JP2005314241A - Suppository base controlling occurrence of crack/fragment and method for producing the same - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To solve problems that, in producing a suppository using a hard fat having ≤10 hydroxy value with slight adverse effect as a base even if formulated with a medicine to be readily hydrolyzed, since quenching and solidification sometimes cause crack/fragment in a suppository, slow cooling is required in solidification for production, and the suppository base is not suitable for mass production by an automatic filling molding machine. <P>SOLUTION: The suppository is obtained by formulating a hard fat having ≤10 hydroxy value with a glycerol monofatty acid ester or a polyglycerol fatty acid ester. Consequently, even quenching and solidification using the automatic filling molding machine control occurrence of crack/fragment, and the suppository is suitable also for mass production. <P>COPYRIGHT: (C)2006,JPO&NCIPI

Description

  The present invention relates to a suppository in which the generation of cracks and cracks comprising a hard fat having a hydroxyl value of 10 or less is suppressed, and a method for producing the same. More specifically, a suppository base that prevents the occurrence of cracks and cracks during solidification of suppository production comprising a hard fat having a hydroxyl value of 10 or less and glycerin monofatty acid ester or polyglycerin fatty acid ester, and production thereof Regarding the law.

Conventionally, a suppository manufacturing method generally uses a drug solution prepared by dissolving or dispersing a drug in a heated and melted suppository base, and an aluminum or plastic suppository container (hereinafter referred to as “suppository container”). And solidified by air cooling and then hermetically sealed.
When solidifying a drug solution, in order to suppress sedimentation of solid drug as much as possible, and to produce efficiently using an automatic suppository filling molding machine, as soon as possible after filling the suppository container with the molten drug solution It is desirable to solidify. In order to solidify faster, it is necessary to lower the ambient temperature during solidification after filling the suppository container. However, if the temperature of the atmosphere at the time of solidification is lowered, there is a difference in the shrinkage rate between the outside and inside of the suppository during solidification, which may cause cracking or cracking of the suppository. This tendency is remarkable when the hydroxyl value of the hard fat is 10 or less, whereas when it is 35 or more, cracks and cracks hardly occur even when rapidly cooled. Therefore, hard fats having a hydroxyl value of 30 to 50 are generally used as hard fats for mass production of suppositories.

However, when a hard fat with a hydroxyl value of 15 or more is used, drugs that are susceptible to hydrolysis such as ester bonds and amide bonds in the molecule, such as prednisolone acetate and acetylsalicylic acid, are decomposed in a relatively short period of time and their efficacy decreases. There is a problem of doing. Therefore, when a suppository is produced using a hard fat having a hydroxyl value of 10 or less, the drug is kept stable for a long period of time, but since the apparent solidification start temperature of the hard fat is lowered, it is cooled in a lower atmosphere. Otherwise, the suppository will not solidify. However, when a hard fat having a hydroxyl value of 10 or less is rapidly cooled and solidified in a low atmosphere, as described above, a phenomenon occurs in which the suppository is cracked or cracked due to the difference in shrinkage rate inside and outside the suppository. Thus, there is a difficult problem that is incompatible between using a hard fat having a hydroxyl value of 10 or less in order to keep the drug stable and efficiently producing suppositories without cracks or cracks. It was.
A technique for blending a fatty acid monoglyceride having 14 to 18 carbon atoms and a fatty acid monoglyceride having 10 to 12 carbon atoms into a hard fat having a hydroxyl value of 15 or more in anticipation of sustained release of the drug (Patent Document 1). Technology for blending polyglycerin fatty acid esters of HLB 8 or less to obtain suppositories (Patent Document 2), Technology for blending polyglycerin fatty acid esters to enhance the adhesion of suppositories to the gastrointestinal mucosa (Patent Document 3), Technology that uses polyethylene and polyglycerin fatty acid esters to prevent cracking and cracking of suppositories during transportation and storage (Patent Document 4) Technology that incorporates fatty acid glycerides having 14 to 18 carbon atoms and a lower rectal retention base component (Patent Document 5) and the like are known, but in each document, cracks and cracks are generated when a hard fat having a hydroxyl value of 10 or less is used. There is no description at all about the preventive measures and.
JP-A-4-346916 JP-A-6-298667 Japanese Unexamined Patent Publication No. 7-330582 JP 2000-281590 A WO2002 / 024161

  An object of the present invention is to use a hard fat having a hydroxyl value of 10 or less as a suppository base that can stably hold a drug that is easily hydrolyzed, and to produce suppositories efficiently using an suppository automatic filling molding machine. It is also an object of the present invention to provide a suppository composition that does not cause cracks and cracks during production, and a method for producing the same.

  As a result of intensive studies to solve the above problems, the present inventors have found that when a glycerin monofatty acid ester or polyglycerin fatty acid ester is blended with a hard fat having a hydroxyl value of 10 or less at the time of suppository production, Knowing that the occurrence of cracks and cracks in the suppository is suppressed even after rapid cooling after filling into the container, the present invention was completed by further studies based on this knowledge.

That is, the present invention
(1)
A suppository containing a drug, a hard fat having a hydroxyl value of 10 or less, and glycerin monofatty acid ester or polyglycerin fatty acid ester, the generation of cracks and cracks being suppressed,
(2)
The suppository according to claim 1, wherein the fatty acid of the glycerol mono-fatty acid ester or polyglycerol fatty acid ester has 18 to 22 carbon atoms.
(3)
The suppository according to (2), wherein the glycerin monofatty acid ester is glycerin monostearate or glycerin monobehenate.
(4)
The suppository according to (2), wherein the polyglycerin fatty acid ester is decaglycerin decastearic acid ester or decaglycerin dodecavehenic acid ester,
(5)
The glycerol mono fatty acid ester is contained in an amount of 0.2 to 10% by weight based on the entire suppository, or the polyglycerol fatty acid ester is contained in an amount of 0.05 to 10% by weight based on the entire suppository (1) or (2) Suppositories,
(6)
The suppository according to any one of (1) to (5), wherein the drug is a drug susceptible to hydrolysis, an antibiotic, a biochemical preparation or an enzyme,
(7)
Corticosteroids whose drugs have ester bonds or amide bonds, local anesthetics, antipyretic analgesics and anti-inflammatory agents, anti-inflammatory / antipruritic / wound healing agents, vitamins, sulfa drugs, antibiotics, antifungal agents, bactericides, vasoconstrictors, The suppository according to (6), which is one or more selected from the group consisting of an antihistamine and a narcotic;
(8)
A drug, glycerin monofatty acid ester or polyglycerin fatty acid ester and a hard fat having a hydroxyl value of 10 or less are heated and melted to 40 to 100 ° C. to obtain a uniform liquid, and the temperature is adjusted to 35 to 45 ° C. A method for producing a suppository in which the generation of cracks and cracks during the production of a suppository that is filled and solidified under an atmosphere of 20 ° C. or less is suppressed,
(9)
The method for producing a suppository according to (8), wherein generation of cracks or cracks in which the fatty acid of the glycerin monofatty acid ester or polyglycerin fatty acid ester has 18 to 22 carbon atoms is suppressed,
(10)
The glycerin monofatty acid ester is contained in an amount of 0.2 to 10% by weight based on the whole suppository, or the polyglycerin fatty acid ester is contained in an amount of 0.05 to 10% by weight based on the whole suppository. Manufacturing method,
(11)
(12) The suppository manufacturing method according to any one of (8) to (10), wherein the drug is a drug, antibiotic, biochemical preparation or enzyme that is susceptible to hydrolysis.
Corticosteroids whose drugs have ester bonds or amide bonds, local anesthetics, antipyretic analgesics and anti-inflammatory agents, anti-inflammatory / antipruritic / wound healing agents, vitamins, sulfa drugs, antibiotics, antifungal agents, bactericides, vasoconstrictors, A method for producing a suppository according to (9), which is one or more selected from the group consisting of an antihistamine and a narcotic;
It is.

The “hard fat” used in the present invention means those described in “Pharmaceutical Additive Standards” edited by the Examination Management Section of the Pharmaceutical Safety Bureau of the Ministry of Health and Welfare in 1998, and mainly saturated fatty acids [CH ₃ (CH ₂ ) _n COOH, n has a hydroxyl value of 10 or less, preferably 1 to 10, more preferably 3 to 7 among the triglycerides of 6 to 16].

The glycerin monofatty acid ester used in the present invention is preferably a monosaturated fatty acid ester of glycerin having 18 to 22 carbon atoms, and particularly preferably glycerin monostearate and glycerin monobehenate.
The polyglycerol fatty acid ester used in the present invention is preferably obtained by esterifying polymerized glycerol with a saturated fatty acid. The polymerization number of glycerin is about 2 to 10, preferably about 4 to 10, and the carbon number of fatty acid is preferably about 18 to 22. The fatty acid forming the ester is preferably stearic acid or behenic acid. Specific examples of polyglycerol fatty acid esters include, for example, tetraglycerol pentastearate, hexaglycerol pentastearate, decaglycerol pentastearate, decaglycerol decastearate, decaglycerol undecavehenate, decaglycerol dodeca Examples thereof include behenic acid esters.
Among these, decaglycerin decastearic acid ester and decaglycerin dodecabehenic acid ester are particularly preferable.
The blending ratio of the glycerin monofatty acid ester with respect to the total amount of the suppository base is usually 0.2 to 10% by weight, preferably 0.5 to 5% by weight, and the blending ratio of the polyglycerin fatty acid ester is usually 0.05. -10 wt%, preferably 0.1-5 wt%.

In the suppository of the present invention, a drug having a property that it is easily decomposed by a hard fat having a hydroxyl value of 15 or more can be blended. Many drugs that are easily decomposed by a hard fat having a hydroxyl value of 15 or more have bonds that are susceptible to hydrolysis by hydroxyl groups, such as various ester bonds and amide bonds, in the molecule.
However, these hydrolyzable drugs can also be used without any problem in the present invention.

  Specific examples of the drug compounded in the suppository of the present invention include corticosteroids such as prednisolone acetate, prednisolone phosphate, prednisolone, hydrocortisone acetate, hydrocortisone, cortisone acetate, cortisone, dexamethasone acetate, dexamethasone, valeric acid Prednisolone acetate or triamcinolone acetate, local anesthetics such as lidocaine hydrochloride, dibucaine hydrochloride, procaine hydrochloride, tetracaine hydrochloride, chloroprocaine hydrochloride, chloroprocaine, bupivacaine hydrochloride, proparacaine hydrochloride, proparacaine, meprilucaine hydrochloride, ethyl aminobenzoate, orthocaine , Oxesazein, parabutylamino hydrochloride, diethylaminoethyl benzoate, oxypolyethoxydecane or funnel extract, antipyretic analgesic anti-inflammatory agent For example, aspirin, acetaminophenone, trifenamic acid, phenacetin, diclofenac sodium, indomethacin, mefenamic acid, aminopyrine, ibuprofen, etenzaamide or piroxicam, anti-inflammatory, antipruritic, wound healing agents such as glycyrrhetinic acid, dimethylisopropylazulene, ectamol, Crotamiton, lysozyme chloride, tribenoside, potassium aluminum sulfate, chicone extract, horse chestnut seed extract, hamame extract, processed egg yolk, purified egg yolk lecithin, egg yolk oil, eucalyptus oil, allantoin or aluminum chlorohydroxy allantoinate, vitamin, for example, acetic acid Tocophenol, tocophenol, ergocalciphenol, retinol palmitate, retinoacetate Pyridoxine hydrochloride, pyridoxamine hydrochloride, pyridoxamine phosphate, pyridoxal hydrochloride, pyridoxal phosphate, riboflavin, riboflavin butyrate, vitamin A oil, strong liver oil or liver oil, sulfa drugs such as sulfadiazine, sulfisomidine, sulfisomidine sodium or homosulfamine , Antibiotics or antifungal agents such as erythromycin, tetracycline, tetracycline hydrochloride, oxytetracycline hydrochloride, streptomycin sulfate, gentamicin sulfate, fradiomycin sulfate, kanamycin sulfate, clotrizomar, miconazole, tinidazole, miconazole nitrate, oxyconazole, Metronidazole, isconazole nitrate, tricomycin, pimaricin or econazole nitrate, Bactericides such as acrinol, alkylpolyaminoethylglycine, isopropylmethylphenol, cetylpyridinium chloride, denikal chloride, berberine chloride, benzalkonium chloride, chlorhexidine hydrochloride, chlorhexidine gluconate, cetrimide, vasoconstrictors such as hydrochloric acid Epinephrine, ephedrine hydrochloride, tetrahydrozoline hydrochloride, naphazoline hydrochloride, phenylephrine hydrochloride or dl-methylephedrine hydrochloride, antihistamines such as diphenhydramine, diphenhydramine hydrochloride, diphenhydramine tannate, diphenhydramine lauryl sulfate, chlorpheniramine maleate, diphenylpyraline hydrochloride, drug hemp For example, morphine hydrochloride, ethyl morphine hydrochloride, morphine sulfate, phosphorus Codeine, dihydrocodeine phosphate, cocaine hydrochloride, but like pethidine hydrochloride and the like, but is not limited thereto.

The proportion of the drug in the suppository cannot be generally specified, but is usually about 0.01 to 10% by weight. If necessary, the suppository of the present invention may further contain appropriate amounts of absorption regulators, surfactants, solubilizers, water, stabilizers, preservatives, excipients and the like.
The suppository is produced by a method known per se, for example, a suppository base is melted at 40 to 80 ° C., and the drug and other necessary components are uniformly dispersed or dissolved therein, and the temperature is adjusted to 35 to 45 ° C. And then filled in a suppository container and solidified in an atmosphere at 20 ° C. or lower, preferably 3 to 20 ° C., more preferably 5 to 15 ° C., particularly preferably 7 to 12 ° C., preferably in a temperature-controlled room. It can be carried out. The suppository of the present invention has a solidification time shortened by blending glycerin monofatty acid ester or polyglycerin fatty acid ester, and the time required for solidification is usually within 15 minutes when the atmosphere is 20 ° C. or lower. The solidified suppository is preferably stored in a low temperature thermostatic chamber and then stored in an atmosphere of 25 ° C. or lower.

  According to the present invention, the suppository can be obtained by mass production with rapid cooling using an ordinary suppository automatic filling and molding machine, even though a hard fat having a hydroxyl value of 10 or less having a low apparent solidification start temperature is used. No cracks or cracks. Moreover, even if a drug that is susceptible to hydrolysis is blended, the drug can be retained in the suppository without being decomposed over a long period of time.

  Hereinafter, the present invention will be specifically described with reference to Examples, Comparative Examples, and Experimental Examples, but the present invention is not limited thereto. In the experimental examples, examples, and comparative examples, the parts are parts by weight.

Prescription
Prednisolone acetate 0.1g
Glycerin monobehenate 0.35g
Hard fat (Hydroxyl value = 5)
175g
Glycerin monobehenate and prednisolone acetate are added to a hard fat previously melted at 80 ° C., mixed uniformly, poured into an aluminum container containing 100 suppositories, adjusted to a temperature of about 40 ° C. on a water bath, 10 A suppository was produced by cooling in a thermostatic bath at 15 ° C. for 15 minutes.

Prescription
Prednisolone acetate 0.1g
Glycerin monobehenate 8.75g
Hard fat (Hydroxyl value = 5)
175g
A suppository was obtained in the same manner as in Example 1 using the suppository raw material having the above formulation.

Prescription
Prednisolone acetate 0.1g
Glycerin monobehenate 17.5g
Hard fat (Hydroxyl value = 5)
175g
A suppository was obtained in the same manner as in Example 1 using the suppository raw material having the above formulation.

Prescription
Prednisolone acetate 0.1g
Glycerin monostearate 1.75g
Hard fat (Hydroxyl value = 5)
175g
A suppository was obtained in the same manner as in Example 1 using the suppository raw material having the above formulation.

Prescription
Prednisolone acetate 0.1g
Glycerin monostearate 17.5g
Hard fat (Hydroxyl value = 5)
175g
A suppository was obtained in the same manner as in Example 1 using the suppository raw material having the above formulation.

Prescription
Prednisolone acetate 0.1g
Decaglycerin decastearic acid ester 1.75g
Hard fat (Hydroxyl value = 5)
175g
A suppository was obtained in the same manner as in Example 1 using the suppository raw material having the above formulation.

Prescription
Prednisolone acetate 0.1g
Decaglycerin dodecavehenate 0.0875g
Hard fat (Hydroxyl value = 5)
175g
A suppository was obtained in the same manner as in Example 1 using the suppository raw material having the above formulation.

Prescription
Prednisolone acetate 0.1g
Decaglycerin dodecavehenate 1.75g
Hard fat (hydroxyl value = 5)
175g
A suppository was obtained in the same manner as in Example 1 using the suppository raw material having the above formulation.

Prescription
Prednisolone acetate 0.1g
Decaglycerin dodecavehenate 8.75g
Hard fat (Hydroxyl value = 5)
175g
A suppository was obtained in the same manner as in Example 1 using the suppository raw material having the above formulation.
[Comparative Example 1]

Prescription
Prednisolone acetate 0.1g
Hard fat (Hydroxyl value = 5)
175g
A suppository was obtained in the same manner as in Example 1 using the suppository raw material having the above formulation.
[Experimental Example 1]

  The suppositories obtained in Examples 1 to 9 and Comparative Example 1 were allowed to stand at 10 ° C. for 24 hours and then taken out from the aluminum container, 10 pieces were randomly extracted, and the degree of cracks and cracks was visually observed. . The evaluation criteria are shown in Table 1, and the evaluation results of each suppository are shown in Table 2.

  As is apparent from Table 2, the suppository of Comparative Example 1 in which neither glycerin monofatty acid ester nor polyglycerin fatty acid ester was blended had an evaluation score of 20 and cracks were conspicuous. In the suppositories of the present invention obtained in 1 to 9, the number of evaluation points was 10 or less, and the number and degree of cracks and cracks were greatly reduced.

When producing a suppository using a hard fat having a hydroxyl value of 10 or less that does not adversely affect a drug that is susceptible to hydrolysis, cracking and cracking may occur in the suppository when solidified by rapid cooling. The hard fat having a hydroxyl value of 10 or less was a base that was not suitable for production involving rapid solidification.
According to the present invention, by adding a hard fat having a hydroxyl value of 10 or less and a glycerin monofatty acid ester or polyglycerin fatty acid ester to a suppository base, even in a production method involving rapid cooling and solidification using an ordinary automatic filling molding machine The occurrence of cracks and cracks in the suppository was suppressed, enabling efficient mass production.

Claims (12)

  A suppository containing a drug, a hard fat having a hydroxyl value of 10 or less, and cracking or cracking comprising glycerin monofatty acid ester or polyglycerin fatty acid ester.   The suppository according to claim 1, wherein the fatty acid of the glycerol mono-fatty acid ester or polyglycerol fatty acid ester has 18 to 22 carbon atoms.   The suppository according to claim 2, wherein the glycerin monofatty acid ester is glycerin monostearate or glycerin monobehenate.   The suppository according to claim 2, wherein the polyglycerin fatty acid ester is decaglycerin decastearic acid ester or decaglycerin dodecavehenic acid ester.   The seat according to claim 1 or 2, wherein the glycerin monofatty acid ester is contained in an amount of 0.2 to 10% by weight based on the whole suppository, or the polyglycerin fatty acid ester is contained in an amount of 0.05 to 10% by weight based on the entire suppository. Agent.   The suppository according to any one of claims 1 to 5, wherein the drug is a drug, antibiotic, biochemical preparation or enzyme susceptible to hydrolysis.   Corticosteroids with an ester bond or amide bond, local anesthetics, antipyretic analgesics, antiphlogistics, antiphlogistics, wound healing agents, vitamins, sulfa drugs, antibiotics, antifungals, bactericides, vasoconstrictors, The suppository according to claim 6, wherein the suppository is one or more selected from the group consisting of an antihistamine and a narcotic.   A drug, glycerin monofatty acid ester or polyglycerin fatty acid ester and a hard fat having a hydroxyl value of 10 or less are heated and melted to 40 to 100 ° C. to obtain a uniform liquid, and the temperature is adjusted to 35 to 45 ° C. A method for producing a suppository in which the generation of cracks and cracks which are filled and solidified in an atmosphere of 20 ° C. or less is suppressed.   The method for producing a suppository according to claim 8, wherein the occurrence of cracks or cracks in which the fatty acid of the glycerin monofatty acid ester or polyglycerin fatty acid ester has 18 to 22 carbon atoms is suppressed.   The suppository according to claim 8, wherein the glycerin monofatty acid ester is contained in an amount of 0.2 to 10% by weight based on the whole suppository, or the polyglycerin fatty acid ester is contained in an amount of 0.05 to 10% by weight based on the whole suppository. Manufacturing method.   The method for producing a suppository according to any one of claims 8 to 10, wherein the drug is a drug, antibiotic, biochemical preparation or enzyme that is susceptible to hydrolysis. Corticosteroids whose drugs have ester bonds or amide bonds, local anesthetics, antipyretic analgesics and anti-inflammatory agents, anti-inflammatory / antipruritic / wound healing agents, vitamins, sulfa drugs, antibiotics, antifungal agents, bactericides, vasoconstrictors, The method for producing a suppository according to claim 9, wherein the suppository is one or more selected from the group consisting of an antihistamine and a narcotic.