JP2003095921A - Suppository and method for producing the same - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a suppository that has excellent heat resistance and good drug releasability with the melting and disintegration time shortened at the application site, because the conventional suppository produced by using an oily base material through the melting method is unsatisfactory in heat resistance and requires a longer time for its melting and disintegration to delay the exhibition of effect of a drug. SOLUTION: An oily base material including sucrose and a drug component is mixed with water in which a surfactant is dispersed or dissolved and the resultant pasty emulsion is dried and pulverized and compressed to the objective suppository.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a suppository applied to the rectum, urethra, vagina and the like and a method for producing the same. Especially under high temperature storage conditions, suppositories and suppositories that have excellent heat resistance such as no deformation, cracking, cracking, or other quality deterioration, and have excellent disintegration and drug release properties at the applied site. It is about law.

[0002]

BACKGROUND OF THE INVENTION Suppositories are solid drugs that are administered to the rectum, urethra, vagina, etc., which soften or melt at body temperature or dissolve in mucus to absorb the drug from the mucous membrane into the body. In addition, in topical suppositories such as hemorrhoids, the suppository base oil and fat acts as a lubricant during defecation to suppress the deterioration of symptoms. Most commercially available suppositories use an oily base such as hard fat and isocaca butter, and their melting points are set below the body temperature in order to soften or melt them near the body temperature. For this reason, the storage conditions are usually cold (15 ° C or less), control temperature such as 30 ° C or less at the highest, and care that the suppository tip is set upside down and stored. There are many storage restrictions. In the environment where suppositories are exposed to high temperatures for a long time, such as in the summer or in the middle of a car during transportation, it is quite difficult to manage within the above storage conditions, and particularly good management after reaching the patient's hand is difficult. However, problems of quality deterioration such as deformation, cracks and cracks occur. On the other hand, the suppository using macrogol or the like fulfills its function by being dissolved in local mucus, and therefore its melting point is set high.
Therefore, although problems such as suppositories using the oily base described above are unlikely to occur, physical irritation to the local area is strong due to absorption of local mucus, resulting in hyperemia or erythema on the mucous membranes, which may affect patients. May cause distress.

[0003]

In such a situation, the object of the present invention is to prevent deterioration of the quality such as deformation, cracks and cracks even under high temperature storage conditions, and to release the drug at the application site and absorb it from the mucous membrane. It is to provide a suppository having excellent properties and safety and a method for producing the suppository.

[0004]

[Means for Solving the Problems] Under these circumstances,
The present inventors have developed a melted oily base, a drug, a surfactant,
Mix the mixture containing sucrose homogeneously with water, or mix the homogeneous mixture containing the melted oily base, drug, surfactant and sucrose with water to make a continuous phase from the oil phase to the aqueous phase. It was found that a suppository produced by phase inversion, drying, powdering and compression molding solves the above problems, and based on this knowledge, further research was conducted to complete the present invention. That is,
In the present invention, (1) a mixture comprising an oily base, a drug, sucrose, water and a surfactant is mixed at a temperature equal to or higher than the melting point of the oily base, dried and then powdered and compression molded. The resulting suppository, (2) the weight ratio of sucrose to the oily base is 1: 0.6 to 1.9, and the weight ratio of water is 1: 0.15.
˜0.37 and the weight ratio of the surfactant is 1: 0.01
The suppository according to (1), wherein the content of sucrose is 30 to 60% by weight based on the total amount of the suppository (1) or (2). The suppository according to (1) or (2), wherein the amount of water used is 7 to 15% by weight based on the total amount of the suppository, (5) the surfactant is a sucrose fatty acid ester of HLB 8 to 16 (1) or (2) Suppository, (6)
The amount of surfactant used is 0.2-5% by weight with respect to the total amount of suppositories.
The suppository according to (1) or (2), wherein (7) the oleaginous base has a melting point of 10 to 45 ° C, and the suppository according to (1) or (2), (8) the oleaginous group. One or a mixture of two or more kinds of hard fat derived from cacao butter, laurin butter, beef tallow or semi-synthetic product, or coconut oil, palm kernel oil, camellia oil, olive oil, soybean oil, sesame oil which is liquid at room temperature. , Corn oil, medium-chain fatty acid triglyceride, liquid paraffin, or isopropyl myristate, or one or more kinds thereof, (1) or (2), the suppository, (9) the powder has an average particle size of 20. ˜2000 μm (1) or (2)
The suppository described above, (10) the drug is a corticosteroid, a local anesthetic, an antipyretic analgesic / antiphlogistic, an antiphlogistic / antipruritic / wound healing agent, a vitamin, a sulfa drug, an antibiotic, an antifungal agent, a bactericidal agent,
Vasoconstrictor, antihistamine, narcotics, sleep sedative, anxiolytic, antiepileptic, stimulant / stimulant, antiparkinson, central nervous system agent, skeletal muscle relaxant, autonomic nerve agent, antispasmodic agent, analgesic agent, Cardiotonic agents, arrhythmic agents, diuretics, antihypertensive agents, coronary vasodilators, peripheral vasodilators, hyperlipidemia agents, respiratory stimulants, antidiarrheal / rectifying agents, peptic ulcer treatment agents, bronchodilators, allergies The suppository according to (1) or (2), which is one kind or two or more kinds selected from an ointment, a laxative, an enema, a choleretic agent, and various hormones. (11) Oily base,
A method for producing a suppository in which a mixture containing a drug, sucrose, water and a surfactant is mixed at a temperature equal to or higher than the melting point of an oily base, dried and then powdered, and compression-molded, and (12) drying is reduced pressure The production method according to (11), which is drying or freeze-drying.

[0005]

BEST MODE FOR CARRYING OUT THE INVENTION The oily base used in the present invention includes, for example, one or a mixture of two or more kinds of cacao butter, laurin fat, beef tallow or hard fat derived from a semi-synthetic product, or a room temperature ( One or more of palm oil, palm kernel oil, camellia oil, olive oil, soybean oil, sesame oil, corn oil, medium chain fatty acid triglyceride, liquid paraffin or isopropyl myristate, which are liquid at 15 to 25 ° C., are added. However, hard fat is preferable. The oily base used in the present invention has a melting point adjusted to usually 10 to 45 ° C, preferably 25 to 38 ° C. Water and sucrose used in the present invention may be of any quality as long as they can be used in medicine.

The ratio of sucrose content to the total amount of suppositories is 30 to 60% by weight, preferably 35 to 50% by weight. The weight ratio of sucrose to the oily base is 1: 0.6 to 1.9, preferably 1: 0.75 to 1.
35. The amount of water used with respect to the total amount of suppositories is 7 to 15% by weight, preferably 8 to 12% by weight. The weight ratio of water to the oily base is 1: 0.15.
It is 0.37, preferably 1: 0.18 to 0.35.

The surfactant used in the present invention is HLB.
Is a surfactant of 8 to 16 and can be used in medicine, but is preferably a sucrose fatty acid ester having an HLB of 9 to 15. Examples of the fatty acid that constitutes the sucrose fatty acid ester include lauric acid, myristic acid, palmitic acid, stearic acid, and oleic acid.
Stearic acid esters are preferred. The amount of the surfactant used relative to the total amount of the suppository is usually 0.2 to 5% by weight,
It is preferably 0.5 to 3% by weight. Further, the weight ratio of the surfactant to the oily base is 1: 0.01-0.
2, and preferably 1: 0.01 to 0.1.
Examples of the drug used in the present invention include corticosteroids, local anesthetics, antipyretic and analgesic anti-inflammatory agents, anti-inflammatory / anti-pruritic agents.
Wound healing agents, vitamins, sulfa drugs, antibiotics, antifungal agents, fungicides, vasoconstrictors, antihistamines, narcotics, sleep sedatives, anxiolytics, antiepileptics, stimulants, stimulants, antiparkinson agents, central Nervous agent, skeletal muscle relaxant, autonomic nerve agent, antispasmodic agent, antiphlogistic agent, cardiotonic agent, arrhythmic agent, diuretic, antihypertensive agent, coronary vasodilator, peripheral vasodilator, hyperlipidemic agent, respiration Examples include accelerating agents, antidiarrheal / intestinal regulating agents, peptic ulcer treating agents, bronchodilators, allergic agents, laxatives, enema agents, choleretic agents, and various hormone agents. The amount of drug used varies depending on the type of drug, the type of disease, the subject to be administered, etc., so it cannot be generally stated.
It is about% by weight.

The suppository of the present invention may contain polyethylene or polyglycerin fatty acid ester in order to improve heat resistance. Further, if necessary, an appropriate amount of an absorption regulator, a dissolution aid, a stabilizer, a preservative, an excipient, a lubricant and the like may be added. Polyethylene that can be used in the present invention is obtained by polymerizing ethylene, and its average molecular weight is usually about 500 to 30,000,
It is preferably about 1,000 to 5,000. The content of polyethylene is 1 to 20% by weight with respect to the total amount for suppositories.
And preferably 3 to 15% by weight. The polyglycerin fatty acid ester that can be used in the present invention is obtained by polymerizing glycerin and esterifying with glycerin. The polymerization number of glycerin is about 2-10, preferably about 4-10, and the number of fatty acids is about 1-10, preferably about 5-10. The fatty acid is not particularly limited, but stearic acid is preferable. Specific examples of the polyglycerin fatty acid ester include tetraglyceryl pentastearate, hexaglyceryl pentastearate, decaglycer pentastearate, decaglyceryl decasterate,
It is not limited to these. The blending ratio of the polyglycerin fatty acid ester to the total amount of the suppository base is usually 0.5 to 10% by weight, preferably 1 to 7% by weight.
The weight ratio of polyethylene to the oily base or the mixture of the oily base and the polyglycerin fatty acid ester is usually 1: 0.10 to 0.5, preferably 1: 0.0.
It is 3 to 0.3.

The suppository production method of the present invention comprises, for example, melting an oily base for suppositories at 50 to 120 ° C.
Sucrose and other compounds are added and uniformly mixed, and then gradually added to water in which a surfactant is dispersed or dissolved to form a paste-like emulsion. The obtained emulsion is dried under reduced pressure as it is, or the emulsion is cooled and solidified and then dried under reduced pressure or freeze-dried, but the emulsion is preferably cooled and solidified and then dried. The obtained plate-like solid is, as it is, or after being divided into a suitable size, dried under reduced pressure at a temperature not lower than the melting point of the oily base, preferably at a temperature not higher than 80 ° C, or by freeze-drying, The water content is 5% by weight or less, preferably 3% by weight or less. The dried product obtained is pulverized by, for example, a pulverizer. The average particle size of the powder is usually 20-2000μ
m, preferably about 300 to 1500 μm.

This powder is preferred as a suppository on a compression molding machine.
It is compression molded into a good shape. Compression pressure is usually 100-1500
kgf / cm^Two, Preferably 200 to 1000 kgf /
cm ^TwoIs. Oily base and sucrose in the obtained suppositories
Are similar to each other evenly mixed with each other in the presence of a surfactant.
Sometimes both fat and sucrose melt or dissolve, respectively
Each is solid because it is solidified from the state
It has a structure that is connected by a dynamic mesh structure. Especially the show
The network structure formed by sugar is heat-resistant and mechanically strong.
The suppository is deformed and cracked even when exposed to high temperature and vibration.
It does not cause such quality deterioration. Moreover, the suppository of the present invention
When administered locally, mucus disrupts the sucrose network.
By rapidly disintegrating the suppository,
The release is fast and the drug's effect is rapidly expressed.

[0011]

EXAMPLES The present invention will be specifically described below with reference to Examples, Comparative Examples and Test Examples. In addition, "part" means "part by weight" unless otherwise specified. Example 1 Formulation Prednisolone acetate 1.0 part Sucrose 700 parts Purified water 175 parts Sucrose fatty acid ester (HLB 11) ^* 17.5 parts Ethanol 17.5 parts Hard fat 839 parts ( ^* DK ester F-110, Daiichi Industrial Pharmaceutical Co., Ltd.
Manufacturing method) A mixture of hard fat, sucrose and prednisolone acetate melted at 60 ° C was added to a mixture of sucrose fatty acid ester (HLB 11), ethanol and purified water heated at 60 ° C, and kneaded well to form a paste. To obtain an emulsion.
The paste-like material was poured into a petri dish so as to have a thickness of about 5 mm and cooled to 10 ° C. to be solidified. 6 solidified
It was vacuum dried at 0 ° C. and the water content was adjusted to 3.0 w / w% or less.
The dried product was crushed with a co-mill for 10 minutes under cooling at -5 ° C,
A powder having an average particle diameter of 350 to 550 μm was obtained. The obtained powder was loaded into a mold of a manual compression tableting machine at 1750 mg per suppository, and the powder was placed at 800 ° C. under an ambient temperature of 10 ° C.
100 suppositories were produced by compression molding under a pressure of Kgf / cm ² .

Comparative Example 1 Hard fat was melted at 60 ° C., poured into a suppository mold made of aluminum, cooled at room temperature (20 to 25 ° C.),
100 suppositories were prepared at 1750 mg / piece.

Test Example 1 The suppositories of Example 1 and Comparative Example 1 were left for 2 days at 25 ° C.
The following tests were conducted respectively. Test items and test method 1) Deformation test (n = 10) Ten suppositories were left standing for 1 hour at a temperature of 60 ° C and then cooled at room temperature of 25 ° C for 1 hour. The appearance was observed, and the number of suppositories with deformation or cracking was counted. 2) Hardness test (n = 3) Using a suppository hardness tester manufactured by Erweka, 30 ° C (±
The hardness was measured at 1 ° C. That is, the suppository is left to stand at 30 ° C (± 1 ° C) for 2 days or more in advance, and the tip of the suppository is inserted into the suppository insertion tool of the hardness tester in a room heated to the same temperature. I put a hanging bracket on it. Place a 200g disk weight on the lower table every 1 minute,
The disintegration time of the suppository was measured, and the hardness was determined from the value. 3) Measurement of liquefaction or disintegration time by the setonical method (n =
3) By the method of Setnikar et al. ^* , 37 ℃ (±
The time until the suppository was completely liquefied or disintegrated was measured at 0.2 ° C. ^* Setnikar, WH et al .: J.Pharm.Sci., 51, 566 (1962) 4) Measurement of peak apex temperature by DSC method Suppositories about 3 mg were placed in an aluminum crimp cell and placed in a nitrogen atmosphere at -20 ° C to 60 ° C. The temperature was raised up to 2 ° C./min and differential scanning calorimetry was carried out with a differential scanning calorimeter DSC6200 (Seiko Instruments Inc.), and the peak apex temperature showing the maximum shift was determined as the melting point. The results are shown in Table 1.

[0014]

[Table 1]

As is clear from Table 1, the suppository of Example 1 was superior to the suppository of Comparative Example 1 in heat resistance, and showed a fast disintegration time even in the setonical method. Suppository 3 of Example 1
The hardness at 0 ° C is lower than that of Comparative Example 1, but 0.6
If it is Kg or more, there is no problem in practical use.

Example 2 Formulation Prednisolone acetate 1.0 part Sucrose 700 parts Sucrose fatty acid ester (HLB 11) ^* 17.5 parts Purified water 175 parts Hard fat 857.4 parts ( ^* DK Ester F-110 Daiichi Kogyo) Pharmaceutical Co., Ltd. Manufacturing method A mixture of hard fat, sucrose, and prednisolone acetate melted at 60 ° C. was mixed with sucrose fatty acid ester and 60%.
The mixture was added to a mixture of purified water heated to ℃ and kneaded well to obtain a paste. Put this paste on a petri dish to a thickness of 5
It was poured so as to have a size of about mm and cooled to 10 ° C. to be solidified. The solidified product is vacuum dried at 60 ° C. to remove water by 3.0 w /
It was set to w% or less. The dried product was ground in a co-mill for 10 minutes under cooling at -5 ° C, and the obtained powder was sieved to have a particle size of 850.
The particle size was adjusted to ˜1400 μm. The obtained powder is 10
300 Kgf by manual compression tableting machine at ambient temperature of ℃
100 suppositories weighing 1750 mg were produced by compression molding under a pressure of / cm ² .

Examples 3 to 7 [Table 2] shows components for producing suppositories and parts by weight thereof. Using these components, 100 suppositories each weighing 1750 mg were produced in the same manner as in Example 2.

[0018]

[Table 2]

Test Example 2 Ten suppositories each obtained in Examples 2 to 7 and Comparative Example 1 were laid sideways at 20 ° C., 40 ° C., 50 ° C. and 60 ° C. for 1 hour or 1 hour. The appearance of the suppositories when stored for a day and later cooled to room temperature of 20 ° C. was observed, and the number of suppositories that were deformed or cracked was counted. The results are shown in [Table 3].

[0020]

[Table 3]

As is clear from [Table 3], the suppositories of Comparative Example 1 all deformed or cracked when stored at a high temperature of 40 to 60 ° C, whereas the suppositories of Examples 2 to 7 of the present invention. Under all conditions, no deformation or cracking occurred.

[0022]

EFFECTS OF THE INVENTION The suppository of the present invention is superior in heat resistance to the suppository prepared by the conventional melting method, and has an extremely fast disintegration time at the application site such as rectum and excellent drug releasing property. Play.

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Claims (12)

[Claims] 1. A mixture obtained by mixing an oil-and-fat base, a drug, sucrose, water and a surfactant at a temperature not lower than the melting point of the oil-and-fat base, dried and powdered, followed by compression molding. Suppository. 2. The weight ratio of sucrose to the oily base is 1:
0.6 to 1.9, and the weight ratio of water is 1: 0.15.
0.37, and the weight ratio of the surfactant is 1: 0.01-
The suppository according to claim 1, which is 0.20. 3. The content of sucrose is 30 to 6 with respect to the total amount of suppositories.
The suppository according to claim 1 or 2, which is 0% by weight. 4. The suppository according to claim 1, wherein the amount of water used is 7 to 15% by weight based on the total amount of the suppository. 5. The suppository according to claim 1 or 2, wherein the surfactant is a sucrose fatty acid ester of HLB 8-16. 6. The suppository according to claim 1, wherein the amount of the surfactant used is 0.2 to 5% by weight based on the total amount of the suppository. 7. The suppository according to claim 1 or 2, wherein the oily base has a melting point of 10 to 45 ° C. 8. One or two kinds of hard fat derived from cacao butter, lauric fat, beef tallow or semi-synthetic product as the oily base.
Mixtures of two or more kinds, or one or more kinds of palm oil, palm kernel oil, camellia oil, olive oil, soybean oil, sesame oil, corn oil, medium-chain fatty acid triglyceride, liquid paraffin or isopropyl myristate, which are liquid at room temperature. The suppository according to claim 1, wherein the suppository is added. 9. The suppository according to claim 1, wherein the powder has an average particle size of 20 to 2000 μm. 10. The drug is a corticosteroid, a local anesthetic, an antipyretic analgesic / antiinflammatory agent, an antiphlogistic / antipruritic / wound healing agent, a vitamin agent, a sulfa drug, an antibiotic, an antifungal agent, a fungicide, a vasoconstrictor, an antihistamine, Narcotics, sleep sedatives, anxiolytics, antiepileptics, stimulants / stimulants, antiparkinson's,
Central nervous system agents, skeletal muscle relaxants, autonomic nerve agents, antispasmodics,
Antiphlogistic, cardiotonic, arrhythmic, diuretic, antihypertensive, coronary vasodilator, peripheral vasodilator, hyperlipidemic agent, respiratory stimulant, antidiarrheal / intestinal agent, peptic ulcer treatment, bronchodilation Agent,
One or more selected from allergic agents, laxatives, enema agents, choleretic agents and various hormone agents.
The suppository described. 11. A suppository for compression molding, which comprises mixing a mixture comprising an oily base, a drug, sucrose, water and a surfactant at a temperature not lower than the melting point of the oily base, and then drying and powdering the mixture. Manufacturing method. 12. The production method according to claim 11, wherein the drying is reduced pressure drying or freeze drying.