JP2006016372A - Enteric hard capsule formulation - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a practical enteric hard capsule of an enteric cellulose derivative which can be industrially produced, a composition and an enteric hard capsule formulation prepared by filling contents in the capsule. <P>SOLUTION: The enteric hard capsule is prepared by compounding the enteric cellulose derivative with a nonpolar gelling agent and at least one plasticizer chosen from triacetin, glycerin fatty acid ester, polysorbate 80 (Tween 80) and polyethylene glycol. <P>COPYRIGHT: (C)2006,JPO&NCIPI

Description

  The present invention is characterized in that an enteric cellulose derivative, a non-polar gelling agent and a plasticizer include triethyl citrate, triacetin, glycerin fatty acid ester, polysorbate 80 (one or two or more selected from Tween 80 and polyethylene glycol). The present invention relates to an enteric hard capsule, a method for producing the same, a composition thereof, and an enteric hard capsule containing a content in the capsule.

As is well known, hard capsules for pharmaceuticals and health foods are usually based on gelatin, and plasticizer-like substances such as sodium lauryl sulfate, glycerin or sorbitol, and if necessary, opacifying agents, dyes or pigments are appropriately used. Molded from an additive blended coating composition. And this thing has about 10 to 15 weight% of water | moisture content normally in this capsule membrane | film | coat.
When the moisture content in the capsule film becomes 10% by weight or less, the plasticity of the film is lost, and the impact resistance during the filling operation of the medicine, health food, etc. into the capsule is remarkably impaired, so that it cannot be used. Therefore, in such known gelatin hard capsules, it is necessary to keep a certain amount of moisture in the film as described above.

However, this gelatin hard capsule has a moisture content in the film when the medicine filled in the capsule is susceptible to hydrolysis or when two or more kinds of interactive medicines are contained. For this reason, the medicine may be decomposed to cause inconveniences such as a decrease in the potency of the main drug, alteration, discoloration, and insolubilization of the hard capsule film.
Further, gelatin used as a hard capsule base is an animal protein, and a hard capsule replacing a gelatin capsule has been demanded from the viewpoint of the risk of mad cow disease infection in recent years.

On the other hand, as one of the dosage forms of an orally administered preparation, there is a so-called “enteric” preparation which does not dissolve in the stomach but dissolves when moving below the small intestine. This “enteric” preparation is mainly used for applications such as long-acting preparations, protecting the active pharmaceutical ingredient against acidic solutions or enzymes in the stomach and using the time it takes for the preparation to drain from the stomach to the small intestine. Has been.
As one form, when manufacturing enteric hard capsules using cellulose derivatives, gelatin hard capsules or water-soluble hydroxypropylmethylcellulose (HPMC) hard capsules are generally coated with an enteric base. In order to industrially produce enteric hard capsules by this method, since the capsules are coated again after filling the drug, the number of production steps increases.

  Although the manufacturing method of the hard capsule using water-soluble hydroxypropyl methylcellulose (HPMC) and a gelling agent as a capsule base is known (patent document 1), an enteric base is not described at all, It is not intended for enteric hard capsules. In this known method, examples of the gelling agent include agar and carrageenan. However, as a preferable gelling agent, a carrageenan which is a polar gelling agent is used, and nothing is described about the use of a plasticizer. Not.

  Also known is an enteric-coated hard empty capsule characterized in that a capsule cap is bonded to the capsule body in a semi-locked state, and an enteric film (such as cellulose acetate phthalate) is formed on the entire surface in the semi-locked state. (Patent Document 2). In this hard empty capsule, the surface of the gelatin hard capsule is coated with an enteric substance, and the nonpolar gelling agent and plasticizer used in the present invention are not used. Is different.

  In addition, an enteric hard capsule designed using water-soluble hydroxypropylmethylcellulose (HPMC) as a capsule base and coating the HPMC capsule with an enteric base so that the drug is not released from the capsule in the stomach. Known (Patent Document 3). In this capsule, an enteric substance is coated on the surface of the HPMC capsule, but nonpolar gelling agents such as agar and starch are not used, and the use of a plasticizer is not described. It is different from the enteric hard capsule of the present invention.

  In addition, an enteric capsule is characterized in that a molding bottle is immersed in an aqueous solution containing an alkali metal salt of hydroxypropylmethylcellulose acetate succinate (HPMCAS), which is an enteric base, and gelatin, and then immersed in an acid aqueous solution. Is known (Patent Document 4). However, in this known method, no non-polar gelling agent such as agar and starch used in the present invention is used, and no plasticizer is used.

In addition, an enteric capsule characterized by comprising a base material containing agar and granules made of an enteric material uniformly dispersed in the base material is known (Patent Document 5). This known document describes hydroxypropyl methylcellulose phthalate (HPMCP) as an enteric material. However, this enteric capsule has a structure in which the granules of the enteric material are uniformly dispersed in the agar base, whereas the enteric hard capsule of the present invention does not contain enteric cellulose derivatives and non-agar. There is a difference in that it is composed of a homogeneous phase with a polar gelling agent.
In addition, enteric capsules using glycerin as a suitable plasticizer are known (Patent Document 6). However, when glycerin is used as a plasticizer, when the capsule is stored over time, when the filled drug is a liquid drug, the capsule may be softened or deformed, or the filled drug may leak. Further, when the filling drug is a solid drug, there is a risk of moisture absorption. Since a plasticizer other than glycerin is used in the present invention, such a problem does not occur.
These known enteric capsules described above are difficult to industrially mass-produce, and are not practical enteric hard capsules in view of moldability, stability, quality, and the like.

JP 2000-136126 A JP 2003-325642 A Japanese translation of PCT publication No. 2002-525314 JP 58-138458 A JP-A-5-32543 JP-A-57-32230

  An object of the present invention is to provide a practical enteric cellulose derivative hard capsule, its production method, its composition, and its contents, which can be industrially mass-produced without using gelatin as a capsule base. It is to provide a hard capsule filled with an object. In the case of producing capsules with enteric cellulose derivatives, gelatin capsules and hydroxypropylmethylcellulose (HPMC) capsules were conventionally coated with enteric bases, but this method requires a large number of steps for industrial mass production. It is hard to say that it is a practical enteric hard capsule. In addition, gelatin base, which is an animal protein, has a risk of contamination with mad cow disease.

  As a result of intensive studies to solve the above problems, the inventors of the present application have selected from enteric cellulose derivatives, nonpolar gelling agents and plasticizers from triethyl citrate, triacetin, glycerin fatty acid ester, polysorbate 80 (Tween 80) and polyethylene glycol. Addition of one or two or more types improves the moldability, and does not produce hard capsules by coating conventional enteric bases, but dipping method (immersion molding method), which is a capsule production method As a result, the present invention was completed.

That is, the present invention
(1) One or more selected from enteric cellulose derivatives, non-polar gelling agents and plasticizers selected from triethyl citrate, triacetin, glycerin fatty acid ester, polysorbate 80 (Tween 80) and polyethylene glycol Enteric hard capsule,
(2) The enteric hard capsule according to (1), wherein the amount of the enteric cellulose derivative is 70% by weight or more based on the solid content of the entire hard capsule,
(3) The above-mentioned (1) or (), wherein the enteric cellulose derivative is one or more selected from hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, carboxymethylethylcellulose and cellulose acetate phthalate Enteric hard capsules according to 2),
(4) Any of the above (1) to (3), wherein the nonpolar gelling agent is one or more selected from agar, starch, mannan, methylcellulose, hydroxypropylcellulose and hydroxypropylmethylcellulose Enteric hard capsules according to
(5) An enteric hard capsule characterized by filling the content in the enteric hard capsule described in any of (1) to (4) above,
(6) The hard capsule according to (5), wherein the content is a drug,
(7) The hard capsule according to (5), wherein the content is a liquid drug,
(8) As the enteric cellulose derivative, nonpolar gelling agent and plasticizer, a solution in which one or more selected from triethyl citrate, triacetin, glycerin fatty acid ester, polysorbate 80 (Tween 80) and polyethylene glycol is mixed is used. A method for producing enteric hard capsules,
(9) An enteric cellulose derivative, a nonpolar gelling agent, and a plasticizer containing one or more selected from triethyl citrate, triacetin, glycerin fatty acid ester, polysorbate 80 (Tween 80) and polyethylene glycol A composition,
About.

  According to the present invention, high-quality enteric hard capsules, compositions and enteric hard capsules based on enteric cellulose derivatives can be industrially mass-produced. The hard capsule obtained by the method of the present invention is free from cracks due to moisture after filling the contents, alteration of the contents, discoloration, etc., and has excellent intestinal solubility and mechanical strength of the capsule film, and appearance. It is an enteric hard capsule which is improved. Since the enteric hard capsule of the present invention does not use gelatin as a conventional capsule base, it is not affected by mad cow disease contamination and can be stably supplied to the market. The composition of the present invention is an excellent composition suitable for producing such hard capsules.

  The enteric hard capsule of the present invention may be produced by a method capable of forming a capsule, but generally, in the same manner as known hard gelatin capsules or hard capsules of cellulose ethers, the usual dipping method (immersion molding method) is used. It is manufactured according to the above (for example, see Patent Document 4). That is, an enteric cellulose derivative is dispersed in a non-organic solvent, and a base, preferably ammonia, is added to the dispersion and dissolved therein. As a non-polar gelling agent and a plasticizer, triethyl citrate, triacetin, glycerin fatty acid ester, One or more selected from polysorbate 80 (Tween 80) and polyethylene glycol are added, the capsule-forming pin is immersed in the gel-phase capsule immersion liquid of the uniform phase to be formed, and then this is pulled up and immersed on the pin Enteric hard capsules can be produced by drying the liquid gel.

  Here, the viscosity of the capsule immersion liquid is not particularly limited, but is preferably 100 to 10,000 mPa · s, particularly preferably 1000 to 8000 mPa · s at the capsule immersion temperature (about 40 to 70 ° C.). This viscosity is a value measured by a B-type rotational viscometer. When the viscosity is low, there are few capsule raw materials adhering to the capsule forming pin and the film thickness of the capsule may be thinned, and when the viscosity is too high, it is generally difficult to control the capsule shape.

  The characteristics of the method for producing a hard capsule of the present invention using a cellulose derivative as an enteric base material include not only the addition of a nonpolar gelling agent and a plasticizer that give good results to the moldability of the hard capsule, but also the capsule The preparation of the immersion liquid is carried out in a non-organic solvent system (for example, water) without using an organic solvent, and gelatin that is likely to be contaminated with mad cow disease is not used as a capsule base. Moreover, in the capsule manufacturing method using an organic solvent, a solvent recovery process, work environment contamination, and a fire / explosion countermeasure are required, and there is a concern that the solvent may remain in the product.

In addition, although additives, such as a pigment | dye and a pigment, can be mix | blended with the said capsule immersion liquid as needed, these components may be added in any step.
In this manufacturing process, the body part and the cap part of the hard capsule can be respectively obtained by the size of the capsule forming pin. The body part and the cap part of the cellulose ether hard capsule thus obtained are filled with the contents, and then the body part is covered with the cap part, and the body part and the cap part are joined by fitting them together. Let Then, if necessary, the sealing agent is applied to the surface of the body part and the surface of the cap part with a constant width around the edge of the cap part in the circumferential direction of the body part and the cap part one to several times, preferably By applying once or twice, the fitting part can be sealed to make an enteric capsule. In FIG. 1, the manufacturing process of the enteric cellulose hard capsule and enteric cellulose hard capsule of this invention is typically shown.
Another manufacturing method is an injection molding method.

As an enteric cellulose derivative that is a capsule base used in the manufacture of the enteric hard capsule of the present invention, any cellulose derivative that does not dissolve in the stomach when administered and can be dissolved in the intestine. Specific examples include hydroxypropylmethylcellulose phthalate (HPMCP), hydroxypropylmethylcellulose acetate succinate (HPMCAS), carboxymethylethylcellulose (CMEC), and cellulose acetate phthalate (CAP). Propylmethylcellulose phthalate (HPMCP) or hydroxypropylmethylcellulose acetate succinate (HPMCAS). These enteric cellulose derivatives can be used alone or as a mixture of two or more.
The amount of the enteric cellulose derivative is about 70 to 99% by weight, preferably about 75 to 97% by weight, more preferably about 80 to 95% by weight, based on the total solid content of the hard capsule. When the amount of the derivative is less than this amount, it is generally difficult to form a hard capsule having a stable quality. Here, the solid content of the hard capsule means the weight of the empty hard capsule (hereinafter the same).

  The non-polar gelling agent used for the production of the enteric capsule of the present invention 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 can be used as long as it melts at -80 ° C and solidifies the capsule at room temperature (about 25-50 ° C). Examples of such nonpolar gelling agents include polysaccharides and celluloses. Specific examples of polysaccharides include agar, starch, and mannan. Specific examples of celluloses include methylcellulose, hydroxypropylcellulose, Hydroxypropyl methylcellulose and the like are exemplified, but agar, starch and mannan are preferred, and agar and starch are more preferred. Examples of starch include corn starch, potato starch, rice starch, and wheat starch. In addition, a nonpolar gelatinizer can be used individually or in mixture of 2 or more types. The enteric cellulose derivative has a carboxylic acid in the molecule, and in the case of a polar gelling agent, ions and the like are used as a gelling aid, so these ions interact with the enteric cellulose derivative and gel There is a risk of becoming difficult. On the other hand, in the case of a non-polar gelling agent, it is not necessary to use the above-mentioned gelling aid, and it can be gelled without causing an interaction with the enteric cellulose derivative.

  The amount of the non-polar gelling agent is about 0.4 to 20.0% by weight, preferably about 1.0 to 10.0% by weight, more preferably about 2. 0 to 5.0% by weight. If the amount of the non-polar 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.

In the production of the enteric capsule of the present invention, the addition of a plasticizer gives more favorable results regarding the moldability of the hard capsule. The plasticizer to be added is not particularly limited as long as the moldability of the hard capsule is not impaired, but examples include triethyl citrate, triacetin, glycerin fatty acid ester, polysorbate 80 (Tween 80), polyethylene glycol, and the like. Triethyl citrate. In addition, 1 type (s) or 2 or more types can be suitably selected and used for these plasticizers. The compounding amount of the plasticizer is 1.0 to 15.0% by weight, preferably 2.0 to 13.0% by weight, more preferably 5.0 to 10.0% by weight, based on the entire solid content of the hard capsule. is there. If the blending amount is less than this amount, the physical strength of the capsule cannot be obtained, and the capsule becomes brittle. In addition, the said plasticizer can be used individually or in mixture of 2 or more types.
Since a plasticizer other than glycerin is used in the present invention, the problems seen when glycerin is used as a conventional plasticizer, that is, when the capsule is stored over time, the capsule softens when the filled drug is a liquid drug. There is no possibility that the problem that there is a possibility that the loaded drug may leak or the filled drug may leak or that the filled drug is a solid drug may absorb moisture.

  As the size of the hard capsule, there are 00, 0, 1, 2, 2, 3, 4, 5, 9, etc., but in the present invention, any size hard capsule is manufactured and used. be able to.

  The composition of the present invention contains an enteric cellulose derivative, a nonpolar gelling agent, and one or more selected from triethyl citrate, triacetin, glycerin fatty acid ester, polysorbate 80 (Tween 80) and polyethylene glycol as a plasticizer. And can be produced by a method known per se in the art. The form of the composition may be any form known per se in the art, but is not particularly limited as long as the desired hard capsule can be produced. In view of the above, a non-organic solvent (for example, water) liquid is preferable. In addition, examples of enteric cellulose derivatives, nonpolar gelling agents, plasticizers, and the like contained in the composition, blending amounts, and the like can include those used in the production of the hard capsule soaking liquid described above. Moreover, the manufacturing method of an above-described hard capsule immersion liquid is applicable to the manufacturing method of the composition of this invention.

  Examples of the contents to be filled in the hard capsule of the present invention include human or animal and plant medicines or drugs, health foods, etc., and those that do not dissolve the hard capsule film of the enteric cellulose derivative or do not react with the hard capsule film. Any of them can be filled. Further, the content 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, health foods, etc., but also as a so-called quasi-drug filling capsule for the purpose of disinfecting and cleaning dentures, glasses, contact lenses, etc. Is also applicable.

  Examples of the medicament used in the present invention include nourishing tonics, antipyretic analgesics, antipsychotics, anxiolytics, antidepressants, hypnotic sedatives, antispasmodics, central nervous system agonists, brain metabolism improving agents, brain Circulatory improvement agent, antiepileptic agent, sympathomimetic agent, gastrointestinal agent, antacid, antiulcer agent, antitussive expectorant, antiemetic agent, respiratory stimulant, bronchodilator, allergic agent, oral and oral medicine, antihistamine, Cardiotonic agent, arrhythmia agent, diuretic, antihypertensive agent, vasoconstrictor, coronary vasodilator, peripheral vasodilator, hyperlipidemic agent, biliary agent, antibiotic, chemotherapeutic agent, diabetes agent, bone One or two selected from anti-porosis agents, anti-rheumatic drugs, skeletal muscle relaxants, antispasmodics, hormones, alkaloid narcotics, sulfa drugs, gout treatments, anticoagulants, anti-neoplastic agents The above 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. Gastrointestinal drugs include, for example, gastrointestinals such as diastase, sugar-containing pepsin, funnel extract, cellulase AP3, lipase AP, and cinnamon oil, and intestinals such as berberine chloride, resistant lactic acid bacteria, and bifidobacteria.

  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.

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 contents into the enteric hard capsule of the present invention is performed by a capsule filling machine known per se, for example, 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.) can be used.

  Hereinafter, the present invention will be described in detail with reference to examples, but the present invention is not limited thereto.

(1) Composition As a composition of the capsule preparation liquid, 20 parts by weight of hydroxypropylmethylcellulose phthalate (HPMCP; 14th revised Japanese Pharmacopoeia substitution degree 200731), 1 part by weight of agar, 1.5 parts by weight of triethyl citrate, and an appropriate amount of ammonia are added. The whole was made up to 100 parts by weight with water.
(2) Manufacturing method HPMCP was dispersed in water, and ammonia was added little by little in a state heated to about 60 ° C. to dissolve. A predetermined amount of an agar solution prepared to 5% (w / w) and triethyl citrate were added thereto, and deaerated. A metal pin was immersed in the above solution at about 55 ° C., then pulled up, secured to a shape, and dried at 25 to 50 ° C. to obtain an enteric hard capsule.
(3) Evaluation The enteric hard capsule obtained in (2) above is filled with 60 mg of acetaminophen, 210 mg of lactose and 30 mg of croscarmellose per capsule, and is defined in the 14th revised Japanese Pharmacopoeia disintegration test method. When the first liquid and the second liquid were used and evaluated by the paddle method (50 rotations) described in the dissolution test method of the same pharmacopoeia, acetamino was only 5% or less in the first liquid even 2 hours after the start of the test. Although phen did not elute, 80% or more of acetaminophen eluted in the second solution within 20 minutes after the start of the test. The elution rates of acetaminophen in the first liquid and the second liquid are shown in FIGS. 1 and 2, respectively.

(1) Composition As a composition of the capsule preparation liquid, an appropriate amount of ammonia was added to hydroxypropylmethylcellulose phthalate (HPMCP; 14th revised Japanese Pharmacopoeia, substitution degree 220824), agar and triethyl citrate, and the whole was made up to 100 parts by weight with water. The solid content composition of the capsule is shown in Table 1.
(2) Manufacturing method HPMCP was dispersed in water, and ammonia was added little by little in a state heated to about 60 ° C. to dissolve. A predetermined amount of an agar solution prepared to 5% (w / w) and triethyl citrate were added thereto, and deaerated. A metal pin was immersed in the above solution at about 55 ° C., then pulled up, secured to a shape, and dried at 25 to 50 ° C. to obtain an enteric hard capsule.
(3) Evaluation The enteric hard capsule obtained in the above (2) is filled with 60 mg of acetaminophen, 210 mg of lactose and 30 mg of croscarmellose per capsule, and the thus obtained enteric hard capsule (6 capsules) Tested according to the 14th revision Japanese Pharmacopoeia disintegration test method (without disk) and dissolution test method (paddle method, 50 rpm), disintegration time and dissolution rate were measured, and the average values are shown in Table 1 below. Show.

(1) Composition As the composition of the capsule preparation solution, 15 parts by weight of hydroxypropyl methylcellulose acetate succinate (HPMCAS; pharmaceutical additive standard 2003), 1 part by weight of agar, 0.5 to 2 parts by weight of triethyl citrate, and an appropriate amount of ammonia are added. The whole was made up to 100 parts by weight with water.
(2) Manufacturing method HPMCAS was dispersed in water, and ammonia was added little by little in a state heated to about 60 ° C. to dissolve. A predetermined amount of an agar solution prepared to 5% (w / w) and triethyl citrate were added thereto, and deaerated. After immersing a metal pin in the above solution at about 55 ° C., the metal pin was pulled up, secured in shape, and dried at 25-50 ° C.
(3) Evaluation The enteric hard capsule obtained in (2) above is filled with 60 mg of acetaminophen, 210 mg of lactose and 30 mg of croscarmellose per capsule, and the dissolution test method (paddle method, 50 rpm), all capsules elute 5% or less in the first liquid of the same pharmacopoeia in 2 hours, and 80% or more acetaminophen elutes in the second liquid within 20 minutes. did.

(1) Composition The composition of the capsule preparation solution is 20 parts by weight of hydroxypropylmethylcellulose phthalate (HPMCP; 14th revised Japanese Pharmacopoeia substitution degree 200731), 1 part by weight of starch, 0.5 to 3 parts by weight of triethyl citrate, ammonia Was added in an appropriate amount, and the whole was made up to 100 parts by weight with water.
(2) Manufacturing method HPMCP was dispersed in water, and ammonia was gradually added and dissolved in a state heated to about 60 ° C. A predetermined amount of 5% (w / w) corn starch solution and triethyl citrate, which were preheated to 80 ° C. and then 60 ° C., were added thereto for deaeration. After immersing a metal pin in the above solution at about 55 ° C., it was pulled up to ensure its shape and dried at 25-50 ° C. to obtain an enteric hard capsule.
(3) Evaluation The enteric capsule obtained in (2) above was filled with 60 mg of acetaminophen, 210 mg of lactose and 30 mg of croscarmellose per capsule, and the 14th revised Japanese Pharmacopoeia disintegration test method was established. When using the 1st liquid and the 2nd liquid and evaluating by the paddle method (50 rotations) described in the dissolution test method of the same pharmacopoeia, all capsules elute only 5% or less in the first liquid in 2 hours. In the second liquid, 80% or more of acetaminophen was eluted within 20 minutes.

  After 80 kg of hydroxypropylmethylcellulose phthalate (HPMCP; 14th revised Japanese Pharmacopoeia, substitution degree 200731) is dispersed in about 200 kg of room temperature water, the mixture is heated to 60 ° C. and ammonia water is gradually added dropwise to dissolve. To this, 80 kg of an aqueous solution of agar prepared to 5% (w / w) and 8 kg of triethyl citrate were added, mixed well, and the whole was made up to 400 kg with water heated to 60 ° C. This was kept at 55 ° C. and degassed under reduced pressure. This was kept at about 55 ° C., and a stainless steel pin coated with a release agent such as lecithin was immersed in this solution, then pulled up, dried at about 50 ° C. and then returned to room temperature. The capsule was pulled out and cut into a predetermined length to obtain 200,000 enteric capsules.

Examination of plasticizer (1) Experimental method After adding glycerin or triethyl citrate as a plasticizer and forming capsule No. 3 by the method of Example 1 into the capsule shown in the table below, each of the following 8 types of liquid components was filled in 300 mg. The obtained enteric hard capsule was stored at room temperature for 1 week under open conditions. After storage, the capsule state was observed.
Liquid components: soybean oil (manufactured by Nakarai Desk), cottonseed oil (manufactured by Nakarai Desk), rapeseed oil (manufactured by Nakarai Desk), Migliol (medium chain fatty acid triglyceride: registered trademark, Mitsuba Trading), oleic acid, TPGS (tocopherol) Derivatives: Eastman), Labarsol (mono, di, triglyceride and a mixture of fatty acid (caprylic acid / capric acid) ester of polyethylene glycol; registered trademark, manufactured by Gattefosse), Gelucire (mono, di, triglyceride and polyethylene glycol) Of fatty acid (lauric acid) ester: registered trademark, manufactured by Gattefosse)
(2) Experimental results The experimental results of (1) above are shown in Table 3 below.

In the above table, “softening” means that the capsule becomes soft, “deformation” means that the capsule is deformed, and “leakage” means that the liquid component filled in the capsule is retained, although the capsule shape is maintained. Leaking from the joint between the cap and the body, “partially dissolved” means that a part of the capsule is dissolved and a hole is opened.
As is clear from the above table, the capsule 7 containing glycerin as a plasticizer caused phenomena such as softening, deformation, partial dissolution, leakage, etc., and could not maintain the function of the capsule. On the other hand, the capsule 6 according to the present invention does not show phenomena such as softening, deformation, partial dissolution, and leakage, and it can be seen that the capsule 6 is excellent as a capsule.

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

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 step of filling the contents into the hard capsule body. Step (3) shows a step of fitting the cap part to the hard capsule body part containing the contents. 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. Steps (4) and (5) are performed as necessary. The hard capsule obtained in Example 1 of the present invention is based on the paddle method described in the dissolution test method of the pharmacopoeia using the first liquid defined in the 14th revised Japanese Pharmacopoeia disintegration test method. The measured elution rate (%) is shown. The hard capsule obtained in Example 1 of the present invention is based on the paddle method described in the dissolution test method of the pharmacopoeia using the second liquid defined in the 14th revised Japanese Pharmacopoeia disintegration test method. The measured elution rate (%) is shown.

Explanation of symbols

1 Hard capsule cap part 2 Hard capsule body part 3 Contents 4 Filling tube 5 Sealing part (band seal)

Claims (9)

  An intestine characterized in that an enteric cellulose derivative, a nonpolar gelling agent and a plasticizer are blended with one or more selected from triethyl citrate, triacetin, glycerin fatty acid ester, polysorbate 80 (Tween 80) and polyethylene glycol. Soluble hard capsule.   The enteric hard capsule according to claim 1, wherein the amount of the enteric cellulose derivative is 70% by weight or more based on the total solid content of the hard capsule.   The enteric cellulose derivative is one or more selected from hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, carboxymethylethylcellulose, and cellulose acetate phthalate. Soluble hard capsule.   The enteric property according to any one of claims 1 to 3, wherein the nonpolar gelling agent is one or more selected from agar, starch, mannan, methylcellulose, hydroxypropylcellulose and hydroxypropylmethylcellulose. Hard capsule.   An enteric hard capsule comprising the enteric hard capsule according to any one of claims 1 to 4 filled with a content.   The hard capsule according to claim 5, wherein the content is a drug.   The hard capsule according to claim 5, wherein the content is a liquid medicine.   Enteric cellulose capsules, enteric hard capsules by using a mixture of one or more selected from triethyl citrate, triacetin, glycerin fatty acid ester, polysorbate 80 and polyethylene glycol as a non-polar gelling agent and a plasticizer How to manufacture. Composition comprising enteric cellulose derivative, nonpolar gelling agent and plasticizer containing one or more selected from triethyl citrate, triacetin, glycerin fatty acid ester, polysorbate 80 (Tween 80) and polyethylene glycol object.