JP2003095922A - 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: A mixture of an oily base material, a drug, sucrose and water is mixed at a temperature higher than the melting point of the oily base material and the resultant paste is dried, pulverized and compressed to produce 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 local mucus to absorb the drug into the body through mucous membranes. Also,
In suppositories such as hemorrhoids, the suppository base oil and fat acts as a lubricant during defecation to prevent 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, problems such as suppositories using the oily base described above are unlikely to occur, but strong physical irritation locally due to absorption of mucus, resulting in hyperemia and erythema on the mucous membrane, causing pain to the patient. May be given.

[0003]

Under such circumstances, the object of the present invention is to prevent the deterioration of quality such as deformation, cracks and cracks even under high temperature storage conditions, and to provide excellent drug release and good drug release at the application site. It is intended to provide a suppository exhibiting absorption from mucous membranes, safety and the like, and a method for producing the suppository.

[0004]

[Means for Solving the Problems] Under these circumstances,
The inventors of the present invention have found that a suppository produced by uniformly mixing a melted oily base, a drug, and a mixture containing sucrose in warm water, drying and pulverizing and compression-molding solves the above problems. The present invention was completed by further research based on this knowledge. That is, the present invention is obtained by (1) mixing a mixture containing an oily base, a drug, sucrose and water at a temperature equal to or higher than the melting point of the oily base, drying it into powder, and compression molding. Suppositories, (2) The weight ratio of sucrose to the oily base is 1: 0.7 to 1.7, and the weight ratio of water to the oily base is 1: 0.1 to 0.4. (1) The suppository, (3) The content of sucrose is 30 to 60 based on the total amount of the suppository.
The suppository according to (1) or (2), which is 10% by weight based on the total amount of the suppository, and the suppository according to (1) or (2), which is 5% by weight. ) The oily base has a melting point of 10 to 45 ° C. (1) or (2)
The suppository described above, (6) one or a mixture of two or more kinds of hard fat derived from cocoa butter, laurin butter, beef tallow or a semi-synthetic product, or a coconut oil or palm kernel, which is liquid at room temperature. Oil, camellia oil, olive oil, soybean oil, sesame oil, corn oil, medium-chain fatty acid triglyceride, liquid paraffin, and one or more kinds of isopropyl myristate are added (1) or (2). Agent, (7) powder has an average particle size of 20 to 2
The suppository according to (1) or (2) having a size of 000 μm, (8) the drug is a corticosteroid, a local anesthetic, an antipyretic analgesic / antiinflammatory agent, an antiphlogistic / antipruritic / wound healing agent, a vitamin agent,
Sulfa drugs, antibiotics, antifungals, bactericides, vasoconstrictors, antihistamines, narcotics, sleep sedatives, anxiolytics, antiepileptics, stimulants, stimulants, antiparkinson agents, central nervous system agents, skeletal muscle relaxation Agents, agents for autonomic nerves, antispasmodics, antispasmodic agents, cardiotonics, agents for arrhythmia, diuretics, antihypertensive agents, coronary vasodilators, peripheral vasodilators, hyperlipidemic agents, respiratory stimulants,
One or more selected from antidiarrheal / rectifying agents, peptic ulcer treatment agents, bronchodilators, allergic agents, laxatives, enemas, choleretic agents and various hormone agents (1) or (2) The suppository described. (9) A method for producing a suppository, in which a mixture containing an oily base, a drug, sucrose and water is mixed at a temperature equal to or higher than the melting point of the oily base, dried and powdered, and compression molded, and (10) ) The production method according to (9), wherein the drying is reduced pressure 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 two 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., were added. Examples thereof include hard fat. 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: 0.7 to 1.7, preferably 1: 0.75 to 1.
It is 5. The amount of water used relative to the total amount of suppositories is 10 to 18% by weight, preferably 12 to 15% by weight. The weight ratio of water to the oily base is 1: 0.1 to 0.
4, and preferably 1: 0.2 to 0.35.

Examples of the drug include corticosteroids, local anesthetics, antipyretic analgesic and anti-inflammatory agents, anti-inflammatory / pruritic / wound healing agents, vitamins, sulfa drugs, antibiotics, antifungal agents,
Antiseptics, vasoconstrictors, antihistamines, narcotics, sleep sedatives, anxiolytics, antiepileptics, stimulants, stimulants, antiparkinson's agents, central nervous system agents, skeletal muscle relaxants, autonomic nerve agents, antispasmodic agents, Antiphlogistic, cardiotonic, arrhythmic, diuretic, antihypertensive, coronary vasodilator, peripheral vasodilator, hyperlipidemic agent, respiratory stimulant, antidiarrheal / intestinal agent, peptic ulcer treatment, bronchodilation Agent, allergic agent, laxative, enema agent, choleretic agent,
Examples include various hormone agents. The amount of drug used varies depending on the type of drug, the type of disease, the subject of administration, etc., so it cannot be generally stated, but it is usually 0.1 to 15% by weight relative to the suppository
It is a degree.

The suppository of the present invention may be blended with 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, preferably about 1,000 to 5,000. The content of polyethylene is 1 to 20% by weight, preferably 3 to 15% by weight, based on the total amount of suppositories. 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 to 10, preferably about 4 to 10, and the number of fatty acids is 1.
It is about 10 to 10, preferably about 5 to 10. The fatty acid is not particularly limited, but stearic acid is preferable. Specific examples of the polyglycerin fatty acid ester include, but are not limited to, tetraglyceryl pentastearate, hexaglyceryl pentastearate, decaglycer pentastearate, and decaglyceryl decastearate. 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 polyglycerin fatty acid ester is usually 1: 0.10 to 0.5, preferably 1: 0.03 to 0.3. The suppository production method of the present invention is carried out, for example, by melting an oily base for suppositories at 50 to 120 ° C., adding a drug, sucrose and other compounds to this, and uniformly mixing the mixture with warm water. Add gradually to form a paste. The obtained paste-like material is dried under reduced pressure as it is, or after the paste-like material is cooled and solidified, it is dried under reduced pressure or freeze-dried, but preferably the paste-like material is cooled and solidified, and the obtained plate-like solid material as it is, or After dividing into suitable size, it is dried under reduced pressure at a temperature not lower than the melting point of the oily base, preferably not higher than 80 ° C, or freeze-dried to give a water content of 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 diameter of the powder is usually 20 to 2000 μm, 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
Mixes with each other while at the same time adding fat and sucrose
Is also solidified from the dissolved state
And has a structure connected by a three-dimensional network structure. Special
The network structure formed by sucrose has heat resistance and
It has excellent mechanical strength and can be deformed even if the suppository is exposed to high temperature and vibration.
Does not cause quality deterioration such as cracks. Moreover, the seat of the present invention
When the drug is administered topically, the local mucus is a network of sucrose.
Since the suppository is disintegrated promptly by disintegrating the structure,
The drug is released quickly and the effect is rapidly expressed.

[0010]

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 part Sucrose 700 parts Purified water 262 parts Hard fat 787 parts Manufacturing method To the water heated to 60 ° C, a mixture of hard fat, prednisolone acetate and sucrose melted at 60 ° C was added,
It was well kneaded to obtain a paste. This paste-like material is poured into a petri dish so that the thickness is about 5 mm, and the temperature is 10 ° C.
It was cooled to solidify. The solidified product is vacuum dried at 60 ° C.,
The water content was 3.0 w / w% or less. The dried product was ground in a co-mill for 3 minutes under cooling at -5 ° C to give an average particle size of 350 to 5
A powder of 00 μm was obtained. The powder obtained was filled in a mold of a manual compression tableting machine so that the weight per suppository was 1750 mg, and the temperature was 300 Kgf / cm at an ambient temperature of 10 ° C.
100 suppositories were produced by compression molding under a pressure of 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 at 25 ° C. for 2 days, and then the following tests were conducted. 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 was left at 30 ° C. for 2 days or more in advance, and the tip of the suppository was inserted into a suppository insertion tool of a hardness tester in a heating chamber, and a hanging metal fitting was placed on the suppository. A 200 g disk weight was placed on the lower table every measurement for 1 minute to measure the disintegration time of the suppository, 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 following test results are shown in Table 1.

[0013]

[Table 1]

As is clear from Table 1, the suppository of Example 1 was superior in heat resistance to the suppository of Comparative Example 1 and showed a fast disintegration time in the rectal simulated environment by the setonical method.
The hardness of the suppository of Example 1 at 30 ° C. is lower than that of Comparative Example 1, but if it is 0.6 Kg or more, there is no problem in practical use.

Example 2 Formulation Prednisolone acetate 1 part Sucrose 700 parts Purified water 262 parts Hard fat 787 parts Manufacturing method A mixture of hard fat, sucrose and prednisolone acetate melted at 60 ° C. was added to water heated to 60 ° C., It was well kneaded to obtain a paste. 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. The solidified product was vacuum dried at 60 ° C., and the water content was set to 3.0 w / w% or less. The dried product was crushed for 10 minutes with a co-mill under cooling at -5 ° C, and the obtained powder was adjusted to a particle size of 850 to 1400 µm with a sieve. The obtained powder was compression molded under a pressure of 800 Kgf / cm ² by a manual compression tableting machine at an ambient temperature of 10 ° C.
100 suppositories of 50 mg were prepared.

Examples 3 to 6 Using the components shown in Table 2 and following the method of Example 2
100 suppositories of 50 mg each were prepared.

[0017]

[Table 2]

Test Example 2 Ten suppositories each obtained in Examples 2 to 6 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 cooled to room temperature of 20 ° C. was observed, and the number of deformed or cracked suppositories was counted.
The results are shown in Table 3.

[0019]

[Table 3]

As is clear from Table 3, the suppositories of Comparative Example 1 were all deformed or cracked when stored at a high temperature of 40 to 60 ° C., whereas the suppositories of Examples 2 to 6 of the present invention were:
No deformation or cracking occurred at all under any conditions.

[0021]

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.

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁷ Identification code FI theme code (reference) A61K 47/44 A61K 47/44 A61P 29/00 A61P 29/00 F term (reference) 4C076 AA01 AA36 BB21 CC04 DD45A DD46A EE30 EE51A FF04 FF05 FF31 GG06 GG11 4C086 AA01 AA02 DA10 MA03 MA05 MA31 MA34 MA56 NA03 NA12 ZB11

Claims (10)

[Claims] 1. A mixture comprising an oily base, a drug, sucrose and water is mixed at a temperature not lower than the melting point of the oily base,
A suppository obtained by powdering after drying and compression molding. 2. The weight ratio of sucrose to the oily base is 1:
The suppository according to claim 1, which is 0.7 to 1.7 and the weight ratio of water to the oily base is 1: 0.1 to 0.4. 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 10 to 18% by weight based on the total amount of the suppository. 5. The suppository according to claim 1 or 2, wherein the oily base has a melting point of 10 to 45 ° C. 6. One or two of hard fat derived from cocoa butter, laurin fat, beef tallow or semi-synthetic product as the oily base.
Mixture 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 and isopropyl myristate, which are liquid at room temperature. 3. The method according to claim 1, wherein
The suppository described. 7. The suppository according to claim 1, wherein the powder has an average particle size of 20 to 2000 μm. 8. The drug is a corticosteroid, a local anesthetic,
Antipyretic analgesic / anti-inflammatory agent, anti-inflammatory / antipruritic / wound healing agent, vitamin agent, sulfa agent, antibiotics, antifungal agent, fungicide, vasoconstrictor, antihistamine, narcotics, sleep sedative, anxiolytic,
Anti-epileptic agent, stimulant, stimulant, anti-Parkinson's agent, central nervous system agent, skeletal muscle relaxant, autonomic nerve agent, antispasmodic agent, analgesic agent, cardiotonic agent, arrhythmic agent, diuretic, antihypertensive, coronary vasodilator Agent, peripheral vasodilator, hyperlipidemia agent, respiratory stimulant,
3. One or more selected from antidiarrheal / intestinal control agents, peptic ulcer treatment agents, bronchodilators, allergic agents, laxatives, enema agents, choleretic agents and various hormone agents. Suppository. 9. A mixture comprising an oily base, a drug, sucrose and water is mixed at a temperature not lower than the melting point of the oily base,
A suppository manufacturing method in which it is powdered after drying and compression molded. 10. The production method according to claim 9, wherein the drying is reduced pressure drying or freeze drying.