ° C., a rotation speed of 12 rpm, and a measurement time of 1 minute.

(2) Moisture content of capsule film (%)
Each capsule film prepared above was stored for 1 week in an environment of 23 ° C. and a relative humidity of 40%, and the capsule moisture (%) was determined. Specifically, first, the weight (wet weight) of the capsule film was measured and then dried by heating at 105 ° C. for 2 hours, and the weight (dry weight) of each capsule film was measured again. Next, the ratio of moisture content (capsule film moisture content%) that decreases by heating and drying at 105 ° C. for 2 hours according to the following formula from the difference between the weight before drying (wet weight) and the weight after drying (dry weight) Was calculated.

(3) Maximum Stress and Breaking Elongation of Capsule Film Each capsule film (samples 1 to 22) prepared above was subjected to a tensile test according to the method of Experimental Example 1. From the measured stress and tensile stroke of each film, the maximum stress (N) and elongation at break (mm) were determined as described in Experimental Example 1.

Each measurement result is shown in Table 2 together with the ratio of PVA, PVA copolymer and organic acid salt of each capsule film (converted with the total amount of these components as 100% by weight). Here, the converted organic acid% means the amount of the added organic acid salt is converted into the amount of the organic acid and made a percentage with respect to the total amount.

The results of measuring the stress (N) and the tensile stroke (mm) for the capsule films of Samples 1 to 12 are shown in FIG. FIGS. 3 to 13 show the comparison results of the measurement results of the stress (N) and the tensile stroke (mm) of the sample 1 not containing PVA and the measurement results of the samples 2 to 12 containing PVA, respectively.

From this result, as a film component, by using a combination of a PVA copolymer and PVA, the elongation at break is significantly improved as compared with a capsule film prepared without using PVA together, and a capsule preparation solution It can be seen that the viscosity of this also decreases. Further, it was found that the elongation at break is further remarkably improved by further using an organic acid salt in combination with the film component.

Since the maximum stress is within the predetermined range required for capsules (70-130N), the PVA copolymer can be combined with PVA or PVA and an organic acid salt to reduce the moisture content to 5% or less. It is considered that a hard capsule that is resistant to impact and hard to crack even under moisture conditions can be prepared.

Experimental Example 3 Viscosity and Production Yield The relationship between the viscosity of the capsule preparation liquid and the capsule production yield was examined. Specifically, using a PVA copolymer, PVA, gelling agent (carrageenan), gelling aid (potassium chloride), gelatin, HPMC, water, etc., the viscosity of the capsule preparation liquid (52 ° C., B-type rotation) Viscometer, rotor number 3, rotation speed 12 rpm, measuring time 1 minute) adjusted to 500, 1350, 2000, 3100 and 4000 mPa · s, and capsule production yield when capsules are made with each of these capsule preparation solutions Asked.

(1) Calculation of capsule production yield Capsule production yield (%) is determined by a visual inspection machine that sorts out defective products such as bubbles in capsule film and deformation of capsules for hard capsules that have been created. The number of capsules per unit time (number of non-defective products after visual inspection) and the number of theoretical capsules manufactured per unit time (the number of theoretical capsules manufactured) were calculated according to the following formula.

The results showing the relationship between the viscosity (52 ° C.) and the productivity (production yield%) of the capsule preparation liquid are shown in Table 3 below and FIG.

As can be seen from this result, the production yield exceeds 50% by setting the viscosity (52 ° C) of the capsule preparation liquid to about 3100 mPa · s or less, and further to about 2000 mPa · s or less. The production yield exceeds 80%, and in particular, the production yield exceeds 90% by setting it to about 1500 mPa · s or less, particularly 1350 μmPa · s or less (see FIG. 14 and Table 3).

As shown in the result of Experimental Example 2 described above, the viscosity of the PVA copolymer and PVA can be reduced by gradually increasing the proportion of PVA from 90:10 (weight ratio) (PVA copolymer: PVA = 90: 10 (weight ratio), viscosity 3100 mPa · s, PVA copolymer: PVA = 70: 30 (weight ratio), viscosity 2000 mPa · s, PVA copolymer: PVA = 50: 50 (weight ratio) Viscosity 1500 mPa · s, PVA copolymer: PVA = 40: 60 (weight ratio) and viscosity 1350 mPa · s). That is, when the blending ratio of the PVA copolymer and PVA is particularly 50:50 to 1: 100, the capsule preparation liquid has a viscosity of about 1500 mPa · s or less and 40:60 to 1: 100. The viscosity of the preparation liquid can be adjusted to about 1350 mPa · s or less, and as a result, the production yield of capsules can be increased to 90% or more.

Experimental Example 4 Impact Strength Test (1) Preparation of Hard Capsule 48 kg of PVA (partially saponified PVA, polymerization degree 1000, saponification degree 86-90 mol%, manufactured by Wako Pure Chemical Industries, Ltd.) was added to 170 L of purified water at 40 ° C. The PVA was dissolved by dispersing and heating to 82 ° C. This was cooled to 60 ° C. to prepare a 22% PVA aqueous solution. Based on the formulation of the capsule preparation solution shown in Table 4 below, 22.9% PVA copolymer preheated to 60 ° C (POVACOAT Type L, viscosity of 5% aqueous solution is 20 mPa · s at 25 ° C, Daido Kasei Co., Ltd.) A predetermined amount of 10% potassium chloride aqueous solution, 2% carrageenan aqueous solution, 22% PVA aqueous solution and purified water were added and stirred to prepare a capsule preparation solution of sample numbers 23 to 26. These solutions were degassed with gentle stirring for 24 hours. Using the aqueous solution thus prepared (capsule preparation solution) as an immersion liquid, it was charged in a conventional capsule manufacturing apparatus by the immersion method, and the size 1 hard capsule was maintained according to a conventional method while maintaining the temperature of the immersion liquid at 50 to 55 ° C. (Cap, body) was prepared.

(2) Moisture content of hard capsule (%)
The hard capsule water content (%) was determined for each of the hard capsules prepared above and stored for 1 week in an environment of 23 ° C., 12%, 22%, 33%, 43% and 53% relative humidity. Specifically, first, the weight (wet weight) of the hard capsules after the storage was measured, and then dried by heating at 105 ° C. for 2 hours, and the weight (dry weight) of each hard capsule was measured again. Next, the ratio of the amount of water that decreases by heating and drying at 105 ° C. for 2 hours according to the following formula from the difference between the weight before drying (wet weight) and the weight after drying (dry weight) (hard capsule moisture amount%) Was calculated.

The results are shown in Table 5.

(3) Hard capsule crack rate (%)
Each hard capsule prepared above was stored for 1 week in an environment of 23 ° C., 12%, 22%, 33%, 43% and 53% relative humidity, and the cracking rate (%) of the hard capsule was determined. Specifically, a 50 g weight was naturally dropped from a height of 10 cm to each hard capsule after the storage, and the number of broken hard capsules was counted. The cracking rate (%) of the hard capsules was calculated from the number of broken hard capsules according to the following formula.

The results are shown in FIG. From this result, as a film component, by using a combination of a PVA copolymer and PVA (sample numbers 24-26), compared to a capsule film (sample number 23) prepared without using PVA together, It can be seen that crack resistance and impact resistance are improved. It has also been found that by using PVA in combination, a hard capsule that is resistant to impact and hardly cracks can be prepared even under low moisture conditions as compared with the case where PVA is not used in combination.

Experimental Example 5
PVA copolymer (POVACOAT Type F, manufactured by Daido Kasei Co., Ltd., viscosity of 5.5 mPa · s at 25 ° C, 5% aqueous solution), PVA (JP-05, manufactured by Nihon Vinegar-Poval, average polymerization) A band seal preparation solution (formulation examples 1 to 19) having a formulation shown in Table 6 was prepared using a degree of 500, a partially saponified PVA (degree of saponification: 87-89 mol%), and sorbitol. The weight ratio of the PVA copolymer, PVA and sorbitol when the weight of the band seal after drying (dry weight) is 100% by weight is shown below. According to the following method, the viscosity was measured, and the handleability when applied to a hard capsule was evaluated from the viewpoint of dripping, spinnability and fluidity.

Next, the obtained band seal preparation liquid was filled with 470 μL of PEG400 into a hard capsule prepared according to the method of Example 1 using a fully automatic capsule filling and sealing machine (manufactured by Qualicaps Co., Ltd.), and the above band seal preparation was performed. The body part of the hard capsule and the fitting part of the cap part were sealed with a liquid to prepare a hard capsule. The appearance of the sealed hard capsule was visually observed to observe the presence or absence of leakage or sorbitol precipitation, and in accordance with the following method, the temperature was 25 ° C. and the relative humidity was 40%. The band sealability was evaluated from the presence or absence of leakage of the contents after standing for a period of time.

(1) Viscosity of the band seal preparation liquid is measured using a B-type rotational viscometer (rotor number 2 when the viscosity is less than 500 mPa · s, rotor number 3 when the viscosity is 500 mPa · s to less than 2000 mPa · s, and viscosity is 2000 mPa In the case of s or more, the measurement was performed using a rotor number 4) under the conditions of 23 ° C., rotation speed 60 rpm, and measurement time 1 minute.

(2) Evaluation of handling property (presence / absence of dripping, spinnability and fluidity) of band seal preparation liquid Each band seal preparation liquid is applied to a hard capsule from all points of dripping, spinnability and fluidity. The case where the handling conditions were satisfied was evaluated as “appropriate: ○”, and the case where even one of the conditions was not satisfied was evaluated as “inappropriate: ×”.

(3) Evaluation of band sealing properties The sealed hard capsules prepared above were allowed to stand for 1 day at 23 ° C. and RH 43% to observe changes in appearance, particularly the state of the band seal formed around the fitting part. did.

Further, each sealed hard capsule was left on a white copy paper for 12 hours in an environment of a temperature of 25 ° C. and a relative humidity of 40%. After 12 hours, the presence or absence of leakage of the contents (PEG400) from the band seal part was confirmed by the following method and criteria.

(a) Whether the content (PEG400) is attached to the surface of the white copy paper that has been in contact with the sealed hard capsule after standing for 12 hours.
(b) Whether the contents (PEG400) adhere to the surface of the white copy paper when the sealed hard capsule is rolled on the white copy paper after being left for 12 hours.

In both cases (a) and (b), when there is no adhesion of the contents to the white copy paper, that is, no leakage of the contents is recognized, “band sealability: ○”, (a) and (b) In any of the cases, the case where leakage of the contents is recognized is determined as “no band sealability: x”.

The results are also shown in Table 6.

From the above results, the PVA and PVA copolymer can be suitably used as a band seal raw material alone or as a mixture thereof, and even when sorbitol is blended in a proportion of 70% by weight or less, It turned out that it can be used conveniently. The blending ratio of sorbitol is not particularly problematic if it is 70% by weight or less from the viewpoint of band sealability, but less than 40% by weight, preferably 35% by weight or less, more preferably from the point of precipitation of sorbitol. It is preferable that it is 30 weight% or less.

Example 1 Preparation of hard capsule (1) Preparation of hard capsule 48 kg of PVA (partially saponified PVA, polymerization degree 1000, saponification degree 86-90 mol%, manufactured by Wako Pure Chemical Industries, Ltd.) in 170 L of purified water at 40 ° C. In addition, the mixture was dispersed and heated to 82 ° C. to dissolve the PVA. This was cooled to 60 ° C. to prepare an aqueous PVA solution. 10% potassium chloride was added to 34.93 kg of an aqueous solution of 22.9% PVA copolymer (POVACOAT Type L, 5% aqueous solution viscosity at 25 ° C, 20 mPa · s, manufactured by Daido Kasei Co., Ltd.) preheated to 60 ° C. 0.8 kg of aqueous solution, 8 kg of 2% carrageenan aqueous solution, 54.55 kg of PVA aqueous solution and 1.72 kg of purified water were added and stirred. The solution was degassed with gentle stirring for 24 hours. The aqueous solution thus prepared (capsule preparation solution) was used as an immersion liquid and charged into a conventional capsule manufacturing apparatus by an immersion method, and the size No. 1 or No. 2 was maintained according to a conventional method while maintaining the temperature of the immersion liquid at 50 to 55 ° C. Hard capsules (caps, bodies) were prepared.

(2) Filling of contents (PEG400) Using a fully automatic capsule filling machine (LIQFILsuper40, manufactured by Qualicaps Co., Ltd.), 470 μL of polyethylene glycol (PEG400) having an average molecular weight of 400 is filled in the size 1 hard capsule prepared above. did. Next, using a fully automatic capsule filling and sealing machine (Qualicaps, LIQFILsuperFS), a band seal solution composed of the following formulation is applied to the cap and body fitting portion of the hard capsule filled with PEG400 as described above. The hard capsule of the present invention was prepared by drying and filling PEG400 inside.

2 shows a stress-strain curve obtained in the tensile test of Experimental Example 1. In the tensile test of Experimental Example 2, the results of measuring the stress (N) and the tensile stroke (mm) for the capsule films of sample numbers 1 to 12 are shown. In the tensile test of Experimental Example 2, the results of comparing the stress (N) and the tensile stroke (mm) for the capsule films of Sample No. 1 and Sample No. 2 are shown. In the tensile test of Experimental Example 2, the results of comparing the stress (N) and the tensile stroke (mm) for the capsule films of Sample No. 1 and Sample No. 3 are shown. In the tensile test of Experimental Example 2, the results of comparing the stress (N) and the tensile stroke (mm) for the capsule films of Sample No. 1 and Sample No. 4 are shown. In the tensile test of Experimental Example 2, the results of comparing the stress (N) and the tensile stroke (mm) for the capsule films of Sample No. 1 and Sample No. 5 are shown. In the tensile test of Experimental Example 2, the results of comparing the stress (N) and the tensile stroke (mm) for the capsule films of Sample No. 1 and Sample No. 6 are shown. In the tensile test of Experimental Example 2, the results of comparing the stress (N) and the tensile stroke (mm) for the capsule films of Sample No. 1 and Sample No. 7 are shown. In the tensile test of Experimental Example 2, the results of comparing the stress (N) and the tensile stroke (mm) for the capsule films of Sample No. 1 and Sample No. 8 are shown. In the tensile test of Experimental Example 2, the results of comparing the stress (N) and the tensile stroke (mm) for the capsule films of Sample No. 1 and Sample No. 9 are shown. In the tensile test of Experimental Example 2, the results of comparing the stress (N) and the tensile stroke (mm) for the capsule films of Sample No. 1 and Sample No. 10 are shown. In the tensile test of Experimental Example 2, the results of comparing the stress (N) and the tensile stroke (mm) for the capsule films of Sample No. 1 and Sample No. 11 are shown. In the tensile test of Experimental Example 2, the results of comparing the stress (N) and the tensile stroke (mm) for the capsule films of Sample No. 1 and Sample No. 12 are shown. In Experimental Example 3, it is a graph which shows the result of having investigated the correlation of the viscosity of a capsule preparation liquid, and the production yield% of a hard capsule. In Experimental Example 4, the results of evaluating the cracking rate (%) at various relative humidity (%) for various hard capsules (sample numbers 23 to 26) are shown.

Claims (17)

1. Hard capsule made of a film containing polyvinyl alcohol copolymer and polyvinyl alcohol.
2. The hard capsule according to claim 1, wherein the weight ratio of the polyvinyl alcohol copolymer and the polyvinyl alcohol contained in the film is 99: 1 to 1:99.
3. The hard capsule according to claim 1, wherein the weight ratio of the polyvinyl alcohol copolymer and the polyvinyl alcohol contained in the film is 50:50 to 1:99.
4. The hard capsule according to claim 1, further comprising a gelling agent.
5. Further, the hard capsule according to claim 4, further comprising a gelling aid.
6. 2. The hard capsule according to claim 1, wherein the moisture content of the film is 3 to 5% and the elongation at break is 5 to 20 mm.
7. A hard capsule obtained by filling the hard capsule according to any one of claims 1 to 6 with a composition containing polyethylene glycol or polyethylene glycol.
8. The hard capsule according to claim 7, wherein the polyethylene glycol is a low molecular weight polyethylene glycol having an average molecular weight of 200 to 600.
9. The hard capsule according to claim 7, wherein the fitting part between the body part and the cap part is sealed with a band seal containing a polyvinyl alcohol copolymer, polyvinyl alcohol or a mixture thereof.
10. The hard capsule according to claim 8, wherein the band seal further contains sorbitol as a plasticizer.
11. Capsule molding pins are dipped in a capsule preparation solution containing polyvinyl alcohol copolymer and polyvinyl alcohol and pulled up, the capsule preparation solution adhering to the molding pins is gelled and dried, and this is removed from the molding pins. The method for producing a hard capsule according to any one of claims 1 to 6, wherein the hard capsule is obtained by separation and collection.
12. After filling the hard capsule according to any one of claims 1 to 6, the cap portion and the body portion are fitted, and the formed fitting portion has a polyvinyl alcohol copolymer, polyvinyl alcohol, or these. A method for preparing a hard capsule, comprising applying a band seal preparation solution containing a mixture of the above, followed by drying and sealing.
13. The method for preparing a hard capsule according to claim 12, wherein the content is polyethylene glycol or a composition containing polyethylene glycol.
14. A method for improving the elongation at break of a capsule film containing a polyvinyl alcohol copolymer, wherein a polyvinyl alcohol copolymer and polyvinyl alcohol are used in combination as a component of the capsule film.
15. 15. The method for improving the elongation at break of a capsule film according to claim 14, wherein the weight ratio of the polyvinyl alcohol copolymer and polyvinyl alcohol to be blended in the capsule film is 99: 1 to 1:99.
16. 15. The capsule film breaking elongation improving method according to claim 14, wherein at least one selected from the group consisting of an organic acid and a salt thereof is further used as a component of the capsule film.
17. The method for improving elongation at break of a capsule film according to claim 16, wherein the salt of the organic acid is an alkali metal salt of an organic acid.

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