WO2006082842A1

WO2006082842A1 - Hard capsule having improved solubility

Info

Publication number: WO2006082842A1
Application number: PCT/JP2006/301645
Authority: WO
Inventors: Satoshi Sakuma
Original assignee: Qualicaps Co., Ltd.
Priority date: 2005-02-03
Filing date: 2006-02-01
Publication date: 2006-08-10
Also published as: JPWO2006082842A1

Abstract

A hard capsule produced by adding a sugar alcohol to a base material for a hard capsule such as a water-soluble cellulose ether or pulluran to thereby improve solubility and molding processability; a process for producing the hard capsule; and a hard capsule preparation comprising the hard capsule and a medicine, food, health food, veterinary medicine or medicated cosmetic encapsulated in the hard capsule.

Description

Specification

Hard capsule with improved solubility

Technical field

[0001] The present invention relates to a hard capsule comprising a water-soluble cellulose ether or pullulan as a main component of a capsule skin, wherein a sugar alcohol is blended in the capsule skin, a method for producing the hard capsule, and The present invention relates to a hard capsule in which the hard capsule is filled.

Background art

[0002] Gelatin hard capsules are widely used as capsules for filling medicines, foods, and health foods. However, if the medicine filled in the capsule is susceptible to hydrolysis, the capsule skin retains about 15% of water, so the medicine decomposes and the potency of the active ingredient Deterioration, deterioration, and discoloration may occur. Also, it may cause inconveniences such as insolubility of gelatin hard capsule film.

Furthermore, gelatin used as a hard capsule base is an animal protein. In recent years, there has been a demand for a hard capsule that replaces the gelatin capsule in view of the risk of mad cow disease infection. Yes.

[0003] 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). A hard capsule using a pullulan polysaccharide as a capsule base has also 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 over time compared to normal gelatin capsules. is doing. However, there was a problem that the dissolution was slightly delayed compared to hard gelatin capsules. These Patent Documents 1 to 4 disclose that the elution property of capsule is improved.

Patent Document 5 discloses that a water-soluble substance (saccharide) is added to the shell of a gelatin capsule to improve the solubility of the capsule. However, a large amount of 101-200 parts by weight of water-soluble substance (saccharide) must be added to 100 parts by weight of gelatin. There is a concern that the capsule strength may decrease. Also, capsules based on water-soluble cellulose ethers and pullulan have been disclosed!

Similarly to Patent Document 5, Patent Documents 6 to 8 are described as capsules in which saccharides are blended in capsule skins. However, there is a difference in soft capsules whose physical properties are significantly different from hard capsules. Disclosed are hard capsules based on water-soluble cellulose ethers and pullulan.

The above known hard capsules and soft capsules are not practical capsules in view of elution, moldability, stability, quality, etc., which are difficult to industrially mass produce.

[0004] Patent Document 1: Japanese Patent Application Laid-Open No. 2000-136126

Patent Document 2: JP-A-8-208458

Patent Document 3: Japanese Patent No. 2552937

Patent Document 4: Special Table 2003-505565 (WO01 / 007507) Publication

Patent Document 5: Japanese Patent Laid-Open No. 9-202727

Patent Document 6: Japanese Unexamined Patent Application Publication No. 2004-167084

Patent Document 7: Japanese National Patent Publication No. 8-511795 (WO95 / 00123)

Patent Document 8: Special Table 2001—505925 (W098 / 42316)

Disclosure of the invention

Problems to be solved by the invention

[0005] Gelatin hard capsules are commonly 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. Gelatin hard capsules also have an undesirable phenomenon of insolubility due to changes over time. In view of the above, there is a need for capsules that replace gelatin hard capsules. As an alternative to such hard gelatin capsules, water-soluble cellulose ethers or hard capsules based on the polysaccharide pullulan have been developed. There remains room for improvement in their dissolution and moldability. It was.

Means for solving the problem

[0006] As a result of intensive studies to solve the above-mentioned problems, the present inventors have found that a water-soluble cellulose agent. It has been found that the solubility of water-soluble cellulose ethers or pullulan capsules can be improved by adding sugar alcohols, preferably monosaccharide alcohols, to hard capsules of tellurium or pullulan. That is, by incorporating monosaccharide alcohols, more preferably D-manntol or D sorbitol into the capsule skin, the elution of the hard capsules is remarkably improved and the moldability is excellent. I found it. In addition, in the manufacture of hard-pressed capsules, the viscosity of the capsule preparation liquid is high, leading to a decrease in productivity. Further, the gelling property is improved as the amount of the gelling agent used at the time of manufacturing the hard capsule is increased, so that the moldability of the capsule is improved while the solubility of the capsule is lowered. As an additive for enhancing the gelability of the gelling agent, sugar alcohols, preferably monosaccharide alcohols, more preferably D-manntol and D-sorbitol are suitable. It has been found that the viscosity of the gel is lowered, the gelling property of the gelling agent is improved, and the effect is produced, which greatly contributes to the improvement of the capsule productivity. The present invention has been completed based on these findings.

That is, the present invention

(1) a hard capsule containing a water-soluble cellulose ether or pullulan as a base of the capsule skin, characterized by containing sugar alcohols in the capsule skin;

(2) The hard capsule according to (1) above, wherein the sugar alcohol is capable of making water-soluble cellulose ethers or pullulan amorphous.

(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 Z or D sorbitol,

(5) The hard capsule according to the above (1), wherein the water-soluble cellulose ether is hydroxyalkylalkyl cellulose,

(6) The hard capsule according to the above (5), wherein the hydroxyalkylalkylcellulose is hydroxypropylmethylcellulose,

(7) The hard capsule according to (4) above, wherein D-mannitol and Z or D sorbitol are 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 filling the hard capsule described in any one of (1) to (7) above with a filler,

(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) Water-soluble cellulose ethers or pullulans are incorporated into capsule skins, and water-soluble cellulose ethers or pullulans are incorporated into capsule skins. A method for improving the dissolution of hard capsules,

(12) the use of sugar alcohols to improve the dissolution of hard-pressed pellins based on water-soluble cellulose ethers or pullulan, and

(13) Use of sugar alcohols to make water-soluble cellulose ethers or pullulan amorphous in hard capsules based on water-soluble cellulose ethers or pullulan

About.

The invention's effect

[0008] The hard capsule of the present invention is excellent in moldability, and a hard capsule produced by filling the hard capsule with a medicine, food, health food, veterinary medicine, quasi drug, etc. Or, since it has excellent solubility during ingestion or handling, the effect of the filler can be quickly demonstrated in the body or outside the body to achieve the purpose.

Brief Description of Drawings

[0009] [Fig. 1] A schematic diagram of a process for producing a hard capsule of the present invention. Step (1) shows a step of separating the body portion and the cap portion of the hard capsule. Step (2) shows a filling step of filling the hard capsule body. Step (3) shows a step of fitting the cap portion to the hard capsule body portion containing the 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. FIG. 2 shows X-ray diffraction patterns of cast films obtained by putting a certain amount of the solutions of Example 2 and Comparative Example 1 in a petri dish and then drying at room temperature.

Explanation of symbols

[0010] 1 hard capsule cap

2 Hard capsule body

3 Filling

4 Filling tube

5 Sealing part (band seal)

BEST MODE FOR CARRYING OUT THE INVENTION

[0011] The present invention relates to a hard capsule having improved moldability and solubility, characterized in that a sugar alcohol is blended with a hard capsule base of water-soluble cellulose ethers or polysaccharide pullulan, and the hard capsule And 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 dating 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 mixture of alcohols, and sugar alcohol is added and dissolved in the water-soluble cellulose ether solution, and the resulting capsule soaking solution is used for capsule formation. A pin can be dipped at a predetermined temperature, and then a capsule dipping solution adhering to the pin can be gelled to form a hard capsule. Further, if necessary, a gelling agent and a gelling aid (for example, potassium ion, ammonium ion, etc.) may be appropriately added. If necessary, colorants (eg titanium oxide, bengara, blue No. 2, yellow No. 5 etc.), opacifiers (titanium oxide etc.), fragrances, slip improvers, plasticizers etc. can do.

[0012] As the sugar alcohol to be added, water-soluble cellulose ethers or those having a preferable effect on the moldability and solubility of hard capsules of pullulan, preferably water-soluble cellulose ethers or pullulan are used in an amorphous form. Can form a solid dispersion with water-soluble cellulose ethers or pullulan, more preferably water-soluble cellulose Any sugar alcohol can be used as long as it can make the ether or pullulan amorphous. Specifically, monosaccharide alcohols are preferred, more preferably D-mannitol, D-sorbitol or a mixture thereof. Here, monosaccharide alcohols are sugar alcohols having 5 to 6 carbon atoms. The mixing 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. . In addition, the amount of sugar alcohols is about 20 to 40% by weight, preferably about 17.5 to 35% by weight, more preferably about 15 to 30% by weight, based on the total solid content of the capsule skin. It is. If the amount 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, “to become amorphous” means that in the structure of the corresponding substance, the molecules are not regularly arranged but arranged in a disorderly manner. In the case of amorphization, a solid dispersion may or may not be formed. Here, the “solid dispersion” is a substance in a state where other solid components are uniformly dispersed and stabilized in the polymer carrier. The formation of an amorphous material and a solid dispersion can be confirmed by X-ray diffraction. When the material is made non-quality, the characteristic peak observed in crystallization often disappears.

[0014] Examples of water-soluble cellulose ethers used as capsule bases include methyl cellulose, hydroxypropino retino resenorelose, hydroxy ethino reseno relose, hydroxy methyl methyl cellulose, hydroxy ethyl cellulose, and hydroxypropyl cellulose. Among them, hydroxyalkylalkylcellulose is preferable.

Specifically, hydroxypropylmethylcellulose is more preferred and exemplified as a base. The blending ratio of the water-soluble cell mouth 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. In addition, blending of water-soluble cellulose ethers with respect to the solid content of the entire capsule skin Amount will range from about 65 to 95 weight ^_0/0, preferably from about 70 to 90 weight ^_0/0, more preferably to about 72.5 to 87.5 wt%. 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 higher than this, the solubility of the capsule may be lowered.

[0015] The gelling agent used in the production of the hard capsules of the water-soluble cellulose ethers is not particularly limited, but has a functional group capable of forming a salt such as a carboxyl group, a sulfate group, or an amino group. Any one that melts at 40 to 80 ° C. and solidifies the capsule at room temperature (about 25 to 50 ° C.) can be used. Examples of such gelling agents include polysaccharides and celluloses. Specific examples of polysaccharides include carrageenan, agar, starch, and mannan. Specific examples of celluloses include methylcellulose and hydroxypropylcellulose. , Hydroxypropyl methylcellulose, and the like are preferable. Carrageenan, agar, starch, and mannan are preferable, and carrageenan, agar, and denpen are more preferable. Examples of the starch include corn starch, potato starch, rice starch and wheat starch. The gelling agent can be used alone or as a mixture of two or more.

[0016] The blending ratio of the gelling agent in the capsule preparation liquid is about 0.01 to: LO wt%, preferably about 0.025 to 5 wt%, more preferably about 0.03 to 3 wt%. It 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 total solid content of the 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.

[0017] In addition, as a gelling aid, for example, potassium ions, ammonium ions and the like can be appropriately added to improve gelling properties and improve moldability. The mixing ratio of the gelling aid in the capsule preparation solution 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. About 0.05 to 20 on the solid content of the entire capsule skin. 0 wt ^_0/0, preferably from about 0.075 to 10.0 wt ^_0/0, more favorable Mashiku about 0.1 to 5. 0% by weight. If the amount of gelling aid is less than this amount, it may generally be difficult to form a force capsule, and if it is greater than this amount, Capsule disintegration may worsen.

On the other hand, hard capsules based on pullulan can be manufactured 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 adhering to the pin is gelled and dried on this pin.

Here, pullulan is an a-1,6-linked natural polysaccharide with maltotriose obtained by culturing Aureobasidium Pul lulans, a kind of black yeast, using starch as a raw material. It has been known for a long time as an additive for cosmetics and the like, and commercially available products such as pullulan PI-20 (manufactured by Hayashibara Co., Ltd.) can be used.

[0019] 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, 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 total solid content of the capsule shell. 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.

[0020] The gelling agent to be added to the pullulan hard capsule preparation liquid can be exemplified by the same gelling agents as the water-soluble cellulose ethers, and a substance that easily gels due to temperature change is preferred. More specifically, xanthan gum, locust bean gum, gellan gum, carrageenan, tamarind seed polysaccharide, pectin, curdlan, gelatin, fur celerane, agar, etc. It can also be used.

Among them, xanthan gum Z locust bean gum, dielan gum, and carrageenan are suitable for Punoreran. In particular, by using dielan gum, a fast-dissolved capsule can be obtained. 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. About 0.05 to 20 on the solid content of the entire capsule skin. 0 wt%, preferably about 0. 075-10. 0 wt ^_0/0, more preferably about 0.1 to 5.0 wt% is there. Gelling agent power If less than this amount, it is generally difficult to form capsules. If the amount is more than the amount of octopus, the disintegration property of the capsule may be deteriorated.

[0021] In the case of using kappa carrageenan (Kappa Ichiroku Laginan) as a gelling agent for pullulan hard capsules, water-soluble compounds that give potassium ions, ammonium ions, calcium ions as gelling aids, For example, salt potassium, salt ammonium, acetate acetate, salt calcium, etc. can be used. Water-soluble compounds can be used. In addition, when dilanthanum is used as a gelling agent, water-soluble compounds that give sodium ions, potassium ions, calcium ions, magnesium ions as gelling aids, such as sodium chloride sodium, salt potassium, salt匕 Calcium, magnesium sulfate and the like can be used, and organic acids and water-soluble salts thereof such as citrate or sodium taenoate can be used.

[0022] When the gelling aid is used, 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 0.00. 5% by weight, more preferably about 0.07-0.4% by weight. About 0.05 to 20 on the solid content of the entire capsule skin. 0 wt ^_0/0, preferably about 0.075 to 10.0 wt ^_0/0, more preferably about 0.1 to 5.0 weight %. If the amount of the gelling aid is less than this blending amount, it may generally be difficult to form capsules, and if it is more than this blending amount, the disintegration property of the capsule may be deteriorated.

[0023] When producing 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. As the opaque agent, titanium oxide is preferably used.

[0024] Preferable hydroxypropylmethylcellulose capsules in the present invention! /, The combination of ingredients is hydroxypropylmethylcellulose, kappa rugassin, potassium chloride, D-manntol and Z or D-sorbitol, and titanium oxide. May be added. The amount of preparation of the capsule, generally hydroxy propyl cellulose of about 5 to 30 wt%, kappa Ichiriki Raginan about 0.01 to 10 weight ^_0/0, potassium chloride of about 0.05 to 0. 6 weight ^_0/0, D- Man - tall and Z or D- Sol Bi torr to about 0.5 to 10 wt%, if added Sani匕titanium, about 0.1 to 5 wt%, seminal The water production is about 65-95% by weight. . Preferably, hydroxypropylmethylcellulose about 7.5 to 25 wt%, kappa Ichiriki Raginan about 0.025 to 5 wt%, potassium chloride of about 0.06 to 0 5 weight ^_0/0, D-Man - Toll and Z or D-sorbitol are about 1-8% by weight, if added with titanium dioxide, about 0.2-3% by weight, purified water is about 70-90% by weight. More preferably, hydroxypropyl methylcellulose about 10-20 weight ^{_0/0, κ} -. Carrageenan about 0.03 to 3 wt%, potassium chloride of about 0.07 to 0 4% by weight, D-Man two tall and Z or D- sorbitol approximately 1.5 to 7.5 weight ^_0/0, if added Caro titanium oxide, about 0.3 to 6 wt%, purified water is about 75 to 85 wt%.

[0025] The solid content in the capsule shell of hydroxypropylmethylcellulose capsules in the present invention is generally about 65 to 95% by weight of hydroxypropylmethylcellulose, about 0.05 to 20% by weight of Kappa lagonin, and potassium chloride. There about 0.05 to 20 wt%, D- Man - tall and Z or D- sorbitol from about 20 to 40 weight ^_0/0, if titanium oxide is added, about 0.1 to 10 wt% It is. Preferably, hydroxy propyl cellulose of about 70-90 weight ^_0/0, kappa Ichiriki Raginan about 0.075 to 10.0 wt ^_0/0, potassium chloride of about 0.075 to 10 weight ^_0/0, D - Man - tall and Z or D - sorbitol from about 17.5 to 35 wt%, if titanium oxide is added, is from 0.2 to 7.5 wt ^_0/0. More preferably hydroxypropylmethyl cellulose of about 72.5 to 8 7.5 wt%, kappa Ichiriki Raginan about 0.1 to 5.0 wt%, potassium chloride of about 0.1 to 5.0 weight ^_0/0 , D- Man - tall and Z or D- sorbitol from about 15 to 30 weight ^_0/0, if the acid titanium is added, from about 0.3 to 6 wt%.

[0026] Preferable pullulan capsules in the present invention U, the combination of ingredients is pullulan, kappa one laguinane, potassium chloride, D-manntol and Z or D-sorbitol, with addition of titanium oxide. It may be. The amount of preparation of the capsule, generally pullulan about 5-30 wt%, kappa Ichiriki Raginan about 0.01 to 10 wt%, salt I spoon potassium about 0.05 to 0.6 weight ⁰ / ₀ , D-mannitol and Z or D-sorbitol are about 0.5 to: L0% by weight, about 0.1 to 5% by weight of titanium oxide, about 65% purified water ~ 95% by weight. Preferably, pullulan about 7.5 to 25 wt%, kappa Ichiriki Ragi one Nan about 0.025 to 5 weight ^_0/0, potassium chloride of about 0.06 to 0.5 weight ^_0/0, D- Cloak Lumpur and Z or D- sorbitol from about 1-8 weight ^_0/0, if the addition of titanium oxide, about 0.2 to 3 wt%, purified water is about 70 to 90 wt%. More preferably, pullulan about 10 to 20 wt%, kappa Ichiriki Raginan about 0.03 to 3 wt%, potassium chloride of about 0.07 to 0 4 wt ^_0/0, D-Man -. Tall and Z Or D-sorbitol is about 1.5 to 7.5% by weight; if acid-titanium is added, about 0.3 to 6% by weight; purified water is about 75 to 85% by weight.

[0027] The solid content in the capsule skin of the pullulan capsules according to the present invention is generally about 65 to 95% by weight of pullulan, about 0.05 to 20% by weight of κ-carrageenan, and about 0.05 of potassium chloride. 20wt ^_0/0, D- Man - tall and Z or D- sorbitol from about 20 to 40 wt%, if titanium oxide is added, Ru about 0.1 to 10 wt% der. Preferably, pullulan about 70-90 weight ^_0/0 One force Raginan about 0. 075- 10.0 wt kappa ^_0/0, potassium chloride of about 0.075 to 10 weight ^_0/0, D-Man - Tall and Z or D—sorbitol is about 17.5-35% by weight, and if titanium oxide is added, 0.2-7.5% by weight. More preferably pullulan about 72.5 to 87.5 weight ^_0/0, kappa Ichiriki Ruggie Nan about 0.1 to 5.0 wt%, potassium chloride of about 0.1 to 5.0 wt%, D -Mannitol and cocoon or D-sorbitol is about 15-30% by weight, and if titanium oxide is added, about 0.3-6% by weight.

[0028] The temperature at which the pin for forming the pullulan hard capsule is immersed is also appropriately selected. The force is preferably about 30 to 80 ° C, particularly about 40 to 60 ° C. The viscosity of the capsule preparation liquid during the pin immersion is about 100 to 10, OOOmPa-s (cps), more preferably 500 to 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 is a risk that the capsule film thickness will be thin due to less capsule raw material adhering to the capsule forming pin. If the viscosity is too high, it may be difficult to control the capsule shape in general. There is.

[0029] The gelling 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 gelation.

[0030] The appearance of the capsules in which the sugar alcohol is blended in the finished coating is almost the same as the capsules in which the sugar alcohol is not blended. Also, when molding, pin bar When peeling from the capsule, the capsule is less likely to break. However, the strength of the finished capsule is practically the same as capsules without sugar alcohol.

[0031] FIG. 1 schematically shows a production process of the hard capsule and the hard capsule of the present invention. Depending on the size of the capsule forming pin, the body part (2) and the cap part (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) through the filling tube (4), and then the body part is covered with the cap part. The body part and the cap part are joined by fitting them together, so that the circle of the body part and the cap part is formed on the surface of the body part and the surface of the cap part with a constant width centered on the edge part of the cap part. The fitting part can be sealed (5) by applying the band-sinole agent once to a plurality of times, preferably once or twice in the circumferential direction. A hard capsule can be obtained by filling a filler (for example, pharmaceutical, food, health food) by a method known per se before sealing the fitting portion.

[0032] 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 4.5 to 6.5 mm for capsules and about 4.0 to 6. Omm for No. 4 capsules are generally preferred. Also, the sealing width is generally about 1.5-3. Omm for No. 3 capsule, and about 1.5-2.8 mm for No. 4 capsule!

[0033] The size of the hard capsule thus obtained includes 00, 0, 1, 2, 3, 4, 5, etc., but in the present invention! Can be manufactured.

[0034] Examples of the filler to be filled in the hard capsule include human or animal pharmaceuticals, foods, health foods, etc., and any one that does not dissolve or react with the hard capsule film of water-soluble cellulose ethers can be used. The properties of the filler may be any of solid, semi-solid, crystalline, oily, solution and the like. Further, the hard pushell 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 / cleaning dentures, glasses, contact lenses, etc. It can also be applied as a capsule for filling.

[0035] As the filling, as examples of liquid filling, alcohols, polyhydric alcohols, Steari Nore Nore = f 1 Nore, Setano Nore, Posiethylene Guino I Nore 600, 800, 1000, 1500, 2000, 3000, 4000, 6000, 8000, 20000, etc. , Peanut oil, corn oil, hydrogenated oil, paraffin oil, honey beeswax and the like, and fatty acids and derivatives thereof include stearic acid, palmitic acid, myristic acid, triethyl citrate, triacetin, and medium-chain fatty acid tridariseide. . It should be noted 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.

[0036] When the liquid capsule is filled into the hard capsule of the present invention, it is necessary to seal the boundary between the hard capsule cap and the body. Sealing of hard capsules is carried out using a capsule filling and sealing machine known per se, such as the capsule filling and sealing machine or the capsule sealing machine (model name: HICAPSEAL 40/100, manufactured by Shionogi Qualicabus Co., Ltd.). Can. Further, like the liquid filler, the capsule of the present invention can be filled with the solid filler.

[0037] Examples of the medicine filled in the hard capsule of the present invention include nourishing tonic health drugs, antipyretic analgesics, antipsychotics, anti-anxiety drugs, antidepressants, hypnotic sedatives, antispasmodics, central nervous system Drugs, cerebral metabolism improving agents, cerebral circulation improving agents, antiepileptic agents, sympathomimetic agents, gastrointestinal agents, antacids, antiulcer agents, antitussive expectorants, antiemetics, respiratory stimulants, bronchodilators, allergic agents , Dental and oral medicine, antihistamine, cardiotonic, arrhythmic agent, diuretic, antihypertensive agent, vasoconstrictor, coronary vasodilator, peripheral vasodilator, hyperlipidemia agent, biliary, antibiotic, chemical Therapeutic agent, antidiabetic agent, osteoporosis agent, antirheumatic drug, skeletal muscle relaxant agent, antipruritic agent, hormone agent, alkaloid narcotic drug, sulfa drug, anti-gout drug, anticoagulant agent, antineoplastic agent, etc. One or more selected ingredients are used .

[0038] Nourishing tonic health drugs include, for example, vitamin A, vitamin D, vitamin E (such as acetic acid d—a-tocopherol), vitamin B1 (such as dibenzoylthiamine, fursultiamine hydrochloride), vitamin B2 ( Such as riboflavin butyrate), vitamin B6 (such as pyridoxine hydrochloride), vitamin C (such as ascorbic acid, sodium L-ascorbate), vitamin B12 (such as hydroxocobalamin acetate, cyanobaramin acetate), calcium, magnesium, This includes minerals such as iron, proteins, amino acids, oligosaccharides, and crude drugs. Examples of antipyretic analgesic anti-inflammatory drugs include Spirin, acetaminophen, ethenzamide, ibuprofen, diphenhydramine hydrochloride, cQ-chlorfelamine maleate, dihydrocodeine phosphate, nospower pin, methyl ephedrine hydrochloride, phenol propanolamine hydrochloride, caffeine, anhydrous caffeine, sera Examples include peptase, lysozyme chloride, tolfenamic acid, mefenamic acid, diclofenac sodium, flufenamic acid, salicylamide, aminobilin, ketoprofen, indomethacin, bucolome, pentazocine and the like.

[0039] Examples of the psychotropic drug include chlorpromazine, reserpine and the like. Examples of anti-anxiety drugs include alprazolam, chlordiazepoxide, diazepam and the like. Examples of the antidepressant include imibramin, maprotiline hydrochloride, amphetamine and the like. Examples of the hypnotic sedative include estazolam, nitrazebam, diazebam, perlapine, sodium phenobarbital and the like. Antispasmodic agents include, for example, scopolamine hydrobromide, diphenhydramine hydrochloride, papaverine hydrochloride, and the like. Examples of central neuropathic drugs include citicoline. Examples of the brain metabolism improving agent include meclofenixate hydrochloride. Examples of the cerebral circulation improving agent include vinpocetine. Antiepileptic agents include, for example, fatin, strong rubamazepine and the like. Examples of sympathomimetic agents include isoproterenol hydrochloride. Gastrointestinal drugs include, for example, healthy stomach antiseptics such as diastase, sugar-containing pepsin, funnel extract, cellulase AP3, lipase AP, keihi oil, intestinal agents such as salt berberine, resistant lactic acid bacteria, and bifidobacteria. included.

[0040] 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, omebrazole, rabeprazole, famotidine, cimetidine, latidine hydrochloride and the like. Examples of the antitussive expectorant include cloperastine hydrochloride, dextromelt fan hydrobromide, theophylline, potassium guaiacol sulfonate, guaifenesin, and codin phosphate. Examples of the antiemetic include diphe-dol hydrochloride, metocloblamide and the like. Examples of the respiration promoting agent include levalorphan tartrate. Examples of bronchodilators include theophylline and salbutamol sulfate. Allergic drugs and Examples include amlexanox and seratrodast. Examples of the dental and oral medicine include oxytetracycline, triamcinolone acetonide, chlorhexidine hydrochloride, lidocaine and the like.

[0041] Examples of the antihistamine include diphenhydramine hydrochloride, promethazine, isothipentyl hydrochloride, dl-chlorfelamin maleate, and the like. Examples of the cardiotonic agent include caffeine and digoxin. Examples of the arrhythmic agent include prokinamide hydrochloride, propranolol hydrochloride, pindolol and the like. Examples of diuretics include isosorbide, furosemide, and hydrothiazide thiazide. Examples of the antihypertensive agent include delapril hydrochloride, captopril, hydralazine hydrochloride, labetalol hydrochloride, mardipine hydrochloride, candesartan cilexetil, methyldono, and perindopril elpmine. Examples of the vasoconstrictor include fe-refrin hydrochloride and the like.

[0042] 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, sympastatin, pravastatin sodium, atorvastatin calcium hydrate and the like. Examples of the astringent include dehydrocholic acid and trepeptone. Antibiotics include, for example, cefemine such as cephalexin, cefaclor, amoxicillin, pipmecillin hydrochloride, cefothiam hexetyl, cephadoxyl, cefixime, cefditoren poxyxil, cefteram pivoxil, cefpodoximiproxetil, ampicillin, Synthetic antibacterial agents such as cyclacin, nalidixic acid, enoxacin, monobatams such as carmonam sodium, penems, and rubapenem antibiotics.

[0043] Examples of the chemotherapeutic agent include sulfamethizole. Examples of the antidiabetic agent include tolptamide, voglibose, pioglitazone hydrochloride, darifenclamide, and trodaridazone. Examples of the osteoporosis agent include ibriflavone. Examples of skeletal muscle relaxants include metocarbamol. Examples of the antispasmodic agent include methalizine hydrochloride and dimenhydrinate. Antirheumatic drugs include mesotrexate and bucillamine. Hormonal agents include, for example, Rioti-Natrium, Dexamethasone Sodium Phosphate, Pred-Zolone, Oxendron, Leuproacetate Examples include relin. 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 alopurinol and colchicine. Examples of the blood coagulation inhibitor include dicumarol. Examples of the antineoplastic agent include 5-fluorouracil, uracil, mitomycin and the like.

[0044] Examples of the health food filled in the hard capsule of the present invention include Coenzyme Q10, royal jelly, propolis, psyllium, maca extract, agaritas and the like.

[0045] 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 is performed 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 and sealing machine ( Model name: LIQFILsuperFS, manufactured by Shionogi Qualicabus Co., Ltd.) and the like.

[0046] The water-soluble cellulose ethers or pullulan hard capsules of the present invention have characteristics such as excellent moldability and elution and can be industrially produced. In addition, the solubility of hard capsules containing water-soluble cellulose ethers or pullulan as the main component of the capsule skin should be improved by adding D-manntool and Z or D-sorbitol into the capsule skin. Can do.

[0047] Based on the 15th revised Japanese Pharmacopoeia paddle method (with sinker), when the second solution of the pharmacy method 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 of the present invention is preferably 10 minutes or less. Furthermore, when acetaminophen is filled as a capsule-filled drug and a dissolution test is conducted with the second solution of the Japanese Pharmacopoeia based on the 15th revised Japanese Pharmacopoeia paddle method (with sinker), the HPMC capsule of the present invention If present, the pullulan capsule of the present invention is preferred to elute more than 55% of acetaminophen 10 minutes after the start of the test and 80% or more after 20 minutes. If present, it is preferable that 25% or more of the aminoaminophene elute after 10 minutes from the start of the test and 70% or more after 20 minutes.

[Example]

Hereinafter, the present invention will be specifically described by describing examples and test examples, but the present invention is not limited to these examples.

Example 1

[0049] Potassium chloride in purified water (76.34 wt%) (0.10 wt ^_0/0) and D- Mann - torr (4 wt%) was添Ka卩was completely dissolved. This was heated to 80 ° C in a water bath, and hydroxypropyl methylcellulose (HPMC) (16% by weight) and titanium oxide (3.5% by weight) were added, and the mixture was thoroughly stirred and dispersed uniformly. (Hereafter, abbreviated as HPMC dispersion). Separately, 4% carrageenan aqueous solution was prepared by adding κ-carrageenan (4 wt%) while stirring purified water heated to 80-90 ° C in a water bath. The 4 wt% carrageenan aqueous solution was added to the HPMC dispersion so that the carrageenan concentration was 0.06 wt%. This was transferred to a pressure reducing desiccator, depressurized at 55 ° C for 1 hour or longer, and degassed. After defoaming, it was stored in an oven at 55 ° C for 1 day. The HPMC dispersion thus obtained 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 above dispersion, it was subjected to aeration drying at room temperature for 2 hours to obtain an HPMC capsule.

Example 2

[0050] HPMC (16% by weight), D-sorbitol (4% by weight), Kappa Lagnan (0.06% by weight), potassium salty salt (0.10% by weight) and purified water (79.84% by weight) No. 3 capsules were prepared in the same manner as in Example 1.

Example 3

[0051] HPMC (16 wt%), D-Man - Thor (2 wt ^_0/0), D-sorbitol (2 wt ^_0/0), .kappa.-carrageenan (0.06 wt%), Shioi匕potassium ( No. 3 capsules were prepared in the same manner as in Example 1 using 0.1% by weight) and purified water (79.84% by weight).

Example 4 [0052] HPMC (15 wt ^_0/0), D-Man - Thor (2 wt ^_0/0), D-sorbitol (3 wt ^_0/0), .kappa.-carrageenan (0.06 wt%), Shioi匕No. 3 capsules were prepared in the same manner as in Example 1 using potassium (0.10% by weight) and purified water (79.84% by weight).

Comparative Example 1

[0053] HPMC (20 wt ^_0/0), kappa Ichiriki Raginan (0.06 wt ^_0/0), using a potassium chloride (0.10 wt%) and purified water (79.84 wt%) Example No. 3 capsules were prepared in the same manner as in 1.

Example 5

[0054] Purified water (79.24 wt ^_0/0) Shioi匕potassium (0.12 weight ^_0/0), pullulan (16 wt ^_0/0) and D- Man - Thor (4 wt%) And dissolved completely. Separately, in a water bath, kappa lagernan (4 wt%) was added to purified water heated to 80 ° C to 90 ° C with stirring to prepare the 4 wt% carrageenan aqueous solution. The 4% by weight 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% by weight. 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 kept at 55 ° C., and a pin bar for capsule production was immersed therein. After pulling out the pin bar solution, it was dried by aeration at room temperature for 2 hours to obtain a pullulan hard capsule.

Example 6

[0055] Pullulan (16% by weight), D-sorbitol (4% by weight), Kappa Lagonan (0.10% by weight), potassium salty salt (0.12% by weight) and purified water (79.78% by weight) No. 3 capsules were prepared in the same manner as in Example 5.

Comparative Example 2

[0056] Pullulan (20 wt ^_0/0), kappa Ichiriki Raginan (0.10 wt ^_0/0), Example using potassium chloride (0.12 wt%) and purified water (79.78 wt%) No. 3 capsules were prepared as in 5.

Test example 1 [0057] Comparative study of capsule opening time

An opening test was performed using the hard capsules manufactured in Examples 1 to 4 and Examples 5 to 6 of the present invention and the hard capsules of Comparative Examples 1 and 2. Opening test, § Seth § amino phen (20 wt ^_0/0), after filling of lactose (70 wt ^_0/0) and croscarmellose composition consisting of sodium (10 wt ^_0/0) a (LOOmg) in each capsule Based on the 15th revised Japanese Pharmacopoeia 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 observed as air bubbles inside the capsule when the capsule begins to dissolve in the test solution and opens (a hole is formed or part of the coating is broken). Therefore, the time when bubbles were generated from the capsule was defined as the opening time. Table 1 shows the results of the opening test.

[0058] [Table 1]

Comparison of force pusher opening times

As is clear from the above table, it was confirmed that all of 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

[0059] Dissolution test of capsule-filled drugs

Hard capsules prepared in Example 1 and Example 6, the hard capsule prepared in Comparative Example 1 and Comparative Example 2, § Seto § amino phen (20 wt ^_0/0), lactose (70 wt ^_0/0) and according after filling croscarmellose sodium (10 wt ^_0/0) force is also composition (LOOmg) in each capsule, a dissolution test, Japanese Pharmacopoeia, 15th Edition of the paddle method (with sinker), soluble An out test was conducted. The results are shown in Tables 2 and 3. The figures in the table are weight percent.

[Table 2]

Comparison of dissolution properties of drugs filled with HPMC hard capsule

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

[Table 3]

Comparison of dissolution properties of drugs loaded with pullulan hard-pusel

As is apparent from Table 3, the pullulan hard capsule obtained in Example 6 of the present invention has a dissolution property with a shorter disintegration time than the pullulan hard capsule of Comparative Example 2 without sugar alcohol in the coating. Was significantly improved.

Test example 3 [0062] Hard capsule moldability test

Use HPMC or pullulan as a hard capsule base, add 19.17% by weight of various saccharides to the entire capsule skin, and then form a capsule soaked solution with additives to form an HPMC hard capsule. Prepared according to Example 1 or Example 5. The capsule composition is shown in Table 4 below. In addition, the numerical value in a table | surface shows weight%.

[0063] [Table 4]

Hard capsule composition for moldability test

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

[Table 5]

Hardness psel moldability evaluation

As can be seen from the above table, HPMC hard capsules or pullulan hard capsules (capsules) manufactured by adding D-mann-tol or D-sorbitol to the entire capsule skin at a solid content of 19.17% by weight. Nos. 1, 2, 4, 5) were confirmed to have no problem with capsule moldability, as no cracks were seen when peeling from the capsule forming pin. It was. As for the appearance of Capsule 36, white spots were seen on the capsule surface. On the other hand, the appearance of Capsule 1 2 4 5 did not have white spots on the capsule surface, and the appearance was almost the same as that of normal HPMC hard capsules containing no sugar allyl.

Test example 4

[0065] Hard capsule moldability test

HPMC is used as a hard capsule base, and various saccharides are added in a solid amount of 15.11% by weight to the entire capsule skin, and a composition containing the additives is molded, and then HPMC hard capsules are prepared as usual. Manufactured according to Each capsule composition is shown in Table 6 below. The numerical values in the table indicate% by weight.

[0066] [Table 6] Hard capsule composition for moldability test

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

[0067] [Table 7] Hard capsule moldability evaluation cuff. Cell

1 2 3 4 5 6

悉

Formability 〇〇 X 〇〇 X

No problem No problem From pin No problem No problem From pin

Exfoliate exfoliate

Sometimes crack sometimes crack

Ru As is apparent from the above table, HPMC hard capsules or pullulan hard capsules prepared by adding D-mann-tol or D-sorbitol to the entire capsule skin in a solid content of 15. 11% by weight Capsule-forming pin force No cracks were observed when peeling, confirming that there was no problem with capsule moldability. As for the appearance of capsules 3 and 6, white spots were seen on the capsule surface. On the other hand, the appearance of capsules 1, 2, 4, and 5 did not have white spots on the capsule surface, and the appearance was almost the same as that of normal HPMC hard capsules without sugar alcohol.

Test Example 5

[0068] 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. The film was X-ray diffracted (see Figure 2).

X-ray diffraction was performed under the following conditions.

• X-ray diffractometer: Cu K-ALPHA1 (50kV / 300mA)

• Divergent slit: lZ2deg

• Scattering slit: lZ2deg

• 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 the crystal was observed at around 20 = 7 °. On the other hand, in the case of Example 2, no sharp peak derived from the crystal was observed, and the strength reflecting the strength of crystallinity was lower in Example 2 than in Comparative Example 1, and in Example 2, HPMC amorphous was suggested.

Industrial applicability

[0069] 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

The scope of the claims

[I] A hard capsule containing a water-soluble cellulose ether or pullulan as a base of the capsule shell, wherein the capsule shell contains a sugar alcohol.

[2] The hard capsule of claim 1, wherein the sugar alcohol is capable of making water-soluble cellulose ethers or pullulan amorphous.

[3] The hard capsule according to claim 1 or 2, wherein the sugar alcohol is a monosaccharide alcohol.

[4] The hard capsule according to any one of claims 1 to 3, wherein the sugar alcohols are D-mannitol and Z or D-sorbitol.

[5] The hard capsule according to claim 1, which is a water-soluble cellulose ether and is hydroxyalkylalkylcellulose.

[6] The hard capsule according to claim 5, which is hydroxypropylalkylcellulose strength hydroxypropylmethylcellulose.

[7] The hard capsule according to claim 4, wherein D mannitol and Z or D sorbitol are contained in an amount of 15 to 30% by weight based on the solid content of the whole capsule skin.

[8] A hard capsule characterized by filling the hard capsule described in any one of claims 1 to 7 with a filler.

[9] The hard capsule according to claim 8, wherein the filling is a medicine, food, health food, veterinary drug or quasi drug.

[10] Manufacture of hard capsules characterized by immersing pins in a solution containing water-soluble cellulose ethers or pullulan containing sugar alcohols and gelling agent, and drying the gel attached to the pins Method.

[II] A water-soluble cellulose ether or pullulan is incorporated into a capsule skin, and a sugar alcohol capable of forming an amorphous form of pullulan into the capsule skin. To improve the dissolution of hard capsules.

[12] 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 pullulans amorphous by using them in hard capsules containing water-soluble cellulose ethers or pullulan as a base for capsule shells.