JP5355215B2 - Hard capsule with improved solubility or hardness - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide: a hard capsule having improved solubility in water and hardness; and a method for producing the same, wherein the hard capsule contains Hypromellose as a base agent. <P>SOLUTION: The hard capsule contains, in addition to Hypromellose, at least one selected from the group consisting of monosaccharide, disaccharide, and starch, as film components. The hard capsule is prepared by a dipping method using a capsule-preparing solution containing, in addition to Hypromellose, at least one selected from the group consisting of monosaccharide, disaccharide, and starch. <P>COPYRIGHT: (C)2011,JPO&amp;INPIT

Description

  The present invention relates to a hard capsule based on hypromellose and a method for producing the same. In particular, the present invention relates to a hard capsule having hypromellose as a film component (base) with improved water solubility and / or hardness and a method for producing the same. Furthermore, the present invention relates to a hard capsule using the hard capsule.

  Gelatin is widely used as a base for hard capsules. Gelatin capsules are capsule bases that have been widely used in the past because of their ease of formulation and ease of administration due to the taste-masking and / or flavoring action of pharmaceutical and food ingredients.

  However, the film (coating) formed from the gelatin has a drawback that its mechanical strength is extremely lowered when the moisture contained in the film is reduced. Specifically, gelatin capsules usually contain about 13 to 15% of moisture in the film. However, if the gelatin capsule becomes 10% or less, the flexibility of the film is lowered and the film becomes extremely brittle. For this reason, at the time of mechanical handling of the capsule in the content filling operation, the capsule film (coating film) may be damaged such as cracks, cracks or chips. In addition, gelatin is an animal protein and has a problem that there is a risk of mad cow disease infection. From this point, a hard capsule that replaces the gelatin capsule is required.

  As an alternative to such a gelatin capsule, for example, there is a hard capsule based on water-soluble cellulose ethers (Patent Document 1). Such hard capsules have excellent characteristics such as being hard to break even when the water content is low and less insolubilized due to changes over time as compared with normal gelatin capsules.

  However, compared with gelatin capsules, there is a problem that solubility in water is low and elution of contents is delayed (Patent Documents 2 to 4). As a method for solving such a problem, Patent Document 2 proposes a method of blending sugar alcohol, particularly monosaccharide alcohol, in addition to water-soluble cellulose ethers. According to this method, it is possible to provide a hard capsule which is remarkably improved in the dissolution property of the hard capsule and excellent in moldability. However, according to Test Example 3 of this document, it has been pointed out that when white sugar is used instead of sugar alcohol, there is a problem that the moldability is remarkably lowered. Patent Document 3 proposes a method in which hypromellose having a viscosity of 2.4 to 5.4 centistokes at 20 ° C. in a 2% aqueous solution is used in combination with carrageenan and calcium ions or potassium ions. However, in this case, it has been pointed out that the film becomes fragile (Patent Document 4). As a method not having such a problem, Patent Document 4 proposes a method using gellan gum and a sequestering agent in addition to cellulose ether as a film component. Patent Document 5 discloses a method for improving the mechanical film strength of hard capsules based on water-soluble cellulose, as a film component, in addition to water-soluble cellulose, sucrose fatty acid ester, potassium pyrophosphate, glacial acetic acid. , Ι-carrageenan and methods using agar have been proposed.

JP-A-3-279325 WO2006 / 082842 EP0714656 JP-T-2001-506692 JP 2006-231022 A

  As described above, hard capsules containing water-soluble cellulose ethers as film components (base) are useful as hard capsules instead of gelatin capsules, but still have water solubility, film brittleness and moldability. There is still room for improvement.

  Accordingly, the present invention aims to improve water solubility or / and film brittleness (capsule hardness) in addition to moldability for hard capsules based on water-soluble cellulose ethers, particularly hypromellose. To do. Specifically, the present invention provides a hard capsule having hypromellose as a film component (base), which is excellent in moldability and improved in water solubility or / and capsule hardness, and a method for producing the same. With the goal.

  The inventors of the present invention have been diligently studying day and night to achieve the above object. As a result, a hard capsule containing hypromellose as a film component (base) has solubility in water and hardness of the hypromellose used. It was deeply related to the viscosity, and it was found that the solubility and hardness of the hard capsule in water can be controlled by adjusting the viscosity. Specifically, the sum of the viscosity (mPa · s) of a 2% by weight aqueous solution of hypromellose used for the film component multiplied by the ratio (parts by weight) to the total amount of hypromellose 100 parts by weight was defined as “hypromellose viscosity value”. In this case, it was found that the smaller the value in the range of 300 to 960, the better the solubility of the hard capsule in water, and vice versa, the higher the value, the higher the hardness of the hard capsule (Experimental Example 1). . That is, as the “hypromellose viscosity value” increases in the range of 300 to 960, the hardness of the hard capsule increases, but the solubility in water decreases. Conversely, as the “hypromellose viscosity value” decreases in the range of 300 to 960, Although the water solubility of the hard capsule is improved, the hardness is lowered.

  Therefore, the present inventors have conducted further studies with the aim of developing a hard capsule having high solubility in water and high hardness. By using monosaccharide or disaccharide as a film component in addition to hypromellose. It is found that the solubility in water can be improved without affecting the hardness of the hard capsule, and the water solubility of the hard capsule decreases as the “hypromellose viscosity value” increases in the range of 300 to 960. It was confirmed that a hard capsule excellent in water solubility can be prepared. By improving the solubility of the hard capsule in water, the content filled in the hard capsule can be eluted out of the capsule at an early stage.

  In addition, it was found that by using monosaccharide or disaccharide in combination with hypromellose, the increase in viscosity of the capsule preparation solution can be suppressed, and by controlling the viscosity of the capsule preparation solution using monosaccharide or disaccharide, work in capsule production It was confirmed that the performance can be improved.

  In addition, by using starch in addition to hypromellose as a film component, it has been found that the hardness can be enhanced without affecting the water solubility of the hard capsule, and the “hypromellose viscosity value” is in the range of 300 to 960. It was confirmed that the hard capsules with excellent hardness can be prepared by making up for the decrease in the hardness of the hard capsules as it gets smaller.

  The present invention has been completed on the basis of such knowledge, and has the following embodiments.

(I) Hard capsule (I-1 ) A hard capsule containing hypromellose and at least one selected from the group consisting of monosaccharides, disaccharides and starch as a film component.
(I-2) As a film component, a hard capsule containing hypromellose at a ratio of a hypromellose viscosity value of 400 to 770, and further comprising at least one sugar selected from the group consisting of monosaccharides and disaccharides The hard capsule according to (I-1), which is contained.
(I-3) A hard capsule containing hypromellose as a film component at a ratio of a hypromellose viscosity value of 300 to 600, further containing starch, the hard capsule according to (I-1).
(I-4) As a film component, a hard capsule containing hypromellose at a ratio of a hypromellose viscosity value of 300 to 770, and at least one sugar selected from the group consisting of monosaccharides and disaccharides, and The hard capsule according to (I-1), which contains starch.
(I-5) The hard capsule according to any one of (I-1), (I-2), and (I-4), wherein the monosaccharide is fructose and the disaccharide is sucrose and maltose.
(I-6) (I-1), (I-2), (I-4) or (I-) containing sugar at a ratio of less than 40 parts by weight with respect to 100 parts by weight of hypromellose contained in the hard capsule The hard capsule according to any one of 5).
(I-7) The hard capsule according to any one of (I-1), (I-3) and (I-4), wherein the starch is corn starch, waxy corn starch, potato starch and tapioca starch.
(I-8) (I-1), (I-3), (I-4) or (I-) containing starch in a proportion of less than 25 parts by weight with respect to 100 parts by weight of hypromellose contained in the hard capsule The hard capsule according to any one of 7).
(I-9) The hard material according to any one of (I-1) to (I-8), further comprising a gelling agent and, if necessary, a gelling aid as a film component capsule.

(II) Hard capsule (II-1) The hard capsule described in any one of (I-1) to (I-9) is filled with one selected from the group consisting of pharmaceuticals and foods , Hard capsule.

(III) Manufacturing method of hard capsule (III-1) Capsule molding pin is immersed in a capsule preparation solution containing at least one selected from the group consisting of hypromellose and monosaccharide, disaccharide and starch. The method for producing a hard capsule according to (I-1), comprising a step of drying a film formed on the outer surface of the pin.
(III-2) The capsule preparation solution contains hypromellose at a ratio of a hypromellose viscosity value of 400 to 770, and further contains at least one sugar selected from the group consisting of monosaccharides and disaccharides The production method according to (III-1).
(III-3) The production method according to (III-1), wherein the capsule preparation liquid contains hypromellose at a ratio of a hypromellose viscosity value of 300 to 600 and further contains starch.
(III-4) The capsule preparation solution contains hypromellose at a ratio of a hypromellose viscosity value of 300 to 770, and further contains at least one sugar selected from the group consisting of monosaccharides and disaccharides and starch. The production method according to (III-1).
(III-5) The production method according to any one of (III-1), (III-2), and (III-4), wherein the monosaccharide is fructose and the disaccharide is sucrose and maltose.
(III-6) The capsule preparation liquid contains sugar at a ratio of less than 40 parts by weight with respect to 100 parts by weight of hypromellose contained in the capsule preparation liquid. (III-1), (III-2 ), (III-4) or (III-5).
(III-7) The production method according to any one of (III-1), (III-3), and (III-4), wherein the starch is corn starch, waxy corn starch, potato starch or tapioca starch.
(III-8) The capsule preparation liquid contains starch in a proportion of less than 25 parts by weight with respect to 100 parts by weight of hypromellose contained in the capsule preparation liquid. (III-1), (III-3) ), (III-4) or (III-7).
(III-9) The production according to any one of (III-1) to (III-8), wherein the capsule preparation liquid further contains a gelling agent and, if necessary, a gelling aid. Method.

(IV) Method for Improving Water Solubility of Hard Capsules (IV-1) As a film component, it is a method for improving the water solubility of hard capsules containing hypromellose at a ratio of hypromellose viscosity value of 400 to 770. The method further comprises blending at least one sugar selected from the group consisting of monosaccharides and disaccharides as a film component.
(IV-2) The method according to (IV-1), wherein the monosaccharide is fructose and the disaccharide is sucrose and maltose.
(IV-3) The method according to (IV-1) or (IV-2), wherein the sugar is blended at a ratio of less than 40 parts by weight with respect to 100 parts by weight of hypromellose contained in the hard capsule.

(V) Hard capsule hardness improving method (V-1) As a film component, a method of improving the hardness of a hard capsule containing hypromellose at a ratio of a hypromellose viscosity value of 300 to 600, further comprising starch as a film component The method characterized by mix | blending.
(V-2) The method according to (V-1), wherein the starch is corn starch, waxy corn starch, potato starch or tapioca starch.
(V-3) The method as described in (V-1) or (V-2) which mix | blends starch in the ratio of less than 25 weight part with respect to 100 weight part of hypromellose contained in a hard capsule.

(VI) Method for improving the hardness and water solubility of hard capsules (VI-1) As a film component, improve the water solubility and hardness of hard capsules containing hypromellose at a ratio of hypromellose viscosity values of 300 to 770 A method comprising blending starch with at least one selected from the group consisting of monosaccharides and disaccharides as a film component.
(VI-2) The method according to (VI-1), wherein the monosaccharide is fructose, and the disaccharide is sucrose and maltose.
(VI-3) The method according to (VI-1) or (VI-2), wherein the sugar is blended at a ratio of less than 40 parts by weight with respect to 100 parts by weight of hypromellose contained in the hard capsule.
(VI-4) The method according to any one of (VI-1) to (VI-3), wherein the starch is corn starch, waxy corn starch, potato starch or tapioca starch.
(VI-5) The method according to any one of (VI-1) to (VI-4), wherein starch is blended at a ratio of less than 25 parts by weight with respect to 100 parts by weight of hypromellose contained in the hard capsule.

  The hard capsule of the present invention is excellent in hardness and / or water solubility in addition to capsule moldability by the dipping method. For this reason, the hard capsules of the present invention are less prone to cracking and chipping during production, distribution and use, and the contents can be eluted quickly after taking. In addition, since the hard capsule of the present invention uses hypromellose as a film component (base), it is less likely to break even if it has a lower moisture content than gelatin, and is less likely to become insoluble due to changes over time.

  The capsule hardness improving method of the present invention eliminates the problem of low hardness while having high water solubility due to the viscosity of hypromellose used in hard capsules containing hypromellose as a film component (base). It can be effectively used to prepare hard capsules with high hardness.

  The method for improving the water solubility of the hard capsule of the present invention is that, in a hard capsule having hypromellose as a film component (base), the water solubility is low while having high hardness due to the viscosity of the hypromellose used. It can be effectively used to solve the problem and prepare hard capsules with high water solubility.

It is a figure which shows the stress-strain curve obtained by the compression test in Experimental example 1 (c). The maximum value of the stress corresponds to “maximum stress”, and the maximum slope until the maximum stress is reached corresponds to “elastic modulus”.

I. Hard capsule and method for producing the same The hard capsule of the present invention is characterized by containing at least one selected from the group consisting of monosaccharides, disaccharides and starches in addition to hypromellose as a film component.

  Here, hypromellose is a cellulose ether in which a hydroxypropyl group (substituent) is introduced into methylcellulose, as shown by the following formula:

  The hypromellose targeted by the present invention includes the following hypromellose defined by the Japanese Pharmacopoeia:

  In addition, hypromellose having the following molecular weight, which is approved for use as a food additive in Japan, is included.

<Molecular weight>
Unsubstituted structural unit: 162.14
Substitution unit: about 180 (degree of substitution 1.19), about 210 (degree of substitution 2.37)
Polymer: about 13,000 (n = about 70) to about 200,000 (n = about 1000).

  Commercially available hypromellose usually has a ratio (Mw / Mn) of weight average molecular weight (Mw) to number average molecular weight (Mn) in the range of 1.5-4. The weight average molecular weight (Mw) and the number average molecular weight (Mn) in calculating the ratio (Mw / Mn) can both be determined by gel chromatography (size exclusion chromatography). The principle and method of gel chromatography are not limited, but for example, the description of “Size-Exclusion Chromatography” in the “Chromatography” chapter of “USP30 The United States Pharmacopeia / NF25 The National Formulary” can be referred to.

  The hypromellose targeted by the present invention includes those having a viscosity of a 2% by weight aqueous solution in the range of 3 to 15 mPa · s. Here, the viscosity of the 2% by weight hypromellose aqueous solution was measured using a B-type rotational viscometer (BL type, rotor number 2) under the conditions of a liquid temperature of 20 ° C. under the conditions of a rotation speed of 12 rpm and a measurement time of 1 minute. It means viscosity. In the present invention, the “viscosity of 2% by weight hypromellose aqueous solution” means the viscosity measured under the above conditions.

  In the present invention, one kind of hypromellose may be used alone, or two or more kinds of hypromellose can be used in any combination, and in each case, the “hypromellose viscosity value” is in the range of 300 to 960, preferably 300 to 960. It is used to be in the range of 770.

  Here, the “hypromellose viscosity value” is the sum of the viscosity (mPa · s) of a 2% by weight aqueous solution of hypromellose used for the production of capsule film multiplied by the ratio (parts by weight) to 100 parts by weight of hypromellose. means. Specifically, when hypromellose having a 2% by weight aqueous solution having a viscosity of 6 mPa · s alone is used for producing a capsule film, the “hypromellose viscosity value” is 600 at “6 mPa · s × 100 parts by weight”. . In addition, in the case of using a combination of 30 parts by weight of hypromellose having a viscosity of 4 mPa · s and 70 parts by weight of 6 mPa · s hypromellose in the production of a capsule film, the “hypromellose viscosity value” is “4 mPas”. “S × 30 parts by weight + 6 mPa · s × 70 parts by weight” is 540.

  The ratio of the hypromellose contained in the hard capsule (capsule film) of the present invention is not particularly limited, but is usually 70 to 99.9% by weight when the weight of the capsule film excluding moisture is 100% by weight, preferably Is 70.5 to 99.8% by weight, more preferably 71 to 99.7% by weight.

  Monosaccharides used in the present invention include fructose, psicose, sorbose, tagatose, allose, altrose, glucose, mannose, gulose, idose, galactose, talose, fucose, fucrose, rhamnose, ribulose, xylulose, ribose, arabinose, Examples include xylose, lyxose, deoxyribose, erythrulose, erythrol, threose, dihydroxyacetone, and glyceraldehyde, with fructose being preferred. Examples of the disaccharide used in the present invention include sucrose, maltose, lactose, trehalose, tulanose, and cellobiose, with sucrose and maltose being preferred. These sugars may be used alone or in any combination of two or more. However, it is desirable not to use sugar or sucrose because it may adversely affect the moldability of the hard capsule.

  These saccharides can be suitably used when the “hypromellose viscosity value” of hypromellose used in the production of hard capsules is 400 to 770, thus improving the water solubility of the hard capsules. it can. Preferably it is 450-770, More preferably, it is 540-770, Most preferably, it is 580-770. The blending ratio of saccharides may be less than 40 parts by weight, preferably 0.5 to 35 parts by weight, more preferably 0.5 to 25 parts by weight, with respect to 100 parts by weight of hypromellose used for the production of hard capsules. Part.

  The starch used in the present invention is not particularly limited as long as it is an edible starch. For example, corn starch, waxy corn starch, high amylose corn starch, wheat starch, rice starch, bean starch, potato starch (potato starch), sweet potato starch, Although tapioca starch can be mentioned, corn starch, waxy corn starch, potato starch and tapioca starch are preferred. These starches may be used alone or in any combination of two or more.

  These starches can be suitably used when the “hypromellose viscosity value” of hypromellose used for the production of hard capsules is 300 to 600, and thus the hardness of the hard capsules can be improved. Preferably it is 300-580, More preferably, it is 300-560, Most preferably, it is 300-540.

  The blending ratio of starch may be less than 25 parts by weight with respect to 100 parts by weight of hypromellose used for producing hard capsules, preferably 0.5 to 20 parts by weight, more preferably 0.5 to 17 parts. 5 parts by weight can be mentioned.

  Moreover, in addition to the said component, a gelatinizer can also be mix | blended with the hard capsule (capsule film) of this 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. Kappa-carrageenan is preferred. 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 may 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 the 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. In addition, citric acid or sodium citrate can be used as an organic acid or a water-soluble salt thereof.

  As a preferable combination of a gelling agent and a gelling aid, a combination of carrageenan, particularly a combination of kappa-carrageenan and potassium chloride can be preferably mentioned.

  In addition, when the hard capsule (capsule film) of the present invention contains the gelling agent, the content is 0.05 to 2.5 weight when the weight of the capsule film excluding moisture is 100% by weight. %, Preferably 0.1 to 2.3% by weight, more preferably 0.15 to 2% by weight, and still more preferably 0.2 to 1.8% by weight. Further, when a gelling aid such as potassium chloride is included, the content thereof is in the range of 2.5% by weight or less, preferably 0.1 to 2.3% by weight, more preferably 0.15 to 2% by weight, Preferably 0.2-1.8 weight% can be mentioned. The ratio of the gelling agent to 100 parts by weight of hypromellose used for the production of hard capsules is 0.05 to 2.5 parts by weight, preferably 0.1 to 2.25 parts by weight, and the gel to 100 parts by weight of hypromellose. The proportion of the solubilizing aid is 2.5 parts by weight or less, preferably 0.1 to 2.25 parts by weight.

  In addition to the above components (hypromellose, saccharide, starch, and gelling agent or gelling aid as necessary), the hard capsule (capsule film) of the present invention, if necessary, 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, macrogol 1 00, macrogol 400, macrogol 4000, macrogol 600, macrogol 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 the 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 of the present invention can be produced 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 is dipped in, 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.

  The density | concentration of each said component contained in a capsule preparation liquid can be suitably adjusted according to the ratio of each component in the capsule film mentioned above. Specifically, about hypromellose, 5-35 weight%, Preferably it is 10-33 weight%, More preferably, 15-30 weight% can be mentioned. For sugars, less than 8% by weight, preferably 0.1-7% by weight, more preferably 0.1-5% by weight, and for starches, less than 5% by weight, preferably 0.1-4% by weight. More preferably, 0.1 to 3.5% by weight can be mentioned. When a gelling agent is used, the concentration in the capsule preparation liquid is 0.01 to 0.5% by weight, preferably 0.02 to 0.45% by weight, more preferably 0.03 to 0.4% by weight. Can be mentioned. Moreover, when using a gelatinization adjuvant, it is 0.5 weight% or less as a density | concentration in the capsule preparation liquid, Preferably it is 0.02-0.45 weight%, More preferably, it is 0.03-0.4 weight%. Can be mentioned.

  The amount of water contained in the capsule preparation liquid is not limited, but under conditions (30 to 80 ° C., preferably 40 to 60 ° C.) that are employed at the time of immersion of the capsule molding pin (temperature of the immersion liquid), The ratio that the viscosity of the capsule preparation liquid is 100 to 20000 mPa · s, preferably 300 to 10000 mPa · s can be mentioned. Usually, the water content is 60 to 90% by weight, preferably 70 to 85% by weight.

  The method for preparing the capsule preparation liquid (immersion liquid) is not particularly limited. For example, in purified water heated to about 70 to 80 ° C., saccharides and starch, and if necessary, a gelling agent and a gelling aid are dissolved, and then hypromellose is dispersed, and this is treated with a desired immersion liquid temperature ( A method of preparing a uniform capsule preparation liquid (immersion liquid) by cooling to 35-60 ° C. (more preferably 40-60 ° C.) and dissolving hypromellose; and in addition to sugars and starch, hypromellose is about 70- Disperse in hot water at about 80 ° C (at this point, saccharides and starch dissolve), once cooled, dissolve hypromellose, and then add gelling agent and gelling aid as necessary to dissolve Then, it is heated again and adjusted to about 30 to 50 ° C. to prepare a uniform capsule preparation liquid (immersion liquid), and a method of adjusting the temperature of the desired immersion liquid can be used without limitation.

The hard capsule of the present invention is obtained by immersing the capsule molding pin in the capsule preparation liquid (immersion liquid) and then pulling it up to gel the solution adhering to the capsule molding pin. Manufactured by drying at ~ 80 ° C. Specifically, the hard capsule used in the present invention can be produced through the following steps.
(1) A step of immersing the capsule molding pin (immersion step) in a capsule preparation solution (immersion solution) containing hypromellose, saccharide or / and starch (and a gelling agent or a gelling aid if necessary),
(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, you may perform the following heating process after the process of said (4) as needed.
(5) After the gelation step (2), before or after the drying step (3) or simultaneously, or after the desorption step (4), the gelled capsule film (gelated film) is heated at 50 to 150 ° C. Process (heating process).

  In addition, when using the solution which does not mix | blend gelatinizers, such as carrageenan, as a capsule preparation liquid (immersion liquid), it uses the gelling process (2) using the fact that hypromellose itself gels at a temperature of 60 ° C. or higher. ) Using a capsule molding pin heated to 60 ° C. or higher (thermal gel method). Specifically, in the dipping step (1), the capsule preparation liquid (immersion liquid) adjusted to a constant temperature of 35 to 50 ° C., preferably 35 to 45 ° C., preferably 60 to 150 ° C. depending on the liquid temperature. Is immersed in a capsule molding pin heated to 60 to 120 ° C., more preferably 70 to 90 ° C., and then in the gelation step (2), the capsule molding pin is pulled up from the capsule preparation liquid (immersion liquid), The capsule base solution attached to the outer surface of the pin is gelled.

  On the other hand, when a solution containing a gelling agent such as carrageenan is used as the capsule preparation liquid (immersion liquid), the temperature around the capsule manufacturing machine is adjusted by utilizing the fact 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 liquid (immersion liquid) adjusted to a constant temperature of 35 to 60 ° C., preferably 40 to 60 ° C., preferably 10 to 30 ° C., preferably depending on 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 adhering to the outer surface of the pin is gelled.

  The drying step (3) can be performed at room temperature. Usually, it is performed by blowing air at room temperature. 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 heating step (5), which is an optional step, can be performed after the gelation step (2), that is, after the capsule preparation liquid is gelled (solidified). The stage of the heat treatment may be any stage as long as it is after the gelation step (2), or before or after the drying step (3), or may be performed simultaneously with heating and drying. Further, it may be after the desorption step (4). Preferably, after the gelation step (2), the gelled capsule film is subjected to a drying step at room temperature, and heat treatment is performed after drying or in a semi-drying stage. Although heating temperature will not be restrict | limited especially if it is the range of 50-150 degreeC, Preferably it is 60-100 degreeC, More preferably, it is the range of 60-80 degreeC. The heat treatment can be usually performed by blowing air at 50 to 150 ° C.

  The capsule film thus prepared can be provided as a hard capsule in a state where the body portion and the cap portion are fitted or not fitted together after being cut and adjusted to a predetermined length.

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. Thus, it can be provided as a hard capsule by joining the body part and the cap part.

  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. After joining the body part and the cap part, the hard capsule is formed with a constant width on the surface of the body part and the surface of the cap part so as to straddle the edge part of the cap part. In the direction, it can be prepared by applying the band seal preparation liquid once to plural times, preferably 1 to 2 times, 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 4-6 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 No. 3 capsule and about 1.5 to 2.8 mm for No. 4 capsule.

  For the band seal formation of the hard capsule of the present invention, a band seal preparation liquid having the same composition as the capsule preparation liquid used for the preparation of the hard capsule described above can be used.

  The contents filled in the hard capsule can include, without limitation, human or animal oral medicine or food. 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.

  In the case of oral medicine, the contents to be filled in the hard capsule are, for example, nourishing tonic, antipyretic analgesic, psychotropic, anxiolytic, antidepressant, hypnotic sedative, antispasmodic, central nervous system drug , Cerebral metabolism improving agent, cerebral circulation modifying agent, antiepileptic agent, sympathomimetic agent, gastrointestinal agent, antacid, antiulcer agent, antitussive expectorant, antiemetic agent, respiratory accelerator, bronchodilator, allergy agent, Dental and oral 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 drugs, blood coagulation inhibitors, anti-neoplastic agents and the like. These medicinal components are not particularly limited and can include a wide variety of known components. Specifically, each component described in paragraphs [0055] to [0060] of WO 2006/070578 Pamplet 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, vitamin Examples include functional components such as Min B2, Vitamin B6, Vitamin B12, Quercetin, Protein, Propolis, Morroheiya, 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. Further, the sealing of the hard capsule can be carried out using a capsule filling and sealing machine known per se, for example, the capsule filling and sealing machine or the capsule sealing machine (model name: HICAPSEAL 40/100, manufactured by Qualicaps). .

  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 that is 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.

  The hard capsule of the present invention thus obtained has high hardness and high water solubility.

III. Method for Improving Water Solubility of Hard Capsule The present invention provides a method for improving the water solubility of a hard capsule containing hypromellose as a film component (base). This method is a method for improving water solubility particularly in a hard capsule containing hypromellose at a ratio of “hypromellose viscosity value” of 400 to 770.

  The method can be carried out by using at least one saccharide selected from the group consisting of saccharides, particularly monosaccharides and disaccharides, in addition to hypromellose as a film component (base). The kind of saccharide used here and the blending ratio thereof can be the same as those described in I above. The monosaccharide is preferably fructose, and the disaccharide is preferably sucrose and maltose.

  As described in I, the hard capsule may contain a gelling agent in addition to hypromellose and saccharide, and may further contain a gelling aid as necessary. Those types and blending ratios can also be the same as those described in I above. As a gelling agent used in combination, carrageenan, particularly kappa-carrageenan, and as a gelling aid used in combination therewith, potassium chloride can be preferably mentioned.

  In addition to the above components (hypromellose, saccharides, and gelling agents and gelling aids as necessary), the hard capsules may further include a plasticizer, a metal sequestering agent, an opacifying agent, and a coloring agent. A fragrance or a fragrance can also be blended.

  Although it has been explained here that the monosaccharide or disaccharide used in combination with hypromellose as the film component (base) improves the solubility in water of the hard capsules to be produced, the monosaccharide or disaccharide Has the effect of suppressing an undesired increase in viscosity of the capsule preparation liquid used for capsule preparation when used in combination with hypromellose. According to such properties of saccharides, the viscosity of the capsule preparation liquid containing hypromellose as a film component (base) can be controlled using saccharides, and thus the workability in capsule production is improved. Is possible.

IV. The present invention provides a method for improving the hardness of a hard capsule containing hypromellose as a film component (base). This method is a method for improving capsule hardness, particularly in a hard capsule containing hypromellose at a ratio of “hypromellose viscosity value” of 300 to 600.

  The method can be carried out by using starch in addition to hypromellose as a film component (base).

  The types of starch used here and the blending ratio thereof can be the same as those described in I above. Corn starch, waxy corn starch, potato starch and tapioca starch are preferred.

  As described in I, the hard capsule may contain a gelling agent in addition to hypromellose and starch, and may further contain a gelling aid as necessary. Those types and blending ratios can also be the same as those described in I above. As a gelling agent used in combination, carrageenan, particularly kappa-carrageenan, and as a gelling aid used in combination therewith, potassium chloride can be preferably mentioned.

  For hard capsules, in addition to the above components (hypromellose, starch, and gelling agents and gelling aids as necessary), plasticizers, metal sequestering agents, opacifying agents, coloring A fragrance or a fragrance can also be blended.

V. Method for improving water solubility and hardness of hard capsule The present invention provides a method for improving both water solubility and hardness in a hard capsule containing hypromellose as a film component (base). The method is a method for improving both water solubility and hardness, particularly in a hard capsule containing hypromellose at a ratio of “hypromellose viscosity value” of 300 to 960, preferably 300 to 870, more preferably 300 to 770. It is.

  The method can be carried out by using at least one saccharide selected from the group consisting of saccharides, particularly monosaccharides and disaccharides, and starch in addition to hypromellose as a film component (base).

  The types of sugars and starch used here and the blending ratio thereof can be the same as those described in I above. The monosaccharide is preferably fructose, and the disaccharide is preferably sucrose and maltose. Preferred starches are corn starch, waxy corn starch, potato starch and tapioca starch.

  As described in I, the hard capsule may contain a gelling agent in addition to hypromellose, saccharide and starch, and may further contain a gelling aid as necessary. Those types and blending ratios can also be the same as those described in I above. As a gelling agent used in combination, carrageenan, particularly kappa-carrageenan, and as a gelling aid used in combination therewith, potassium chloride can be preferably mentioned.

  In addition to the above components (hypromellose, saccharides, starch, and if necessary, a gelling agent and a gelling aid), the hard capsule further contains a plasticizer, a metal sequestering agent, an opacifying agent. Further, a coloring agent or a fragrance can be blended.

  EXAMPLES Hereinafter, although an experiment example and an Example are shown and this invention is demonstrated, this invention is not restrict | limited by this Example etc. Unless otherwise specified, “%” in the following means weight%.

Experimental Example 1 Relationship between Hypromellose Viscosity Value, Solubility in Water, and Capsule Hardness Five types of hypromellose having different viscosities (3, 4, 4.5, 6, 15 mPas of 2% aqueous solution) as film components of hard capsules Using s), a hard capsule was prepared according to the formulation described in Table 2 so that the hypromellose viscosity value was 300 to 1050, and the relationship between the hypromellose viscosity value, solubility in water, and capsule hardness was examined. .

  The viscosity of the hypromellose 2% aqueous solution was prepared by dissolving hypromellose in water to prepare a 2% by weight aqueous solution, and then setting the liquid temperature to 20 ° C. with a B-type rotational viscometer (BL type, rotor number 2) at 12 rpm. The measurement time was 1 minute. The hypromellose viscosity value was determined as the sum of the viscosity (mPa · s) of the 2% aqueous solution of hypromellose used and the ratio (parts by weight) of the total amount of hypromellose in 100 parts by weight.

(1) Preparation of hard capsules Five kinds of hypromellose (viscosity of 2% aqueous solution is 3, 4, 4.5, 6, 15 mPa · s), kappa carrageenan as a gelling agent, gelation aid A capsule preparation solution was prepared using potassium chloride and calcium chloride as agents.

  In preparing the capsule preparation liquid, first, a gelling aid was added and dissolved in purified water at about 80 ° C., kappa carrageenan was further added thereto, and these were dissolved while stirring. Next, hypromellose was added to this solution while stirring, and the solution was dispersed in warm water, and then dissolved by cooling the solution temperature to about 50 ° C. The concentration of hypromellose in the capsule preparation solution was adjusted to 10 to 30% (w / w). Next, using this capsule preparation liquid as an immersion liquid, a size 2 hard capsule (cap, body) was prepared using a capsule molding pin according to the immersion method while maintaining the temperature at 50 to 55 ° C.

(2) Evaluation of hard capsule About the obtained hard capsule, (a) Capsule moldability (presence / absence of dripping of capsule preparation liquid, presence / absence of cracks when drying capsule film, etc.), (b) solubility in water And (c) The capsule hardness was evaluated according to the following method.

(A) Capsule moldability Capsule moldability was evaluated from the following viewpoints.

(A-1) Presence or absence of liquid sag of capsule preparation liquid About the capsule preparation liquid (50 to 55 ° C) prepared above, the presence or absence of liquid sag when the capsule molding pin was dipped and pulled up was observed. As a result, when there is no dripping at the time of capsule preparation and a film can be uniformly formed on the surface of the capsule molding pin, “No dripping: ○”, when there is liquid dripping and the film cannot be uniformly formed on the surface of the capsule molding pin Was evaluated as “Liquid dripping: x”.

(A-2) Capsule film cracked Capsule molding pins were dipped in each capsule preparation liquid (immersion liquid) and pulled up, and the capsule preparation liquid adhering to the surface of the capsule molding pins was dried and solidified at 23 ° C. It was observed whether the dry film was cracked or chipped when it was removed or when it was cut to a predetermined length with a dedicated cutter after it was removed. As a result, after drying and solidifying, a case where a dry film (cap and body) usable as a hard capsule was obtained was evaluated as “moldable: ◯”, and a case where it was not obtained was evaluated as “unmoldable: x”. In addition, moldability was not evaluated for those in which liquid sag was confirmed in (a-1) (slashed in the table column).

(B) Solubility in water The solubility in water was evaluated for the hard capsules (without dripping: ○, moldable: ○) that could be molded without dripping by the above method. Specifically, 200 mg of 20 wt% acetaminophen-containing powder (containing 20% acetaminophen, 70% lactose, 10% sodium starch glycolate) was filled in the prepared hard capsule, and this was used as a test sample. About this test sample, the elution test was implemented on condition of the following according to the 2nd method of the elution test of Japanese Pharmacopoeia.

<Test conditions>
Test solution: purified water,
Test solution volume: 900 mL,
Test solution temperature: 37 ° C
Paddle rotation speed: 50rpm,
Sinker: Use.

  The elution rate (%) of acetaminophen was determined by sampling the test solution over time and quantifying the acetaminophen content in the test solution. From the dissolution rate (%) of acetaminophen 10 minutes after the start of the dissolution test, the solubility of the hard capsules was evaluated according to the following criteria.

<Evaluation of solubility>
A: Elution rate is 80% or more O: Elution rate is less than 60-80% ◇: Elution rate is less than 40-60% Δ: Elution rate is less than 30-40% x: Elution rate is less than 30%.

(C) Capsule hardness The capsule hardness was evaluated for the hard capsules (without dripping: ○, moldable: ○) that could be molded without dripping by the above method. Specifically, the prepared hard capsule is stored at 23 ° C. and a relative humidity of 43% for 3 days, and this is used as a test sample. Each test sample is in an environment of 23 ° C. and a relative humidity of 40%. A compression test was performed under the following conditions, and the maximum stress (N) and elastic modulus (N / mm ² ) were measured.

<Compression test conditions>
Test equipment: Autograph AGS-J (manufactured by Shimadzu Corporation)
Compression speed: 10mm / min,
Compression distance: 1 mm.

  FIG. 1 shows a stress-strain curve obtained in this compression test. The maximum value of the stress (N) thus obtained corresponds to “maximum stress”, and the maximum slope until the maximum stress is reached corresponds to “elastic modulus”. The hardness was calculated by multiplying the obtained maximum stress by the elastic modulus and dividing this by 1000. From the hardness thus obtained, the hardness of the hard capsule was evaluated according to the following criteria.

<Evaluation of hardness>
A: Hardness is 27 or more B: Hardness is less than 22-27 ◇: Hardness is less than 18-22 Δ: Hardness is less than 15-18 x: Hardness is less than 15.

  The results are also shown in Table 2. The values of the gelling agent (kappa carrageenan) and the gelling aid (potassium chloride, calcium chloride) in the table mean the ratio (part by weight) to 100 parts by weight of hypromellose, and the hypromellose viscosity value is the value of each hypromellose 2 used. It means the total sum of the viscosity of the% aqueous solution multiplied by the ratio (parts by weight) to 100 parts by weight of total hypromellose.

As shown in this result, when the hypromellose viscosity value is 1050 or more, liquid dripping occurs and the capsule cannot be molded. However, if it is less than that, particularly 960 or less, there is no liquid dripping and no cracks occur after drying. It was confirmed that there was no problem in capsule moldability.
From the above results, it was found that the elution rate (%), that is, the solubility in water (content elution) tends to increase as the hypromellose viscosity value decreases. Contrary to this, it was found that the hardness of the capsule tends to increase as the hypromellose viscosity value increases.

  From the balance between solubility in water and capsule hardness, it is preferable to select the hypromellose to be used for capsule preparation so that the hypromellose viscosity value is 400 to 600, and the hypromellose viscosity value is within such a range. By selecting, it was confirmed that an elution ratio of acetaminophen in 10 minutes after the start of the dissolution test was as good as 30% or more, and a hard capsule having a good balance with a capsule hardness of 15 or more could be prepared. The hypromellose viscosity value is preferably 450 to 580.

Experimental Example 2 Using 5 kinds of hypromellose having different viscosities (viscosity of 2% aqueous solution is 3, 4, 4.5, 6, 15 mPa · s) as hypromellose having improved solubility by sugar combination , the hypromellose viscosity value is 300 to What was mixed so that it might become 770 was used.

  Based on the formulation described in Table 3, in addition to the hypromellose, the gelling agent (kappa carrageenan), and the gelling aid (potassium chloride) according to the method described in Experimental Example 1 (1), sugar (fructose, sucrose) , Maltose) to prepare hard capsules (test samples 18 to 32). The sugar was dissolved after the gelling aid and the gelling agent were dissolved, and hypromellose was added to the solution.

  According to the method described in Experimental Example 1 (2), after evaluating the moldability of each hard capsule, the elution rate (%) of acetaminophen and the capsule of the hard capsule (test samples 18 to 29) that could be molded without any problem Hardness was measured and the effect of sugar formulation was investigated.

  The results are also shown in Table 3. The values of gelling agent (carrageenan) and gelling aid (potassium chloride) and sugar (fructose, sucrose, maltose) in the table mean the ratio (parts by weight) to 100 parts by weight of hypromellose. In addition, evaluation of solubility and hardness was performed according to the criteria described in Experimental Example 1 (2).

  As shown in this result, when 40 parts by weight or more of sugar is added to 100 parts by weight of hypromellose, the dry film cracks and the capsule cannot be molded. No cracks were observed after drying, and it was confirmed that there was no problem in capsule moldability.

  In Experimental Example 1 and Experimental Example 2, when the influence of the sugar composition was observed between test samples having the same hypromellose viscosity value (hypromellose viscosity value 300: test sample 1 and test samples 18-20, hypromellose viscosity value 540: test) Sample 8 and test samples 21 to 23, hypromellose viscosity value 580: test sample 10 and test samples 24-26, hypromellose viscosity value 770: test sample 14 and test samples 27 to 29), sugar when the hypromellose viscosity value is greater than 300 It was confirmed that the solubility of the hard capsule in water was improved, and the effect was increased as the hypromellose viscosity value was larger than 300 (hypromellose viscosity value 540-580: ◇ → ◎, Hypromellose viscosity value 770: x → ◯). On the other hand, it was confirmed that the capsule hardness hardly changed depending on the sugar composition and was not affected.

  In Experimental Example 1, it was shown that the elution rate (%) (solubility) tends to decrease as the hypromellose viscosity value increases. It was confirmed that it was possible.

  From the results of Experimental Examples 1 and 2, when sugar is used in a proportion of less than 40 parts by weight with respect to 100 parts by weight of the total amount of hypromellose, the hypromellose used in the capsule preparation is determined from the balance between solubility in water and capsule hardness. The hypromellose viscosity value is preferably selected to be 400 to 770, and the hypromellose viscosity value is in such a range that the hypromellose viscosity value is in such a range that the elution rate of acetaminophen in 10 minutes after the start of the elution test is 70. It was confirmed that hard capsules having a good balance with a capsule hardness of 15 or more can be prepared. The hypromellose viscosity value is preferably 450 to 770, more preferably 540 to 770, and particularly preferably 580 to 770.

Experimental Example 3 Capsule hardness improvement by blending starch Using five types of hypromellose with different viscosities (viscosity of 2% aqueous solution is 3, 4, 4.5, 6, 15 mPa · s), the hypromellose viscosity value is 300 What was mixed so that it might become -770 was used.

  Based on the formulation described in Table 4, according to the method described in Experimental Example 1 (1), in addition to the above hypromellose, gelling agent (kappa carrageenan), and gelling aid (potassium chloride), starch (waxy corn starch, Hard capsules (test samples 33 to 47) were prepared using potato starch and tapioca starch. The starch was blended immediately after the introduction of hypromellose, and then moved to a dispersing operation. After evaluating the moldability of each hard capsule according to the method described in Experimental Example 1 (2), the elution rate (%) and the capsule hardness were measured for the hard capsules (test samples 33 to 44) that could be molded without problems. The effects of starch blending were examined.

  The results are also shown in Table 4. The values of gelling agent (kappa carrageenan), gelling aid (potassium chloride), and various starches in the table mean a ratio (parts by weight) to 100 parts by weight of the total hypromellose. In addition, evaluation of solubility and hardness was performed according to the criteria described in Experimental Example 1 (2).

  As shown in this result, when 25 parts by weight or more of starch is blended with 100 parts by weight of hypromellose, liquid sagging occurs and the capsule cannot be formed, but if it is less than that, particularly 17.5 parts by weight or less, the liquid sagging also No cracks were observed after drying, and it was confirmed that there was no problem in capsule moldability.

  In Experimental Example 1 and Experimental Example 3, when the effects of starch blending were observed between test samples having the same hypromellose viscosity value (hypromellose viscosity value 300: test sample 1 and test samples 33 to 35, hypromellose viscosity value 540: test Sample 8 and test samples 36 to 38, hypromellose viscosity value 580: test sample 10 and test samples 39 to 41, hypromellose viscosity value 770: test sample 14 and test samples 42 to 44), starch, It was confirmed that the hardness was remarkably improved (hypromellose viscosity value 300: x → ○, hypromellose viscosity value 540: →→ ◎, hypromellose viscosity value 580: ○ → ◎). On the other hand, it was confirmed that the dissolution rate (%) (solubility) of the capsule hardly changed by the starch blending and was not affected.

  In Experimental Example 1, it was shown that the hardness tends to decrease as the hypromellose viscosity value decreases. However, it was confirmed that the decrease can be suppressed by using starch together and can be improved.

  From the results of Experimental Examples 1 and 3, when starch is used in a proportion of less than 25 parts by weight based on 100 parts by weight of hypromellose, from the balance between dissolution rate (%) (solubility in water) and capsule hardness, It is preferable to select the hypromellose to be used for capsule preparation so that the hypromellose viscosity value is 300 to 600. By selecting the hypromellose so that the hypromellose viscosity value falls within this range, the acetoproteose 10 minutes after the start of the elution test is obtained. It was confirmed that a well-balanced hard capsule having a good aminophen elution rate of 30% or higher and a capsule hardness of 23 or higher can be prepared. The hypromellose viscosity value is preferably 300 to 580, more preferably 300 to 560 or 540.

Experimental Example 4 Improvement of solubility and hardness of hard capsule by blending sugar and starch As hypromellose, five types of hypromellose (viscosity of 2% aqueous solution is 3, 4, 4.5, 6, 15 mPa · s) are used. Then, a mixture of hypromellose viscosity values of 300 to 770 was used.

  Based on the formulation described in Table 5, according to the method described in Experimental Example 1 (1), in addition to the hypromellose, the gelling agent (kappa carrageenan), and the gelling aid (potassium chloride), sugar (fructose, sucrose) , Maltose) and starch (corn starch, potato starch, tapioca starch) were used to prepare hard capsules (test samples 48-62). The sugar was mixed and dissolved after the gelling aid and kappa carrageenan were dissolved. In addition, hypromellose and starch were then added. After evaluating the moldability of each hard capsule according to the method described in Experimental Example 1 (2), the elution rate (%) and the capsule hardness were measured for the hard capsules (test samples 48 to 59) that could be molded without problems. The effects of adding both sugar and starch were investigated.

  The results are also shown in Table 5. The values of gelling agent (kappa carrageenan) and gelling aid (potassium chloride), various sugars, and various starches in the table mean a ratio (parts by weight) to 100 parts by weight of hypromellose. In addition, evaluation of solubility and hardness was performed according to the criteria described in Experimental Example 1 (2).

  As shown in this result, when 25 parts by weight or more of starch is blended with 100 parts by weight of hypromellose, liquid dripping occurs and the capsule cannot be molded, but if it is less than that, particularly 20 parts by weight or less, there is no liquid dripping, It was also confirmed that no cracks occurred after drying, and there was no problem in capsule moldability.

  In Experimental Example 1 and Experimental Example 4, when the influence of starch blending was observed between test samples having the same hypromellose viscosity value (hypromellose viscosity value 300: test sample 1 and test samples 48 to 50, hypromellose viscosity value 400: test By blending samples 3-5 and test samples 51-53, hypromellose viscosity value 540: test sample 8 and test samples 54-56, hypromellose viscosity value 770: test sample 14 and test samples 57-59), sugar and starch It was confirmed that the elution rate (%) (solubility in water) and hardness of the hard capsules were improved.

  In Experimental Example 1, it was shown that the dissolution rate (%) (dissolution of the contents) decreased as the hypromellose viscosity value increased, and the hardness tended to decrease as the hypromellose viscosity value decreased. And starch can be used to suppress or improve the dissolution rate when the hypromellose viscosity value is high, and the combined use of sugar and starch reduces the hardness caused when the hypromellose viscosity value is low. It was confirmed that it can be suppressed and rather improved.

  From the results of Experimental Examples 1 and 4, when sugar and starch are used in proportions of less than 40 parts by weight and less than 25 parts by weight, respectively, with respect to 100 parts by weight of the total hypromellose, the hypromellose viscosity value is selected in the range of 300 to 770. By doing so, it can be confirmed that the elution rate is 70% or more, which is excellent in water solubility, the contents can be quickly eluted, and the capsule hardness is 25 or more, and a hard capsule excellent in balance between both can be prepared. It was.

Experimental Example 5 Decrease in Viscosity of Capsule Preparation Solution by Sugar Formulation According to the method described in Experimental Example 1 (1), the above hypromellose, gelling agent (kappa carrageenan), and gelling aid ( In addition to potassium chloride), a capsule preparation solution (test samples 63 to 66) was prepared by blending sugar (fructose) at a ratio of 0 to 45 parts by weight with respect to 100 parts by weight of hypromellose. The liquid temperature of the obtained capsule preparation liquid was set to 52 ° C., and the viscosity was measured with a B-type rotational viscometer (BL type, rotor number 2) under the conditions of a rotational speed of 12 rpm and a measurement time of 1 minute. The results are shown in Table 6. The values of the gelling agent (kappa carrageenan) and the gelling aid (potassium chloride) in the table mean the ratio (parts by weight) to 100 parts by weight of hypromellose.

  As shown in the table, the viscosity of the capsule preparation liquid decreased as the blending amount of sugar (fructose) increased. From this, it is possible to adjust the viscosity of the capsule preparation liquid by using sugar together with hypromellose, and thereby it is possible to suppress an unfavorable increase in viscosity that adversely affects the workability of the capsule molding of the capsule preparation liquid.

Claims (7)

(1) A group comprising hypromellose as a film component in a ratio of a hypromellose viscosity value of 400 to 770, and further comprising 0.5 parts by weight or more and less than 40 parts by weight of monosaccharide and disaccharide with respect to 100 parts by weight of hypromellose Containing at least one sugar selected from
(2) As a film component, it contains hypromellose at a ratio of a hypromellose viscosity value of 300 to 600, and further contains 0.5 parts by weight or more and less than 25 parts by weight of starch with respect to 100 parts by weight of hypromellose, or
(3) A group comprising hypromellose as a film component in a ratio of a hypromellose viscosity value of 300 to 770, and further comprising 0.5 to 40 parts by weight of monosaccharide and disaccharide with respect to 100 parts by weight of hypromellose Containing at least one sugar selected from: and 0.5 to 25 parts by weight of starch with respect to 100 parts by weight of hypromellose;
Hard capsules characterized by (except those containing gum arabic) . As film components, characterized in that it further contains a gelling agent, and gelling aid, if necessary, hard capsule according to claim 1. A hard capsule comprising the hard capsule according to claim 1 or 2 filled with any one selected from the group consisting of pharmaceuticals and foods. (1) A group comprising hypromellose as a film component in a ratio of a hypromellose viscosity value of 400 to 770, and further comprising 0.5 parts by weight or more and less than 40 parts by weight of monosaccharide and disaccharide with respect to 100 parts by weight of hypromellose Containing at least one sugar selected from
(2) As a film component, it contains hypromellose at a ratio of a hypromellose viscosity value of 300 to 600, and further contains 0.5 parts by weight or more and less than 25 parts by weight of starch with respect to 100 parts by weight of hypromellose, or
(3) A group comprising hypromellose as a film component in a ratio of a hypromellose viscosity value of 300 to 770, and further comprising 0.5 to 40 parts by weight of monosaccharide and disaccharide with respect to 100 parts by weight of hypromellose Containing at least one sugar selected from: and 0.5 to 25 parts by weight of starch with respect to 100 parts by weight of hypromellose;
Capsule preparation, wherein, by immersing the capsule-forming pins, comprising the step of drying the film formed on the outer surface of the pin, hard capsule of claim 1 wherein (except those containing gum arabic manufacturing method of the excluded). As a film component, a method for improving the water solubility of hard capsules (except for those containing gum arabic) containing hypromellose at a ratio of a hypromellose viscosity value of 400 to 770, further comprising hypromellose as a film component A method comprising blending at least one sugar selected from the group consisting of a monosaccharide and a disaccharide in an amount of 0.5 to 40 parts by weight with respect to 100 parts by weight . As a film component, a method for improving the hardness of a hard capsule containing hypromellose at a ratio of a hypromellose viscosity value of 300 to 600 (excluding those containing gum arabic) , further comprising 100% hypromellose as a film component 0.5 parts by weight or more and less than 25 parts by weight of starch is blended with respect to parts . As a film component, a method for improving the water solubility and hardness of a hard capsule containing hypromellose at a ratio of a hypromellose viscosity value of 300 to 770 (excluding those containing gum arabic) , Further, at least one selected from the group consisting of monosaccharides and disaccharides of 0.5 parts by weight or more and less than 40 parts by weight with respect to 100 parts by weight of hypromellose and 0.5 parts by weight or more and 25 parts by weight with respect to 100 parts by weight of hypromellose. A method comprising blending less than parts by weight of starch.

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