JPH0676313B2 - Suppository base - Google Patents

Description

TECHNICAL FIELD The present invention relates to a suppository base, and more specifically, an oil and fat having good solidification property in the step of pouring into a mold during molding and having excellent drug stability. It relates to a composition.

Suppositories have long been used as a method of administering pharmaceuticals, and in recent years, due to the development of suppository bases, the development of suppository manufacturing technology, and the elucidation of the mechanism of absorption and drug metabolism of suppositories, The range is expanding not only to local actions such as the anus, but also to drugs administered for the purpose of systemic action such as analgesics and antibiotics. Furthermore, since suppositories have few side effects and can be safely administered, it is being recognized that they are widely used as home remedies.

[Conventional technology]

As a suppository base, cocoa butter has been conventionally used because it has a characteristic that the plastic region is extremely narrow, that is, it is solid at room temperature and maintains sufficient hardness, but it quickly melts when it reaches around body temperature. However, since the cocoa butter has an iodine value of around 34, the fat and oil may be oxidized during long-term storage and the drug may be inactivated. As an alternative, fats and oils mainly composed of lauric acid, which exhibits melting behavior similar to that of cocoa butter, have been widely used. For example, coconut oil,
Examples thereof include lauric oils and fats such as palm kernel oil, and those obtained by mixing palm oil with these and transesterifying and curing. Further, in order to improve the hardness shortage and the solidification rate of these lauric oils and fats, it is proposed to remove glycerides having a low molecular weight and a low melting point containing a fatty acid having 8 to 10 carbon atoms by a combination of transesterification and molecular distillation. Has been
59-16594 and Japanese Patent Publication No. 59-16595). However, in general, the fatty acids of hardened lauric oil are fractionally distilled to remove lower fatty acids, and a saturated fatty acid mixture mainly having a distribution of 12 to 18 carbon atoms and a polyhydric alcohol such as glycerin are esterified. Synthetic oils and fats obtained by chemical reaction are mainly used. These lauric oils and fats have almost no unsaturated fatty acids and have appropriate hardness and meltability, and thus have good properties as a suppository base, but there are still some unsolved drawbacks. is there.

If the suppository base consisting of lauric oil has a hydroxyl value of more than 20, that is, if it has a relatively high hydroxyl value, the suppository raw material is directly injected into the suppository (container) by the melting method and cooled with ice. Alternatively, it can be strongly cooled by other methods. That is, in the cooling step, the supercooled state of the base is suppressed, and the solidifying property is relatively good, so that the molding operation of the suppository can be easily performed. Such bases are widely used for mass production in factories, and the resulting suppositories are robust with relatively few pinholes (central depressions) and cracks.

However, when a suppository containing a drug having an acid group such as aspirin is produced using a base having a relatively high hydroxyl value, that is, a base having a hydroxyl value of more than 20, free salicylic acid is increased. The phenomenon of deactivating the medicinal effect occurs daily. That is, when suppositories are made of antibiotics, biochemical preparations, enzymes, etc. that are susceptible to hydrolysis, the free hydroxyl groups in the base react catalytically with these drugs, causing separation or It causes a fixed price.

In order to prevent such inactivation of the drug, it is necessary to use a base material having a lower hydroxyl value (see JP-A-58-52212). It is desirable to use a base material having a hydroxyl value of 20 or less, preferably 10 or less, but in this case, a new problem occurs in the moldability and operability of the suppository. That is, if a base material having a low hydroxyl value is used, even if the molten suppository is poured into a suppository mold during the molding operation and cooled, the solidification property of the base material is poor and the workability is remarkably lowered. Further, there is a problem that the drug is precipitated during molding because of a large degree of supercooling, and troubles such as pinholes and cracks occur when a strong cooling operation such as ice cooling is performed.

As described above, lauric oils and fats as a suppository base have good performance, but do not satisfy both drug stability and moldability / operability. Therefore, moldability and operability are unsatisfactory for drugs that are susceptible to deactivation such as decomposition and discoloration, but lauric oil and fat bases with a low hydroxyl value are used, and for relatively stable drugs. Uses a lauric oil and fat base having a high hydroxyl value that can improve productivity. That is, the present situation is that different lauric oil and fat bases having different hydroxyl values are used depending on the drug.

However, as the use of suppositories develops, various kinds of drugs are blended, and mass production technology is required. For that purpose, a suppository base having both drug stability and moldability / operability can be expected to have great effectiveness, and is desired.

[Problems to be solved by the invention]

An object of the present invention is to mainly use lauric oils and fats having both good drug stability and moldability / operability without impairing the physical properties (melting property / hardness) as a suppository base. Providing a suppository base. That is, the hydroxyl value suppressing free hydroxyl groups is 20 or less, preferably 10 or less, and has good solidification property during suppository molding, and even if forced cooling such as ice cooling is performed from the overheated molten state. It is intended to provide a suppository base excellent in moldability and operability without causing troubles such as holes and cracks.

[Means for solving problems]

The present inventors have conducted extensive studies on the performance of various glyceride compositions as suppository bases mainly for the purpose of achieving the above objects, and as a result, specific lauric oils and fats having 20 or more carbon atoms. Suppository bases, which consist of a combination of saturated fatty acids and unsaturated fatty acids having 16 to 22 carbon atoms with specific triglycerides of mixed acid groups, are said to have excellent drug stability and moldability / operability. The fact was found and the present invention was completed.

That is, the present invention provides (i) 80 to 99% by weight of a lauric oil or fat containing a glyceride of a fatty acid having 8 to 18 carbon atoms as a main component and having a hydroxyl value of 20 or less, and (ii) a saturated fatty acid having 20 or more carbon atoms as a constituent fatty acid. Contains 30 to 70% by weight of fatty acids and 20 to 60% by weight of unsaturated fatty acids having 16 to 22 carbon atoms, and is mainly mixed acid triglyceride of saturated fatty acids having 20 or more carbon atoms and unsaturated fatty acids having 16 to 22 carbon atoms The present invention relates to a suppository base comprising 1 to 20% by weight of fats and oils.

The suppository base of the present invention has a hydroxyl value of 20 or less, and even a drug unstable to a free hydroxyl group does not deactivate its efficacy. When a drug that is more unstable with respect to free hydroxyl groups is mixed, it is preferable to use a base having a hydroxyl value of 5 or less. In any case, despite the low hydroxyl value, due to the combination of the specific lauric oil and fat and the specific mixed acid triglyceride oil and fat,
The suppository has excellent solidification properties when molded, and pinholes, cracks, etc. do not occur, and a good quality suppository can be manufactured.

As the lauric oil and fat used as the base of the present invention, coconut oil, palm kernel oil, palm oil and the like are used as raw material oils and fats which have been subjected to processing such as hardening, fractionation, transesterification and distillation. In order to make the base of the present invention even more effective, a lauric oil or fat containing a fatty acid glyceride of a saturated fatty acid having 12 to 18 carbon atoms and having lower fatty acids having 8 to 10 carbon atoms removed is used. Good to use.

The suppository base of the present invention contains 20% by weight of the fat or oil mainly composed of the specific mixed acid group triglyceride in the base.
By limiting to the following, the melting characteristics and the appropriate hardness required as a base are not impaired, and the oxidation stability due to unsaturated fatty acids is not reduced.
However, when the content is 1% by weight or less, the solidified state becomes poor, and it is not possible to exert a remarkable effect on the moldability and operability during the production of suppositories.

The method for producing a specific fat or oil mainly composed of a mixed acid group triglyceride of a saturated fatty acid having 20 or more carbon atoms and an unsaturated fatty acid having 16 to 22 carbon atoms used in the base of the present invention is not particularly limited, but the following method is preferable. . Fatty acid triglyceride containing 40% by weight or more of saturated fatty acids having 20 or more carbon atoms, such as behenic acid triglyceride or extremely hardened yersin oil
A vegetable oil containing 60% by weight or more of unsaturated fatty acid (eg, soybean oil, olive oil, rapeseed oil, safflower oil, etc.) and / or a mixed oil thereof is subjected to a transesterification reaction, and the transesterified oil is subjected to solvent fractionation for the purpose. Can be obtained.

〔Example〕

The present invention will be further described below with reference to Comparative Examples and Examples. All percentages in the examples are weight percentages.

(Preparation of lauric oil and fat) Laurin oil and fat (A) -lauric acid 55 g, myristic acid 2
1g, palmitic acid 9g, stearic acid 15g and glycerin 14g were kept at 230 ° C for 8 hours without catalyst under nitrogen atmosphere, and after dehydration esterification reaction, water and some unreacted at 230 ° C under reduced pressure of 1mmHg. Fatty acids were removed to obtain 103 g of lauric oil and fat (A).

Laurin oil (B) -lauric acid 60g, myristic acid 2
After 1g, palmitic acid 13g, stearic acid 6g and glycerin 12g were kept in a nitrogen atmosphere at 230 ° C without catalyst for 8 hours to carry out dehydration esterification reaction, water and some unreacted fatty acid were removed under reduced pressure of 1mmHg at 230 ° C. Was removed to obtain 101 g of lauric oil and fat (B).

Laurin oil (C) -lauric acid 52 g, myristic acid 2
1 g, palmitic acid 10 g, stearic acid 17 g and glycerin 17 g were kept under nitrogen atmosphere at 230 ° C for 8 hours without a catalyst to carry out dehydration esterification reaction, and then water and some unreacted fatty acid were removed at 230 ° C under reduced pressure of 1 mmHg. Removed, lauric oil and fat (C)
103 g were obtained.

Laurin-based transesterified oil (D) -hydrogenated palm oil (iodine value 0.4) 91 g and hydrogenated palm oil (iodine value 0.
7) 0.2g of sodium methylate was added to the blended oil with 9g, and stirring was continued at 70 ° C for 60 minutes in a nitrogen stream to carry out random transesterification reaction. Then, purification was carried out according to a usual method to obtain 97 g of lauric transesterified oil and fat (D).

(Preparation of Suppository Base of the Present Invention) Example 1 Tribehen (stearic acid 10.9%, arachidic acid 8.5%,
Behenic acid 80.6%) 50g and soybean oil (palmitic acid 10.6%,
Stearic acid 4.1%, oleic acid 24.4%, linoleic acid 53.
7% and linolenic acid 7.2%) 50 g were mixed, sodium methylate 0.15 g was added, and stirring was continued at 20 mmHg and 70 ° C. for 60 minutes to carry out a random transesterification reaction. This transesterified oil / fat is dissolved in 4 ml of n-hexane per 1 g of oil / fat and cooled to 15 ° C to separate the precipitated high melting point portion.
The liquid is further cooled to 0 ° C., the solvent is removed from the precipitated medium melting point portion, and then purified according to a conventional method to obtain a saturated fatty acid having 20 or more carbon atoms and unsaturated having 16 to 22 carbon atoms suitable for the present invention. An oil and fat (I) mainly composed of a mixed acid group triglyceride of fatty acid was obtained (yield 29 g). The compositional analysis values of the oil / fat (I) are shown in Tables 1 and 2.

Next, a suppository base consisting of 95% by weight of the above-mentioned lauric oil and fat (A) and 5% by weight of the oil and fat (I) obtained here was prepared.

Example 2 Fats and oils mainly composed of 95% by weight of the above-mentioned lauric oil and fat (B) and the mixed acid group triglyceride of the saturated fatty acid having 20 or more carbon atoms and the unsaturated fatty acid having 16 to 22 carbons obtained in Example 1 (I )
A suppository base consisting of 5% by weight was prepared.

Example 3 50 g of tribehen and rapeseed oil (palmitic acid 3.6%, stearic acid 1.7%, oleic acid 57.7%, linoleic acid 22.2%,
50 g of linolenic acid (12.7%) was mixed, 0.15 g of sodium methylate was added, and stirring was continued at 20 mmHg and 70 ° C. for 60 minutes to carry out a random transesterification reaction. Dissolve this transesterified oil / fat in 4 ml of n-hexane per 1 g of oil / fat,
Cool to 5 ° C and separate the precipitated high melting point portion. The liquid is further cooled to 0 ° C., the solvent is removed from the precipitated medium melting point portion, and then purified by a conventional method to obtain a saturated fatty acid having 20 or more carbon atoms and an unsaturated fatty acid having 16 to 22 carbon atoms suitable for the present invention. An oil (II) containing mainly mixed acid triglyceride was obtained (yield 33 g). The compositional analysis values of the oil (II) are shown in Table-1 and Table-2.

A suppository base consisting of 90% by weight of the above-mentioned lauric oil and fat (B) and 10% by weight of the oil and fat (II) obtained here was prepared.

Example 4 95% by weight of the above-mentioned lauric transesterified oil / fat (D), the saturated fatty acid having 20 or more carbon atoms and the carbon number obtained in Example 3
A suppository base consisting of 5% by weight of oil (II), which is mainly composed of a mixed acid group triglyceride of unsaturated fatty acid of 16 to 22, was prepared.

(Melting Characteristics of Suppository Base) The above-mentioned lauric oils (A) to (D) are the most widely used suppository bases at present. These single ones are comparatively 1 to 4. Table 3 shows the melting characteristics, which are the required performances of the suppository bases of Examples 1 to 4 and Comparative Examples 1 to 4. Table-
As is clear from 3, the suppository bases of Examples 1 to 4 according to the present invention do not impair the sharp melting property and the appropriate hardness at all.

(Moldability test of suppository base) Suppository bases of Examples 1 to 4 (mainly composed of a mixed acid group triglyceride of lauric oil and fat, saturated fatty acid having 20 or more carbon atoms and unsaturated fatty acid having 16 to 22 carbon atoms) Suppositories were molded using the oils and fats) and the suppository bases of Comparative Examples 1 to 4 (laurin oils and fats alone). That is, each base was completely melted at 45 ° C., aspirin was added to the base at a concentration of 8% by weight, and the mixture was cooled to 40 ° C. with stirring. The suppository composition melt-dispersed at 40 ° C. was dispensed into a suppository container in 1.9 g portions and rapidly cooled to 5 ° C. and 20 ° C. to obtain a molded suppository. After taking out a total of 100 molded products for each base from the container, observe the surface condition, crack,
Alternatively, the number of items with damage and those with pinholes was counted, and the quality was used to judge the quality of moldability and operability. The results are shown in Table-4.

From the results shown in Table 4, the suppository base of the present invention shows almost no cracks, flaws or pinholes even under forced cooling. Moreover, it can be seen that a good quality suppository having a uniform surface condition and gloss can be produced. Conventional lauric oil and fat bases having a high hydroxyl value have been slightly improved, but suppositories of satisfactory quality cannot be produced.

(Drug stability test) The molded suppository obtained by the moldability test of the suppository base was 20 ° C.
After storing in an incubator at 40 ° C for 6 months, the salicylic acid content (%) in suppositories was quantified by high performance liquid chromatography in order to know the degree of decomposition of aspirin, that is, acetylsalicylic acid. The results are shown in Table-5.

[Effects of the Invention] The suppository base according to the present invention satisfies both drug stability and moldability / operability without impairing the melting properties and hardness, which are the required performances as a base. That is, since the suppository base according to the present invention does not cause troubles such as cracks and pinholes at the time of molding the suppository while maintaining a low hydroxyl value, a suppository which is particularly chemically unstable is used. It is also possible to mass-produce.

Claims (1)

[Claims] (I) Laurin-based oil / fat having a hydroxyl value of 20 or less, which is mainly composed of a glyceride of a fatty acid having 8 to 18 carbon atoms and has a hydroxyl value of 20 or less.
99% by weight and (ii) saturated fatty acids having 20 or more carbon atoms as constituent fatty acids, 30 to 70% by weight, unsaturated fatty acids having 16 to 22 carbon atoms
A suppository base containing 20 to 60% by weight and 1 to 20% by weight of a fat or oil containing a mixed acid group triglyceride of a saturated fatty acid having 20 or more carbon atoms and an unsaturated fatty acid having 16 to 22 carbon atoms.