JPWO2006082842A1 - Hard capsule with improved solubility - Google Patents

Abstract

The present invention relates to a hard capsule having improved solubility and moldability by adding a sugar alcohol to a water-soluble cellulose ether or pullulan hard capsule base, a method for producing the hard capsule, a pharmaceutical, food, health The object is to provide a hard capsule filled with food, veterinary drugs or quasi drugs.

Description

  The present invention relates to a hard capsule comprising a water-soluble cellulose ether or pullulan as a main component of a capsule shell, wherein the sugar capsule is blended in the capsule shell, a method for producing the hard capsule, and the hard capsule The present invention relates to a hard capsule filled with a filler.

Gelatin hard capsules are widely used as capsules for filling medicines, foods, and health foods. However, when the medicine filled in the capsule is susceptible to hydrolysis, the capsule skin contains about 15% of water, so that the medicine is decomposed and the potency of the main drug is reduced or altered. Discoloration may occur. Moreover, inconveniences such as insolubilization of the gelatin hard capsule film may be caused.
Furthermore, gelatin used as a hard capsule base is an animal protein, and a hard capsule that replaces the gelatin capsule has recently been demanded from the viewpoint of the risk of mad cow disease infection which has become a problem in recent years.

As an alternative to the gelatin hard capsule, for example, hard capsules based on water-soluble cellulose ethers are known (Patent Document 1, Patent Document 2, Patent Document 3). In addition, a hard capsule using a pullulan polysaccharide as a capsule base has been reported (Patent Document 4). Hard capsules based on these water-soluble cellulose ethers and pullulan have excellent characteristics such as low moisture content and resistance to cracking, and less insolubilization due to changes over time compared to normal gelatin capsules. . However, there is a problem that the dissolution is slightly delayed as compared with the gelatin hard capsule. These Patent Documents 1 to 4 do not disclose that the dissolution property of the capsule itself is improved.
Patent Document 5 discloses that a water-soluble substance (saccharide) is added to the gelatin capsule shell to improve the solubility of the capsule. However, a water-soluble substance (saccharide) of 101 to 200 parts by weight and a large amount of a water-soluble substance must be added to 100 parts by weight of gelatin, and there is a concern about a decrease in capsule strength. Further, capsules based on water-soluble cellulose ethers and pullulan are not disclosed.
Similarly to Patent Document 5, Patent Documents 6 to 8 describe capsules in which saccharides are blended in a capsule skin, but all of them disclose soft capsules that are significantly different in physical properties from hard capsules. However, hard capsules based on water-soluble cellulose ethers and pullulan are not disclosed.
The above-mentioned known hard capsules and soft capsules are difficult to industrially mass-produce, and are not practical capsules in view of dissolution properties, moldability, stability, quality, and the like.

JP 2000-136126 A JP-A-8-208458 Japanese Patent No. 2552937 Special table 2003-505565 (WO01 / 007507) gazette JP-A-9-202727 JP 2004-167084 A Japanese National Patent Publication No. 8-511795 (WO95 / 00123) JP-T-2001-505925 (WO98 / 42316)

  Generally, gelatin hard capsules are frequently used as hard capsules for pharmaceuticals, foods, health foods, and the like. However, gelatin frequently used as a hard capsule base is an animal protein and there is a risk of mad cow disease infection which has become a problem in recent years. Moreover, the gelatin hard capsule also has an undesirable phenomenon of insolubilization due to aging. In view of the above, there is a need for capsules that replace gelatin hard capsules. As an alternative to such gelatin hard capsules, hard capsules based on water-soluble cellulose ethers or polysaccharide pullulan have been developed, but there remains room for improvement in their dissolution and moldability.

  As a result of intensive studies to solve the above-mentioned problems, the present inventors have added sugar alcohols, preferably monosaccharide alcohols, to water-soluble cellulose ethers or pullulan hard capsule shells, and water-soluble cellulose ethers. It has been found that the solubility of capsules or pullulan capsules can be improved. That is, it has been found that by dissolving monosaccharide alcohols, more preferably D-mannitol or D-sorbitol, in the capsule skin, the elution of the hard capsule is remarkably improved and the moldability is also excellent. It was. In addition, in the production of hard capsules, if the viscosity of the capsule preparation liquid is high, the productivity is reduced. Furthermore, since the gelling property improves as the amount of the gelling agent used at the time of manufacturing the hard capsule increases, the moldability of the capsule is improved while the solubility of the capsule is lowered. Sugar alcohols, preferably monosaccharide alcohols, more preferably D-mannitol and D-sorbitol are suitable as additives for enhancing the gelability of the gelling agent, and these sugar alcohols reduce the viscosity of the capsule soaking solution. Thus, it has been found that the effect of improving the gelation property of the gelling agent is produced, and that it greatly contributes to the improvement of capsule productivity. The present invention has been completed based on these findings.

That is, the present invention
(1) A hard capsule containing water-soluble cellulose ethers or pullulan as a base of the capsule skin, wherein the capsule skin contains sugar alcohols,
(2) The hard capsule according to (1) above, wherein the sugar alcohol is capable of amorphizing the water-soluble cellulose ether or pullulan,
(3) The hard capsule according to the above (1) or (2), wherein the sugar alcohol is a monosaccharide alcohol,
(4) The hard capsule according to any one of (1) to (3) above, wherein the sugar alcohol is D-mannitol and / or D-sorbitol,
(5) The hard capsule according to (1) above, wherein the water-soluble cellulose ether is a hydroxyalkylalkyl cellulose,
(6) The hard capsule according to (5) above, wherein the hydroxyalkylalkylcellulose is hydroxypropylmethylcellulose,
(7) The hard capsule according to the above (4), wherein D-mannitol and / or D-sorbitol is contained in an amount of 15 to 30% by weight based on the solid content of the entire capsule skin,
(8) A hard capsule characterized by being filled with a filler in the hard capsule described in any one of (1) to (7) above,
(9) The hard capsule according to (8) above, wherein the filling is a medicine, food, health food, veterinary medicine or quasi drug,
(10) A method for producing a hard capsule, comprising immersing a pin in a solution containing water-soluble cellulose ethers or pullulan containing a sugar alcohol and a gelling agent, and drying the gel attached to the pin,
(11) Hard capsules containing water-soluble cellulose ethers or pullulan as a base for capsule skins, wherein water-soluble cellulose ethers or sugar alcohols capable of amorphizing pullulan are blended in the capsule skins To improve the dissolution of
(12) Use of sugar alcohols to improve the elution of hard capsules based on water-soluble cellulose ethers or pullulan as capsule base, and (13) Water-soluble cellulose ethers or pullulan in capsule skin Use of sugar alcohols to make water-soluble cellulose ethers or pullulan amorphous in hard capsules based on
About.

  The hard capsule of the present invention has excellent moldability, and a hard capsule manufactured by filling the hard capsule with a medicine, food, health food, veterinary medicine, quasi-drug, etc. Since the solubility is excellent at the time of handling, the effect of the filler can be quickly exhibited in the body or outside the body to achieve the purpose.

The manufacturing process of the hard capsule of this invention is modeled. Step (1) shows a separation step of the body portion and the cap portion of the hard capsule. Step (2) shows a filling step of filling the hard capsule body. A process (3) shows the process of fitting a cap part to the hard capsule body part containing a filler. Step (4) shows a step of sealing the fitted hard capsule with a sealing agent. Step (5) shows a step of drying the sealed hard capsule. The X-ray-diffraction figure of the cast film obtained by putting a fixed quantity of the solution of Example 2 and the comparative example 1 into a petri dish, and drying at room temperature is shown.

Explanation of symbols

DESCRIPTION OF SYMBOLS 1 Hard capsule cap part 2 Hard capsule body part 3 Filling material 4 Filling pipe 5 Sealing part (band seal)

The present invention relates to a hard capsule having improved moldability and solubility, characterized in that a sugar alcohol is blended in a hard capsule base of water-soluble cellulose ethers or polysaccharide pullulan, a method for producing the hard capsule, and The present invention relates to a hard capsule comprising the hard capsule filled with contents.
Hard capsules of these water-soluble cellulose ethers can be produced by a known method capable of molding the capsule, but are produced according to a normal dipping method (immersion molding method) (see: Patent Documents 1 to 3 above). For example, water-soluble cellulose ethers are dispersed and dissolved in water, alcohol or a water-alcohol mixed solution, sugar alcohol is added and dissolved in this water-soluble cellulose ether solution, and the capsule-forming pin is added to the obtained capsule immersion liquid. Can be made into hard capsules by gelling the capsule soaking solution adhering to the pins. Moreover, you may add a gelatinizer and a gelatinization adjuvant (for example, potassium ion, ammonium ion, etc.) suitably as needed. Further, if necessary, a colorant (for example, titanium oxide, bengara, blue No. 2, yellow No. 5, etc.), an opacifier (titanium oxide, etc.), a fragrance, a slip improver, a plasticizer, etc. may be appropriately blended and prepared. it can.

  As sugar alcohols to be added, water-soluble cellulose ethers or those having a favorable action on the moldability and solubility of hard capsules of pullulan, preferably those capable of amorphizing water-soluble cellulose ethers or pullulan More preferably, any sugar alcohol may be used as long as it forms a solid dispersion with water-soluble cellulose ethers or pullulan and can make the water-soluble cellulose ethers or pullulan amorphous. Can do. Specifically, monosaccharide alcohols are preferable, and D-mannitol, D-sorbitol, or a mixture thereof is more preferable. Here, monosaccharide alcohols are sugar alcohols having 5 to 6 carbon atoms. The blending ratio of sugar alcohols in the capsule preparation liquid is generally about 0.5 to 10% by weight, preferably about 1 to 8% by weight, more preferably about 1.5 to 7.5% by weight. Moreover, the compounding quantity of sugar alcohols is about 20 to 40 weight% with respect to the solid content of the whole capsule skin, Preferably it is about 17.5 to 35 weight%, More preferably, it is about 15 to 30 weight%. . If it is less than this amount, the water-soluble cellulose ethers or pullulan may not be made amorphous. On the other hand, if the amount is larger than this amount, the capsule cannot be molded, and even if it can be molded, the capsule strength may decrease, or white spots may appear on the appearance. Here, the “solid content of the entire capsule skin” is the weight excluding the solvent component (for example, purified water) of the capsule preparation liquid.

  Here, “amorphize” means that the structure of the corresponding substance has a structure in which molecules are not regularly arranged but arranged in a disorderly manner. In addition, when amorphizing, a solid dispersion may be formed or it may not be formed. Here, the “solid dispersion” is a substance in which other solid components are uniformly dispersed and stabilized in the polymer carrier. This amorphization and the formation of a solid dispersion can be confirmed by X-ray diffraction. In the case of non-quality, the characteristic peak observed in crystallization often disappears.

  Examples of water-soluble cellulose ethers used as the capsule base include methyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, hydroxyethyl methyl cellulose, hydroxyethyl ethyl cellulose, and hydroxypropyl cellulose. Among them, hydroxyalkyl alkyl cellulose is preferable, specifically Hydroxypropyl methylcellulose is exemplified as a more preferred base. The mixing ratio of the water-soluble cellulose ether in the capsule preparation liquid is generally about 5 to 30% by weight, preferably 7.5 to 25% by weight, more preferably 10 to 20% by weight. Further, the blending amount of the water-soluble cellulose ether is about 65 to 95% by weight, preferably about 70 to 90% by weight, more preferably about 72.5 to 87.87% based on the solid content of the capsule capsule as a whole. 5% by weight. If the blending ratio is less than this, the capsule film becomes thin and the strength of the capsule may be lowered. On the other hand, if the blending ratio is larger than this, the solubility of the capsule may be lowered.

  The gelling agent used in the production of the hard capsules of the water-soluble cellulose ethers is not particularly limited, but does not have a functional group capable of forming a salt such as a carboxyl group, a sulfate group, and an amino group. Any material that melts at -80 ° C and solidifies the capsule at room temperature (about 25-50 ° C) can be used. Examples of such a gelling agent include polysaccharides and celluloses. Specific examples of polysaccharides include carrageenan, agar, starch, and mannan. Specific examples of celluloses include methylcellulose, hydroxypropylcellulose, Hydroxypropylmethylcellulose and the like are exemplified, but carrageenan, agar, starch and mannan are preferred, and carrageenan, agar and starch are more preferred. Examples of starch include corn starch, potato starch, rice starch, and wheat starch. In addition, a gelatinizer can be used individually or in mixture of 2 or more types.

  The blending ratio of the gelling agent in the capsule preparation liquid is about 0.01 to 10% by weight, preferably about 0.025 to 5% by weight, more preferably about 0.03 to 3% by weight. The amount is about 0.05 to 20.0% by weight, preferably about 0.075 to 10.0% by weight, more preferably about 0.1 to 5.0% by weight, based on the solid content of the entire capsule skin. If the amount of the gelling agent is less than this blending amount, it may generally be difficult to form a capsule, and if it is more than this blending amount, the disintegration property of the capsule may be deteriorated.

  Moreover, as a gelatinization adjuvant, potassium ion, ammonium ion, etc. can be added suitably, for example, gelability can be improved and moldability can be improved. The blending ratio of the gelling aid in the capsule preparation liquid is about 0.05 to 0.6% by weight, preferably about 0.06 to 0.5% by weight, more preferably about 0.07 to 0.4% by weight. %. The amount is about 0.05 to 20.0% by weight, preferably about 0.075 to 10.0% by weight, more preferably about 0.1 to 5.0% by weight, based on the solid content of the entire capsule skin. If the gelling aid is less than this blending amount, it may generally be difficult to form capsules, and if it is greater than this blending amount, the disintegration property of the capsule may deteriorate.

On the other hand, the production of hard capsules based on pullulan can be produced according to the description in JP-A-2000-202003. That is, a capsule forming pin is immersed in a capsule preparation solution in which pullulan and a gelling agent are dissolved, and the capsule preparation solution attached to the pin is gelled and dried on this pin.
Here, pullulan is an α-1,6-linked natural polysaccharide based on maltotriose obtained by culturing Aureobasidium Pullulans, which is a kind of black yeast, using starch as a raw material. It has been known for a long time as an additive such as cosmetics, and commercially available products such as Pullulan PI-20 (manufactured by Hayashibara Co., Ltd.) can be used.

  Here, the blending ratio of pullulan in the capsule preparation liquid is generally about 5 to 30% by weight, preferably 7.5 to 25% by weight, and more preferably 10 to 20% by weight. The amount of pullulan is about 65 to 95% by weight, preferably about 70 to 90% by weight, more preferably about 72.5 to 87.5% by weight, based on the solid content of the entire capsule skin. If the blending ratio is less than this, the capsule film becomes thin and the strength of the capsule may be lowered. On the other hand, if the blending ratio is larger than this, the solubility of the capsule may be lowered.

Examples of the gelling agent to be added to the pullulan hard capsule preparation liquid include the same water-soluble cellulose ethers as those described above, and are preferably substances that easily gel due to temperature changes. Xanthan gum, locust bean gum, gellan gum, carrageenan, tamarind seed polysaccharide, pectin, curdlan, gelatin, far selelain, agar and the like, and two or more of these substances can also be used in combination.
Among these, xanthan gum / locust bean gum, gellan gum, and carrageenan are suitable for pullulan. In particular, a fast-dissolving capsule can be obtained by using gellan gum. The blending ratio of the gelling agent in the capsule preparation liquid is about 0.01 to 10% by weight, preferably about 0.025 to 5% by weight, more preferably about 0.03 to 3% by weight. The amount is about 0.05 to 20.0% by weight, preferably about 0.075 to 10.0% by weight, more preferably about 0.1 to 5.0% by weight, based on the solid content of the entire capsule skin. If the amount of the gelling agent is less than this blending amount, it may generally be difficult to form a capsule, and if it is more than this blending amount, the disintegration property of the capsule may be deteriorated.

  When kappa carrageenan (κ-carrageenan) is used as a gelling agent for pullulan hard capsules, water-soluble compounds that give potassium ions, ammonium ions, calcium ions as gelling aids, such as potassium chloride, ammonium chloride, acetic acid Ammonium, calcium chloride, and the like can be used. When iota carrageenan is used, a water-soluble compound that provides calcium ions such as calcium chloride can be used. When gellan gum is used as a gelling agent, water-soluble compounds that give sodium ions, potassium ions, calcium ions, magnesium ions, such as sodium chloride, potassium chloride, calcium chloride, magnesium sulfate, etc., are used as gelling aids. Further, organic acids and water-soluble salts thereof such as citric acid or sodium citrate can be used.

  Moreover, when using the said gelatinization adjuvant, the compounding ratio in the capsule preparation liquid of a gelatinization adjuvant is about 0.05 to 0.6 weight%, Preferably it is about 0.06 to 0.5 weight%. Preferably, it is about 0.07 to 0.4% by weight. The amount is about 0.05 to 20.0% by weight, preferably about 0.075 to 10.0% by weight, more preferably about 0.1 to 5.0% by weight, based on the solid content of the entire capsule skin. If the gelling aid is less than this blending amount, it may generally be difficult to form capsules, and if it is greater than this blending amount, the disintegration property of the capsule may deteriorate.

  In the production of pullulan hard capsules, an appropriate amount of additives usually used for hard capsules such as colorants, opacifiers, fragrances, slip improvers, and plasticizers may be added. Titanium oxide is preferably used as the opacifier.

  Preferred combinations of the components of the hydroxypropylmethylcellulose capsule in the present invention are hydroxypropylmethylcellulose, κ-carrageenan, potassium chloride, D-mannitol and / or D-sorbitol, and titanium oxide may be added thereto. The amount of the capsule preparation liquid is generally about 5 to 30% by weight of hydroxypropyl methylcellulose, about 0.01 to 10% by weight of κ-carrageenan, about 0.05 to 0.6% by weight of potassium chloride, D-mannitol and / or D-sorbitol is about 0.5 to 10% by weight, and if titanium oxide is added, about 0.1 to 5% by weight and purified water is about 65 to 95% by weight. Preferably, hydroxypropyl methylcellulose is about 7.5-25% by weight, kappa-carrageenan is about 0.025-5% by weight, potassium chloride is about 0.06-0.5% by weight, D-mannitol and / or D -Sorbitol is about 1-8 wt%, if titanium oxide is added, about 0.2-3 wt%, purified water is about 70-90 wt%. More preferably, hydroxypropyl methylcellulose is about 10-20% by weight, κ-carrageenan is about 0.03-3% by weight, potassium chloride is about 0.07-0.4% by weight, D-mannitol and / or D- Sorbitol is about 1.5 to 7.5% by weight, and if titanium oxide is added, about 0.3 to 6% by weight and purified water is about 75 to 85% by weight.

  The solid content in the capsule shell of the hydroxypropyl methylcellulose capsule in the present invention is generally about 65 to 95% by weight of hydroxypropyl methylcellulose, about 0.05 to 20% by weight of κ-carrageenan, and about 0.05 to about potassium chloride. 20% by weight, about 20-40% by weight of D-mannitol and / or D-sorbitol, and about 0.1-10% by weight if titanium oxide is added. Preferably, hydroxypropyl methylcellulose is about 70-90% by weight, κ-carrageenan is about 0.075-10.0% by weight, potassium chloride is about 0.075-10% by weight, D-mannitol and / or D-sorbitol. Is about 17.5-35% by weight, and if titanium oxide is added, it is 0.2-7.5% by weight. More preferably, hydroxypropyl methylcellulose is about 72.5 to 87.5% by weight, κ-carrageenan is about 0.1 to 5.0% by weight, potassium chloride is about 0.1 to 5.0% by weight, D-mannitol And / or about 15-30% by weight of D-sorbitol and about 0.3-6% by weight if titanium oxide is added.

  As a preferred combination of components of the pullulan capsule in the present invention, pullulan, κ-carrageenan, potassium chloride, D-mannitol and / or D-sorbitol may be added with titanium oxide. The amount of the capsule preparation liquid is generally about 5 to 30% by weight of pullulan, about 0.01 to 10% by weight of κ-carrageenan, about 0.05 to 0.6% by weight of potassium chloride, D- About 0.5 to 10% by weight of mannitol and / or D-sorbitol, about 0.1 to 5% by weight if titanium oxide is added, and about 65 to 95% by weight of purified water. Preferably, pullulan is about 7.5-25% by weight, kappa-carrageenan is about 0.025-5% by weight, potassium chloride is about 0.06-0.5% by weight, D-mannitol and / or D-sorbitol. Is about 1 to 8% by weight, if titanium oxide is added, about 0.2 to 3% by weight, and purified water is about 70 to 90% by weight. More preferably, pullulan is about 10-20% by weight, κ-carrageenan is about 0.03-3% by weight, potassium chloride is about 0.07-0.4% by weight, D-mannitol and / or D-sorbitol is About 1.5 to 7.5% by weight, if titanium oxide is added, about 0.3 to 6% by weight, purified water is about 75 to 85% by weight.

  The solid content in the capsule skin of the pullulan capsule in the present invention is generally about 65 to 95% by weight of pullulan, about 0.05 to 20% by weight of κ-carrageenan, about 0.05 to 20% by weight of potassium chloride, About 20 to 40% by weight of D-mannitol and / or D-sorbitol, and about 0.1 to 10% by weight if titanium oxide is added. Preferably, the pullulan is about 70-90% by weight, the kappa-carrageenan is about 0.075-10.0% by weight, the potassium chloride is about 0.075-10% by weight, the D-mannitol and / or D-sorbitol is about 17.5-35% by weight, if titanium oxide is added, 0.2-7.5% by weight. More preferably, pullulan is about 72.5-87.5% by weight, κ-carrageenan is about 0.1-5.0% by weight, potassium chloride is about 0.1-5.0% by weight, D-mannitol and / or Or about 15-30% by weight of D-sorbitol and about 0.3-6% by weight if titanium oxide is added.

  The temperature at which the pullulan hard capsule forming pin is immersed is also selected as appropriate, but is preferably about 30 to 80 ° C, particularly about 40 to 60 ° C. In addition, the viscosity of the capsule preparation liquid at the time of this pin immersion is about 100-10,000 mPa * s (cps), More preferably, it is 500-5000 mPa * s (cps). This viscosity is a value measured by a B-type rotational viscometer (20 ° C.). If the viscosity is lower than this, there are few capsule raw materials adhering to the capsule forming pin and the film thickness of the capsule may be thinned. If the viscosity is too high, it is generally difficult to control the capsule shape.

  The gelation after the pins are pulled up is preferably performed by allowing to cool, but may be dried by heating to about 40 to 80 ° C. after the gelation.

  The appearance of the capsule in which the sugar alcohol is blended in the finished coating is almost the same as that of the capsule in which the sugar alcohol is not blended. Even during molding, the capsule is less likely to break when it is peeled off from the pin bar. Moreover, the strength of the completed capsule is practically the same as that of a capsule containing no sugar alcohol.

  In FIG. 1, the manufacturing process of the hard capsule of this invention and a hard capsule is shown typically. Depending on the size of the capsule forming pin, the body portion (2) and the cap portion (1) of the hard capsule can be obtained. The body part and cap part of the water-soluble cellulose derivative or pullulan hard capsule thus obtained are filled with the filler (3) from the filling tube (4), and then the body part is covered with the cap part. The body part and the cap part are joined to each other, and then the body part and the cap part have a constant width around the edge of the cap part in the circumferential direction of the body part and the cap part. The fitting portion can be sealed (5) by applying the band sealant once to a plurality of times, preferably once or twice. A hard capsule can be obtained by filling a filler (for example, pharmaceutical, food, health food) by a known method before sealing the fitting portion.

  When fitting both the body part and the cap part of the hard capsule, the fitting width in which the outer circumference of the body part and the inner circumference of the cap part overlap each other is approximately 4. About 4.0-6.0 mm is generally preferred for a 5-6.5 mm, No. 4 capsule. The sealing width is generally about 1.5 to 3.0 mm for No. 3 capsules and about 1.5 to 2.8 mm for No. 4 capsules.

  As the size of the hard capsule thus obtained, there are 00, 0, 1, 2, 2, 3, 4, 5, etc., but any size of hard capsule can be produced in the present invention. .

  Examples of the filler to be filled in the hard capsule include human or animal pharmaceuticals, foods, health foods and the like, and any hard capsule film of water-soluble cellulose ethers that does not dissolve or does not react is filled. The properties of the filler may be any of solid, semi-solid, crystalline, oily, solution and the like. The hard capsule of the present invention is not only a container for oral administration of pharmaceuticals, foods, health foods, etc., but also a so-called quasi-drug for the purpose of disinfecting and cleaning dentures, glasses, contact lenses, etc. It can also be applied as a capsule for filling.

  Examples of the filler include liquids, alcohols and polyhydric alcohols such as stearyl alcohol, cetanol, polyethylene glycol 600, 800, 1000, 1500, 2000, 3000, 4000, 6000, 8000, 20000, and the like. Examples of oils and fats include sesame oil, soybean oil, peanut oil, corn oil, hydrogenated oil, paraffin oil, and beeswax. Fatty acids and derivatives thereof include stearic acid, palmitic acid, myristic acid, triethyl citrate, and triacetin. And medium chain fatty acid triglycerides. Note that an active substance such as a pharmaceutical may be dissolved in the liquid filling, but the active substance may be suspended in the liquid filling, or the liquid filling itself may be an active substance solution.

  When filling the liquid capsule with the hard capsule of the present invention, it is necessary to seal the boundary between the cap and the body of the hard capsule. Hard capsule sealing is performed using a capsule filling and sealing machine known per se, such as the capsule filling and sealing machine or capsule sealing machine (model name: HICAPSEAL 40/100, manufactured by Shionogi Qualicaps Co., Ltd.). Can do. Moreover, it is also possible to fill the capsule of the present invention with a solid filler as in the case of the liquid filler.

  Examples of the medicine filled in the hard capsule of the present invention include nourishing tonic health drugs, antipyretic analgesics, antipsychotics, anxiolytics, antidepressants, hypnotic sedatives, antispasmodics, central nervous system drugs, brain Metabolic improver, cerebral circulation improver, antiepileptic agent, sympathomimetic agent, gastrointestinal agent, antacid, antiulcer agent, antitussive expectorant, antiemetic agent, respiratory accelerator, bronchodilator, allergic agent, dental oral cavity Drugs, antihistamines, cardiotonic agents, arrhythmic agents, diuretics, antihypertensive agents, vasoconstrictors, coronary vasodilators, peripheral vasodilators, hyperlipidemia agents, antibacterial agents, antibiotics, chemotherapeutic agents, Selected from diabetes, osteoporosis, antirheumatic, skeletal muscle relaxant, antispasmodic, hormone, alkaloid narcotic, sulfa, gout treatment, anticoagulant, anti-neoplastic One or more components are used.

  For example, vitamin A, vitamin D, vitamin E (such as d-α-tocopherol acetate), vitamin B1 (such as dibenzoylthiamine, fursultiamine hydrochloride), vitamin B2 (such as riboflavin butyrate), vitamins Vitamins such as B6 (pyridoxine hydrochloride, etc.), vitamin C (ascorbic acid, sodium L-ascorbate, etc.), vitamin B12 (hydroxocobalamin acetate, cyanocobalamin, etc.), minerals such as calcium, magnesium, iron, proteins, amino acids, oligosaccharides, Contains crude drugs. Antipyretic analgesics and anti-inflammatory agents include, for example, aspirin, acetaminophen, etenzamide, ibuprofen, diphenhydramine hydrochloride, dl-chlorpheniramine maleate, dihydrocodeine phosphate, noscapine, methylephedrine hydrochloride, phenylpropanolamine hydrochloride, caffeine, anhydrous caffeine , Serrapeptase, lysozyme chloride, tolfenamic acid, mefenamic acid, diclofenac sodium, flufenamic acid, salicylamide, aminopyrine, ketoprofen, indomethacin, bucolome, pentazocine and the like.

  Examples of psychotropic drugs include chlorpromazine, reserpine and the like. Examples of anti-anxiety drugs include alprazolam, chlordiazepoxide, diazepam and the like. Examples of the antidepressant include imipramine, maprotiline hydrochloride, amphetamine and the like. Examples of the hypnotic sedative include estazolam, nitrazepam, diazepam, perlapine, phenobarbital sodium and the like. Antispasmodic agents include, for example, scopolamine hydrobromide, diphenhydramine hydrochloride, papaverine hydrochloride, and the like. Examples of central nervous system drugs include citicoline. Examples of the brain metabolism improving agent include meclofenixate hydrochloride. Examples of the cerebral circulation improving agent include vinpocetine. Examples of the antiepileptic agent include phenytoin and carbamazepine. Examples of the sympathomimetic agent include isoproterenol hydrochloride. The gastrointestinal drugs include, for example, gastrointestinal agents such as diastase, sugar-containing pepsin, funnel extract, cellulase AP3, lipase AP, cinnamon oil, etc., berberine chloride, resistant lactic acid bacteria, bifidobacteria and the like.

  Examples of the antacid include magnesium carbonate, sodium hydrogen carbonate, magnesium aluminate metasilicate, synthetic hydrotalcite, precipitated calcium carbonate, magnesium oxide and the like. Examples of the anti-ulcer agent include lansoprazole, omeprazole, rabeprazole, famotidine, cimetidine, ranitidine hydrochloride and the like. Examples of the antitussive expectorant include cloperastine hydrochloride, dextromelt fan hydrobromide, theophylline, potassium guaiacol sulfonate, guaifenesin, and codeine phosphate. Examples of the antiemetic include diphenidol hydrochloride and metoclopramide. Examples of the respiratory accelerator include levallorphan tartrate. Examples of bronchodilators include theophylline and salbutamol sulfate. Examples of allergic drugs include amlexanox and seratrodast. Examples of dental and oral drugs include oxytetracycline, triamcinolone acetonide, chlorhexidine hydrochloride, lidocaine and the like.

  Examples of the antihistamine include diphenhydramine hydrochloride, promethazine, isothipentyl hydrochloride, dl-chlorpheniramine maleate, and the like. Examples of the cardiotonic agent include caffeine and digoxin. Examples of the arrhythmic agent include procainamide hydrochloride, propranolol hydrochloride, pindolol and the like. Examples of the diuretic include isosorbide, furosemide, hydrochlorothiazide and the like. Examples of antihypertensive agents include delapril hydrochloride, captopril, hydralazine hydrochloride, labetalol hydrochloride, manidipine hydrochloride, candesartan cilexetil, methyldopa, and perindopril erbumine. Examples of the vasoconstrictor include phenylephrine hydrochloride.

  Examples of the coronary vasodilator include carbochromene hydrochloride, molsidomine, and perapamil hydrochloride. Examples of peripheral vasodilators include cinnarizine. Examples of the hyperlipidemia agent include cerivastatin sodium, simvastatin, pravastatin sodium, atorvastatin calcium hydrate and the like. Examples of the bile agent include dehydrocholic acid and trepeptone. Antibiotics include, for example, cephem series such as cephalexin, cefaclor, amoxicillin, pimecillinam hydrochloride, cefotiam hexetyl hydrochloride, cefadroxyl, cefixime, cefditoren pivoxil, cefteram pivoxil, cefpodoximiproxetil, ampicillin, dicycline acid, And synthetic antibacterial agents such as enoxacin, monobactams such as carmonam sodium, penems and carbapenems.

  Examples of the chemotherapeutic agent include sulfamethizole. Examples of the agent for diabetes include tolbutamide, voglibose, pioglitazone hydrochloride, glibenclamide, troglidazone and the like. Examples of the osteoporosis agent include ipriflavone. Examples of skeletal muscle relaxants include metocarbamol. Examples of antispasmodic agents include meclizine hydrochloride and dimenhydrinate. Antirheumatic drugs include methotrexate, bucillamine and the like. Examples of hormone agents include liothyronine sodium, dexamethasone sodium phosphate, prednisolone, oxendron, leuprorelin acetate, and the like. Alkaloid narcotics include opium, morphine hydrochloride, tocone, oxycodone hydrochloride, opium alkaloid hydrochloride, cocaine hydrochloride, and the like. Examples of the sulfa drugs include sulfisomidine and sulfamethizole. Examples of anti-gout drugs include allopurinol and colchicine. Examples of the blood coagulation inhibitor include dicumarol. Examples of the antineoplastic agent include 5-fluorouracil, uracil, mitomycin and the like.

  Examples of the health food filled in the hard capsule of the present invention include Coenzyme Q10, royal jelly, propolis, psyllium, maca extract, agaricus and the like.

These medicaments can be used alone or in combination with other medicaments. In addition, these medicines are filled with known appropriate amounts determined as appropriate according to the disease, age, etc. of the patient.
Filling of the filling into the hard capsule of the present invention can be carried out by a known capsule filling machine such as a fully automatic capsule filling machine (model name: LIQFILsuper80 / 150, manufactured by Shionogi Qualicaps Co., Ltd.), capsule filling / sealing machine ( Model name: LIQFILsuperFS, manufactured by Shionogi Qualicaps Co., Ltd.) and the like.

  The water-soluble cellulose ethers or pullulan hard capsules of the present invention have characteristics such as excellent moldability and dissolution properties and industrial production. In addition, the solubility of the hard capsule which has water-soluble cellulose ethers or pullulan as a main component of a capsule skin can be improved by mix | blending D-mannitol and / or D-sorbitol in a capsule skin.

  Based on the fifteenth revised Japanese Pharmacopoeia Paddle Method (with sinker), when the Pharmacopoeia Second Solution is used as the test solution, the opening time of the HPMC capsule of the present invention is preferably 5 minutes or less. The opening time of the pullulan capsule is preferably 10 minutes or less. Furthermore, when the dissolution test is conducted with the second liquid of the Japanese Pharmacopoeia based on the paddle method (with sinker) of the 15th revised Japanese Pharmacopoeia as a capsule-filled drug, the HPMC capsule of the present invention can be used. For example, it is preferable that 55% or more of acetaminophen elutes 10 minutes after the start of the test and 80% or more 20 minutes after the start of the test. It is preferable that 70% or more of acetaminophen elutes after a minute.

〔Example〕
Hereinafter, the present invention will be specifically described by describing examples and test examples, but the present invention is not limited thereto.

  To purified water (76.34% by weight), potassium chloride (0.10% by weight) and D-mannitol (4% by weight) were added and completely dissolved. This was heated to 80 ° C. in a water bath, hydroxypropylmethylcellulose (HPMC) (16 wt%) and titanium oxide (3.5 wt%) were added, and the mixture was sufficiently stirred and uniformly dispersed (hereinafter referred to as HPMC). Abbreviated dispersion). Separately, while stirring purified water heated to 80 to 90 ° C. in a water bath, κ-carrageenan (4 wt%) was added to prepare a 4% carrageenan aqueous solution. The 4 wt% carrageenan aqueous solution was added to the HPMC dispersion so that the carrageenan concentration was 0.06 wt%. This was moved to the desiccator for pressure reduction, and it depressurized at 55 degreeC for 1 hour or more, and deaerated. After defoaming, it was stored in an oven at 55 ° C. for 1 day. The HPMC dispersion obtained in this manner was poured into an acrylic container that had been preliminarily kept at 55 ° C., and a pin bar for capsule production was immersed therein. After pulling out the pin bar from the dispersion, aeration drying was performed at room temperature for 2 hours to obtain HPMC capsules.

  Performed with HPMC (16 wt%), D-sorbitol (4 wt%), κ-carrageenan (0.06 wt%), potassium chloride (0.10 wt%) and purified water (79.84 wt%) In the same manner as in Example 1, No. 3 capsules were prepared.

  HPMC (16 wt%), D-mannitol (2 wt%), D-sorbitol (2 wt%), κ-carrageenan (0.06 wt%), potassium chloride (0.10 wt%) and purified water (79 No. 3 capsules were prepared in the same manner as in Example 1.

  HPMC (15 wt%), D-mannitol (2 wt%), D-sorbitol (3 wt%), κ-carrageenan (0.06 wt%), potassium chloride (0.10 wt%) and purified water (79 No. 3 capsules were prepared in the same manner as in Example 1.

Comparative Example 1

  No. 3 capsule in the same manner as in Example 1 using HPMC (20% by weight), κ-carrageenan (0.06% by weight), potassium chloride (0.10% by weight) and purified water (79.84% by weight) Was prepared.

  To purified water (79.24% by weight), potassium chloride (0.12% by weight), pullulan (16% by weight) and D-mannitol (4% by weight) were added and completely dissolved. Separately, κ-carrageenan (4 wt%) was added to purified water heated to 80 ° C. to 90 ° C. in a water bath with stirring to prepare the 4 wt% carrageenan aqueous solution. The 4 wt% carrageenan aqueous solution was added to the pullulan solution heated to 80 ° C in a water bath so that the carrageenan concentration was 0.06 wt%. This was transferred to a desiccator for decompression, and degassed by depressurizing at 55 ° C. for 1 hour or more. After defoaming, it was stored in an oven at 55 ° C. for 1 day. The solution thus obtained was poured into an acrylic container which had been previously kept at 55 ° C., and a pin bar for capsule production was immersed therein. After pulling out the pin bar from the solution, it was air-dried at room temperature for 2 hours to obtain a pullulan hard capsule.

  Performed with pullulan (16 wt%), D-sorbitol (4 wt%), κ-carrageenan (0.10 wt%), potassium chloride (0.12 wt%) and purified water (79.78 wt%) In the same manner as in Example 5, No. 3 capsules were prepared.

Comparative Example 2

  No. 3 capsule in the same manner as in Example 5 using pullulan (20 wt%), κ-carrageenan (0.10 wt%), potassium chloride (0.12 wt%) and purified water (79.78 wt%) Was prepared.

Test example 1

Comparative test of capsule opening time An opening test was performed using the hard capsules manufactured in Examples 1-4 and Examples 5-6 of the present invention and the hard capsules of Comparative Examples 1-2. In the opening test, each capsule was filled with a composition (100 mg) consisting of acetaminophen (20 wt%), lactose (70 wt%) and croscarmellose sodium (10 wt%), and then the 15th revised Japanese Pharmacopoeia In accordance with the paddle method (with sinker), the second solution was used as the test solution. The opening time was confirmed visually.
Note that the opening time is such that when the capsule starts to dissolve in the test solution and opens (a hole is formed or a part of the coating is broken), the air inside the capsule is exposed to the outside and is observed as bubbles. The time when air bubbles emerged from the capsule was defined as the opening time. The opening test results are shown in Table 1.

上表から明らかなように、本発明の硬カプセルはいずれも、比較例のカプセルに比べて、開口時間が非常に速やかであることが確認された。

As is clear from the above table, it was confirmed that all the hard capsules of the present invention had a very quick opening time as compared with the capsule of the comparative example.

Test example 2

Dissolution test of capsule-filled drug The hard capsules prepared in Example 1 and Example 6 and the hard capsules prepared in Comparative Example 1 and Comparative Example 2 were mixed with acetaminophen (20% by weight) and lactose (70% by weight). And after filling each capsule with a composition (100 mg) composed of sodium croscarmellose (10 wt%), the dissolution test was performed according to the paddle method (with sinker) of the 15th revised Japanese Pharmacopoeia. The results are shown in Tables 2 and 3. In addition, the numerical value in a table | surface shows weight%.

上表から明らかなように、本発明の実施例１で得られたＨＰＭＣ硬カプセルは、比較例の標準ＨＰＭＣ硬カプセルに比べて、崩壊時間が短く、溶出性が顕著に改善された。

As is clear from the above table, the HPMC hard capsule obtained in Example 1 of the present invention has a shorter disintegration time and significantly improved dissolution as compared with the standard HPMC hard capsule of the comparative example.

表３から明らかなように、本発明の実施例６で得られたプルラン硬カプセルは、剤皮に糖アルコールを含まない比較例２のプルラン硬カプセルに比べて、崩壊時間が短く、溶出性が顕著に改善された。

As is clear from Table 3, the pullulan hard capsule obtained in Example 6 of the present invention has a shorter disintegration time and better dissolution than the pullulan hard capsule of Comparative Example 2 that does not contain sugar alcohol in the skin. Remarkably improved.

Test example 3

Hard capsule moldability test Using HPMC or pullulan as a hard capsule base, 19.17% by weight of various sugars are added to the entire capsule skin, and a capsule soaking solution with further additives is molded. HPMC hard capsules were prepared according to Example 1 or Example 5. Each capsule composition is shown in Table 4 below. In addition, the numerical value in a table | surface shows weight%.

上記組成の硬カプセルの成型性についての評価を下記表５に示す。

Table 5 below shows the evaluation of moldability of the hard capsule having the above composition.

上表から明らかなように、Ｄ−マンニトールあるいはＤ−ソルビトールをカプセル剤皮全体に対して固形分量で１９．１７重量％添加して製造されたＨＰＭＣ硬カプセルあるいはプルラン硬カプセル（カプセル番号：１、２、４、５）は、カプセル形成用ピンから剥離するときに割れが見られず、カプセル成型性について問題がないことが確認された。また、カプセル３、６の外観は、カプセル表面に白い斑点がみられた。これに対し、カプセル１、２、４、５の外観は、カプセル表面に白い斑点がみられず、糖アルコールを配合しない通常のＨＰＭＣ硬カプセルと外観はほとんど変わらなかった。

As is apparent from the above table, HPMC hard capsules or pullulan hard capsules (capsule number: 1, capsules produced by adding 19.17% by weight of D-mannitol or D-sorbitol in solid content to the whole capsule skin Nos. 2, 4, 5) were confirmed to have no problem with respect to capsule moldability because no cracks were observed when peeling from the capsule-forming pin. Moreover, as for the external appearance of the capsules 3 and 6, the white spot was seen on the capsule surface. On the other hand, the appearance of the capsules 1, 2, 4, and 5 showed no white spots on the capsule surface, and the appearance was almost the same as that of a normal HPMC hard capsule containing no sugar alcohol.

Test example 4

Hard capsule moldability test Using HPMC as a hard capsule base, 15.11% by weight of various saccharides are added to the entire capsule skin in solid content, and a composition with further additives is molded to form HPMC hard Capsules were produced according to conventional methods. Each capsule composition is shown in Table 6 below. In addition, the numerical value in a table | surface shows weight%.

上記組成の硬カプセルの成型性についての評価を下記表７に示す。

Table 7 below shows the evaluation of the moldability of the hard capsule having the above composition.

上表から明らかなように、Ｄ−マンニトールあるいはＤ−ソルビトールをカプセル剤皮全体に対して固形分量で１５．１１重量％添加して調製されたＨＰＭＣ硬カプセルあるいはプルラン硬カプセルは、カプセル形成用ピンから剥離するときに割れが見られず、カプセル成型性について問題がないことが確認された。また、カプセル３、６の外観は、カプセル表面に白い斑点がみられた。これに対し、カプセル１、２、４、５の外観は、カプセル表面に白い斑点がみられず、糖アルコールを配合しない通常のＨＰＭＣ硬カプセルと外観はほとんど変わらなかった。

As is apparent from the above table, HPMC hard capsules or pullulan hard capsules prepared by adding D-mannitol or D-sorbitol to the entire capsule skin in a solid content of 15.11% by weight are capsule forming pins. No cracks were observed when peeling from the film, and it was confirmed that there was no problem with capsule moldability. Moreover, as for the external appearance of the capsules 3 and 6, the white spot was seen on the capsule surface. On the other hand, the appearance of the capsules 1, 2, 4, and 5 showed no white spots on the capsule surface, and the appearance was almost the same as that of a normal HPMC hard capsule containing no sugar alcohol.

Test Example 5

X-ray diffraction The solutions of Example 2 and Comparative Example 1 were placed in a petri dish and then dried at room temperature to prepare a cast film. This film was X-ray diffracted (see FIG. 2).
X-ray diffraction was performed under the following conditions.
-X-ray diffractometer: Cu K-ALPHA1 (50 kV / 300 mA)
・ Divergent slit: 1/2 deg
・ Scattering slit: 1/2 deg
・ Light receiving slit: 0.15mm
・ Scanning speed: 4 ° / min
As a result of this X-ray diffraction, in the case of Comparative Example 1, a sharp peak derived from crystals was observed in the vicinity of 2θ = 7 °. On the other hand, in the case of Example 2, no sharp peak derived from the crystal was observed, and the intensity reflecting the crystallinity was lower in Example 2 than in Comparative Example 1, and in Example 2, HPMC Amorphization was suggested.

The hard capsule according to the present invention is useful as a container for oral administration of pharmaceuticals, foods, health foods, veterinary drugs, quasi drugs and the like.

Claims (13)

  A hard capsule containing a water-soluble cellulose ether or pullulan as a base of a capsule skin, wherein the capsule skin contains a sugar alcohol.   The hard capsule according to claim 1, wherein the sugar alcohol is capable of amorphizing the water-soluble cellulose ether or pullulan.   The hard capsule according to claim 1 or 2, wherein the sugar alcohol is a monosaccharide alcohol.   The hard capsule according to any one of claims 1 to 3, wherein the sugar alcohol is D-mannitol and / or D-sorbitol.   The hard capsule according to claim 1, wherein the water-soluble cellulose ether is a hydroxyalkylalkyl cellulose.   The hard capsule according to claim 5, wherein the hydroxyalkylalkylcellulose is hydroxypropylmethylcellulose.   The hard capsule according to claim 4, wherein D-mannitol and / or D-sorbitol is contained in an amount of 15 to 30% by weight based on the solid content of the entire capsule skin.   A hard capsule formed by filling a hard capsule according to any one of claims 1 to 7 with a filler.   The hard capsule according to claim 8, wherein the filling is a medicine, food, health food, veterinary drug or quasi drug.   A method for producing a hard capsule, comprising immersing a pin in a solution containing water-soluble cellulose ethers or pullulan containing a sugar alcohol and a gelling agent, and drying the gel attached to the pin.   Dissolvability of hard capsules containing water-soluble cellulose ethers or pullulan as a base for capsule shells, which contains sugar alcohols that can make water-soluble cellulose ethers or pullulan amorphous. How to improve.   Use of sugar alcohols to improve the dissolution of hard capsules based on water-soluble cellulose ethers or pullulan as the base of capsule shells. Use of sugar alcohols for making water-soluble cellulose ethers or pullulan amorphous in hard capsules based on water-soluble cellulose ethers or pullulan.

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