JPS6277313A - Suppository base - Google Patents

Abstract

PURPOSE:A suppository base, containing a specific laurin based oil and specific fat or oil consisting essentially of a triglyceride having mixed acid groups of a >=20C saturated fatty acid and a 16-22C unsaturated fatty acid in combination and having improved stability of drug and excellent moldability and operability. CONSTITUTION:A suppository base consisting of 80-99wt% laurin based fat or oil, consisting essentially of a glyceride of an 8-18C fatty acid and having <=20 hydroxyl value, preferably fat or oil obtained by processing and treating coconut oil, palm kernel oil, palm oil, etc., as a raw material fat or oil and consisting essentially of a glyceride of a 12-18C saturated fatty acid prepared by removing an 8-16C lower fatty acid as a laurin based fat or oil and 1-20wt% fat or oil containing 30-70wt% >=20C saturated fatty acid and 20-60wt% 16-22C unsaturated fatty acid as constituent fatty acids and consisting essentially of a triglyceride having mixed acid groups of a >=20C saturated fatty acid and a 16-22C unsaturated fatty acid. EFFECT:Even a chemically unstable drug can be mass-produced.

Description

[Detailed Description of the Invention] [Field of Industrial Application] The present invention relates to a suppository base, and more specifically, a suppository base that has good solidification properties during the pouring process into a mold during molding, and excellent drug stability. This invention relates to oil and fat compositions.

Base drugs have historically been used with great care as a method of administering pharmaceuticals.In recent years, with the development of suppository bases, advances in base drug manufacturing technology, and elucidation of the mechanisms of absorption and drug metabolism related to base drugs, Its scope is expanding to include not only drugs administered for local effects such as drugs, but also drugs administered for systemic effects such as analgesics and antibiotics. Furthermore, since the main drug has few side effects and can be administered with confidence, it is being recognized as having a wide range of applications as a home remedy.

[Conventional technology]

Cocoa butter has traditionally been used as a suppository base because it has to have an extremely narrow plasticity range, maintaining sufficient hardness as a solid at room temperature, but quickly melting when it reaches body temperature. However, since cacao butter has an iodine value of around 54, there have been drawbacks such as the fact that the fat may be oxidized during long-term storage and the drug may become inactive. As an alternative, oils and fats mainly composed of lauric acid, which exhibit melting behavior similar to cocoa butter, have come to be widely used. Examples include lauric oils and fats such as coconut oil and palm kernel oil, and those obtained by blending these with palm oil and transesterifying and hardening them. In addition, in order to improve the lack of hardness and solidification rate of these lauric oils and fats, it is possible to remove low-molecular weight substances and low-melting point glycerides containing fatty acids with 8 to 10 carbon atoms by a combination of transesterification and molecular distillation. It is presented (Tokuko Sho 59-1
6594 and Special Publication No. 16595/1983)
.

However, in general, fatty acids from hardened lauric oils are fractionated, lower fatty acids are removed, and a saturated fatty acid mixture with a distribution of carbon numbers of 12 to 18 is esterified with a polyhydric alcohol such as glycerin. Synthetic oils and fats that have undergone a chemical reaction are mainly used. These lauric oils and fats contain almost no unsaturated fatty acids and have appropriate hardness and melting properties, so they have good properties as a suppository base.
There are still some difficulties that have not been overcome.

When a suppository base made of lauric oil has a hydroxyl value exceeding 20, that is, when it has a relatively high hydroxyl value, the half-open raw material is directly injected into a suppository (container) using the melting method, and then cooled in water or otherwise. It can be strongly cooled by this method. That is, the supercooling state of the base material is suppressed in the cooling process, and the solidification property is relatively good, so that the molding operation of the insecticide can be easily performed. Such bases are widely used in factories for making Obon products, and the resulting suppositories are robust with relatively few pinholes (center depressions) and cracks.

However, when a suppository containing a drug with an acid group such as aspirin is manufactured using a base with a relatively high hydroxyl value, that is, a base with a hydroxyl value exceeding 20, free salicylic acid increases and oral A phenomenon occurs in which the drug's efficacy is lost. That is, antibiotics that are susceptible to hydrolysis;
When biochemical preparations, enzymes, etc. are used as suppositories, free hydroxyl groups in the base react catalytically with these drugs, resulting in decomposition and a decrease in potency.

In order to prevent such deactivation of drugs, it is necessary to use a base with a lower hydroxyl value (Japanese Patent Application Laid-Open No. 58-52212).
(see publication). Although it is desirable to use a base having a hydroxyl value of 20 or less, preferably 10 or less, in this case, new major problems arise in the moldability and operability of the suppository.

That is, if a base with a low hydroxyl value is used, even if a molten suppository is poured into a half mold during the molding operation and cooled, the solidification of the base will be poor, resulting in a significant decrease in workability. In addition, due to the large supercooled state, the drug may settle during molding, and furthermore, if a strong cooling operation such as water cooling is performed, troubles such as pinholes and cracks may occur.

As mentioned above, although lauric oils and fats have excellent performance as suppository bases, they do not satisfy both drug stability and moldability/operability.

Therefore, for drugs that are easily deactivated due to decomposition, discoloration, etc.
The moldability and operability are unsatisfactory, but the hydroxyl value is low.
Phosphorous oil bases are used, and for relatively stable drugs, lauric oil bases are used because they have a hydroxyl value that can improve productivity. Currently, different lauric oil bases with different hydroxyl values are used depending on the drug.However, as the use of suppositories has developed, a wide variety of drugs have been formulated, and mass production has become even more important. Technology will also be required. To this end, a suppository base that has both drug stability and moldability/operability is expected to be highly effective and is desired.

[Problem that the invention seeks to solve]

The purpose of the present invention is to use diurinic oils and fats as the main ingredient, which have both good drug stability and moldability/operability without impairing the physical properties (melting properties and hardness) as a suppository base. The purpose of this invention is to provide a suppository base made of In other words, the hydroxyl value, which suppresses free hydroxyl groups, should be 20 or less, preferably 10 or less, and solidification properties are good when forming suppositories, and even if forced cooling such as water cooling from an overheated molten state is performed, it will remain stable. The purpose of the present invention is to provide a suppository base with excellent moldability and operability without causing troubles such as holes and cracks.

[Means for solving problems]

In order to achieve the above object, the present inventors have conducted intensive studies on the performance of various glyceride compositions mainly composed of lauric oils and fats as suppository bases. Saturated fatty acids and carbon numbers 16-2
The present invention was completed after discovering the fact that a suppository base made of a combination of a specific fat and oil characterized by a mixed acid group triglyceride of two unsaturated fatty acids has excellent drug stability and moldability/operability. did.

That is, the present invention provides (1) 80 to 99% by weight of lauric fats and oils having a hydroxyl value of 20 or less, which are mainly composed of glycerides of fatty acids having 8 to 18 carbon atoms, and (ii) saturated fatty acids having 20 or more carbon atoms as constituent fatty acids. 30 to 70% by weight of fatty acids, 20 to 60% by weight of unsaturated fatty acids with 16 to 22 carbon atoms, and saturated fatty acids with 20 or more carbon atoms and 16 to 22 carbon atoms
The present invention relates to a suppository base consisting of 1 to 20% fat and oil mainly composed of triglycerides with mixed acid groups of unsaturated fatty acids.

The suppository base of the present invention has a hydroxyl value of 20 or less, so even drugs that are unstable to free hydroxyl groups will not lose their medicinal 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 either case, despite the low hydroxyl value, the combination of the above-mentioned specific lauric oil and fat with the specific mixed acid group triglyceride has extremely good solidifying properties when molded into suppositories, resulting in many pinholes and pinholes. Suppositories with good quality can be produced without the occurrence of cracks, cracks, etc.

The lauric fats and oils used as the base material of the present invention are those obtained by processing such as hardening, fractionation, esterification, distillation, etc. using coconut oil, palm kernel oil, palm oil, etc. as raw material fats and oils. In order to make the base of the present invention even more effective, it is preferable to use a lauric oil containing mainly glycerides of saturated fatty acids having 12 to 18 carbon atoms from which lower fatty acids having 8 to 10 carbon atoms have been removed. It is better to use

The suppository base of the present invention has the melting characteristics necessary as a base and appropriate hardness by limiting the content of fats and oils mainly composed of the specific mixed acid group triglyceride in the base to 20% by weight or less. and does not cause a decrease in oxidative stability due to unsaturated fatty acids.

However, if the content is less than 1% by weight, the solidification state will be poor and no significant effect will be exerted on moldability and operability during the production of suppositories.

The method for producing the specific fat and oil characterized by 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 as the base material of the present invention is not particularly limited, but the following method is preferable. . Fatty acid triglycerides containing 40% by weight or more of saturated fatty acids having 20 or more carbon atoms, such as behenic acid triglyceride or extremely hydrogenated high-quality rapeseed oil, and vegetable oils containing 60% or more of unsaturated fatty acids (e.g. soybean oil, (olive oil, rapeseed oil, safflower oil, etc.) and/or a mixture thereof, and the transesterified oil is subjected to solvent fractionation to obtain the desired fat or oil.

〔Example〕

The present invention will be further explained with reference to comparative examples and examples below. All percentages in the examples are % by weight. (Preparation of lauric oils) Lauric oils (A) - Lauric acid 55f, myristic acid 21P, palmitic acid 9F, stearic acid 15F and glycerin 14F in a nitrogen atmosphere without catalyst. at 260℃
After holding for 8 hours and carrying out the dehydration esterification reaction,
Water and some unreacted fatty acids were removed at 230° C. under a reduced pressure of 11 mHg to obtain 103 t of lauric oil (A).

Lauric oil (B) - Laurin [60ts Myristic acid 21v1 Palmitic acid 13r1s? Allic acid 6f
and glycerin 122 under nitrogen atmosphere without catalyst 23
After being kept at 0°C for 8 hours to carry out the dehydration esterification reaction, 1
Water and a portion of unreacted fatty acids were removed at 230° C. under a vacuum of Hg to obtain 101 t of lacrine fat (B).

Urinic oil (0) - Lauric acid 5221 Myristic acid 21v1 Palbatic acid 10f, Stearic acid 1
7F and glycerin 17F were kept at 230°C for 8 hours without catalyst in a nitrogen atmosphere to carry out a dehydration esterification reaction, then water and some unreacted fatty acids were removed at 230°C under a reduced pressure of 1 x mHg, and lauric oil ( C) 103 f was obtained.

Lauric transesterified oil (D>-hydrogenated coconut oil (iodine value 0.4) 91 t and hydrogenated scarlet balm oil (
Sodium methylate (0.2F) was added to a blended oil with an iodine value of 0.7) 9t, and the mixture was heated at 70℃ in a nitrogen stream for 6 hours.
Stirring was continued for 0 minutes to perform a random transesterification reaction. Next, purification was carried out according to a conventional method to obtain lauric ester-converted Yugetsuji (D) 97f.

(Preparation of suppository base of the present invention) Example 1 Tribehene (10.9% stearic acid, 8% arachidic acid)
5%, behenic acid 8066%) 30r and soybean oil (valmic acid/acid 1o, 6%, stearic acid 4.1%, oleic acid 2
4.4%, linoleic acid 53.7%.

Mix lylunic acid (7.2%) 30P, add sodium methylate 0.15 F, and adjust to 20 mmHg, 7 [J
Stirring was continued for 60 minutes at ℃ to perform a random transesterification reaction. This transesterified fat is p4r per 1f of fat.
ne in D-hexane, cooled to 15° C., and the precipitated high melting point portion was separated.

After further cooling the P solution to 0°C and removing the solvent from the precipitated intermediate melting point part, it is purified according to 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, which are suitable for the present invention. Oils and fats mainly composed of triglycerides with mixed acid groups of saturated fatty acids<
1) was obtained (yield 29v). The composition analysis values of the oil and fat (1) are shown in Table-1 and Table-2.

Next, a suppository base was prepared consisting of the above-described lauric oil (A) at 95° C. % and the obtained oil (1) (5%).

Example 2 The above-mentioned lauric oil (B) 95% needle, the saturated fatty acid having 20 or more carbon atoms obtained in Example 1, and 16 to 2 carbon atoms
A suppository base was prepared comprising 5% by weight of oil (I) mainly consisting of triglyceride with a mixed acid group of unsaturated fatty acids.

Example 3 Tribehen 30 liters and rapeseed oil (palmitic acid 3.6%,
Stearic acid 1.7%, oleic acid 57.7%, linoleic acid 22.2%, lyric acid 12.7%) 301 were mixed, and sodium methylate 0.152 was added to make 20 m
Stirring was continued for 60 minutes at mHg and 70°C to perform a random transesterification reaction. This transesterified fat was dissolved in 4 tnl of n-hexane (1fal) of fat, and 15
Cool to ℃ and separate the precipitated high melting point parts. After cooling the F solution to 0°C and removing the solvent from the precipitated intermediate melting point, it is purified according to 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, which are suitable for the present invention. An oil (1[) mainly composed of triglyceride with a mixed acid group of saturated fatty acids was obtained (yield: 331). The compositional analysis values of the oil and fat OL) are shown in Table-
1 and Table 2.

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

Example 4 The above-mentioned lauric transesterified oil (D) 95 weight tons
% and 5% by weight of oil (II) mainly composed of mixed acid group triglyceride of saturated fatty acid having 20 or more carbon atoms and unsaturated fatty acid having 16 to 22 carbon atoms obtained in Example 5. did.

Table-2 (Note) C! 54; SSU.

C56; ASU.

C58; AAU, BSU.

060; ABUl C62; BBU is the main component; however, S: stearin tLU: ale unsaturated fatty acid; A: arachidic acid; B: behenic acid.

(Melting properties of suppository bases) The above-mentioned lauric oils and fats (A) to (D) are the most widely used suppository bases. Comparative Examples 1 to 4 refer to these alone. Table 6 shows the melting properties of Examples 1 to 4 and Comparative Examples 1 to 4, which are necessary performances as suppository bases. Table -
3, it can be seen that the suppository bases of Examples 1 to 4 according to the present invention do not impair sharp meltability and appropriate hardness in any way.

Table 5: Melting characteristics of suppository base Melting point: "Solid fat amount according to Japanese Pharmacopoeia J: Pulse NMR method (Moldability test of detergent base)" Carbon number 20
Using the above-mentioned oils and fats mainly consisting of mixed acid group triglycerides of saturated fatty acids and unsaturated fatty acids having 16 to 22 carbon atoms) and the inhibitor bases of Comparative Examples 1 to 4 (lauric oils and fats alone), suppositories were prepared. was molded. That is, after each base was completely melted at 45°C, aspirin was added thereto to a concentration of 8% by weight, and the mixture was cooled to 40°C while stirring.

The suppository composition melted and dispersed at 40°C was dispensed in 1.9 t portions into main ingredient containers, and quickly cooled to 5°C and 20°C, respectively, to obtain molded suppositories. 100 total for each base
After each molded product was removed from the container, the surface condition was observed, and the number of cracked or damaged products and those with pinholes were counted, and the quality of moldability and operability was judged based on the number. These results are shown in Table-4.

From the results shown in Table 4, the suppository base of the present invention has almost no cracks, scratches, or pinholes even under forced cooling conditions. Moreover, it is shown that high-quality suppositories with uniform surface conditions and gloss can be produced. Conventional lauric oil bases with high hydroxyl values have been slightly improved, but suppositories of satisfactory quality cannot be produced.

(Drug stability test) Molding main ingredient 20 obtained by moldability test of suppository base
To find out the degree of decomposition of aspirin, i.e. acetylsalicylic acid, after storage for 6 months in a thermostat at 40°C and 40°C.
The amount (%) of salicylic acid in the suppository was determined using high performance liquid chromatography. The results are shown in Table-5.

Table 5: Drug stability of the main molding agent [Effects of the invention] The suppository base according to the present invention has excellent drug stability, moldability, and operability without impairing the melting characteristics and hardness, which are necessary performances as a base. It is something that satisfies both. In other words, the suppository base according to the present invention maintains a low hydroxyl value and does not cause problems such as cracks and pinholes when forming suppositories, making it particularly suitable for suppositories containing chemically unstable drugs. It also becomes possible to mass produce 0

Claims (1)

[Claims] 1(i) Lauric oil and fat having a hydroxyl value of 20 or less and containing glyceride of fatty acids having 8 to 18 carbon atoms as a main component 80 to 99
(ii) Contains 30 to 70% by weight of saturated fatty acids with 20 or more carbon atoms and 20 to 60% by weight of unsaturated fatty acids with 16 to 22 carbon atoms as constituent fatty acids, and saturated fatty acids with 20 or more carbon atoms. A suppository base consisting of 1 to 20% by weight of fats and oils mainly consisting of mixed acid group triglycerides of unsaturated fatty acids having 16 to 22 carbon atoms.