JPS6366283B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to suppository base compositions. Compared to oral drugs, suppositories have the advantage that their medicinal ingredients are less likely to be degraded by acids, alkalis, digestive enzymes, etc. in digestive fluids, cause no gastrointestinal disorders, and can be easily administered, especially to children. In addition, if strong side effects occur when a medicinal ingredient is administered systemically by injection, the side effects can be reduced by locally administering the medicinal ingredient as a suppository to the affected area.
Furthermore, the pain caused by injections can be eliminated, and the effects on muscles can also be eliminated. Currently, two types of suppository bases are mainly used: polyethylene glycol and triglyceride. Both polyethylene glycol and triglyceride are excellent suppository bases, but when making suppositories using highly hydrophilic polyethylene glycol, their use is limited to highly polar medicinal ingredients that are dissolved or uniformly dispersed in polyethylene glycol. Ta.
On the other hand, since triglyceride has strong lipophilic properties, it has been limited to medicinal ingredients with weak polarity that can be dissolved or uniformly dispersed in triglyceride. Since polyethylene glycol and triglyceride are not compatible, they cannot be used in combination, and it has been difficult to use a highly polar medicinal ingredient and a weakly polar medicinal ingredient together. In addition, in the case of triglycerides, the medicinal ingredients are absorbed into the body by dissolution at body temperature, so the melting point is set close to body temperature, so it is sensitive to high temperatures, so it should be stored in a cool, dark place to prevent it from losing its shape. The need arose. There were also problems such as melting during transportation. As a result of intensive research to obtain a suppository base that does not have these drawbacks, the present inventors have found that a specific alkylene oxide derivative described below is excellent as a suppository base, and that it evenly mixes polyethylene glycol and triglyceride. They discovered that these three ingredients have the same ability and invented a new suppository base containing these three ingredients. The suppository base composition of the present invention has an average molecular weight of 200 to
20000 polyethylene glycol 5-95% by weight,
It is characterized by consisting of 2 to 80% by weight of triglycerides of fatty acids having 6 to 22 carbon atoms, and 3 to 80% by weight of a compound represented by the general formula (1) or a compound obtained by esterifying some or all of the hydroxyl groups of the compound. It is something to do. A [(C _o H _2o O) _a H] _n ... (1) where A is the residue of a compound having 1 to 8 active hydrogens, a = 5 to 200, n = 2 to 4, m = 1 ~
It is 8. The polyethylene glycol used in the present invention has an average molecular weight of 200 to 20,000. The triglycerides of fatty acids having 6 to 22 carbon atoms used in the present invention are synthetic triglycerides such as caproic acid, caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, oleic acid, arachidic acid, and behenic acid. There are transesterified oils used alone or in mixtures, or transesterified oils of these mixtures. Furthermore, in addition to coconut oil and cacao butter, hydrogenated fats and oils can also be used. The compound represented by general formula (1) used in the present invention is
It is a compound in which a predetermined amount of alkylene oxide is added to a compound having 1 to 8 active hydrogen atoms. Furthermore, a compound obtained by esterifying some or all of the hydroxyl groups of the compound represented by general formula (1) can also be used. Here, the compounds having 1 to 8 active hydrogens are methyl alcohol, ethyl alcohol, butyl alcohol, octyl alcohol, lauryl alcohol, myristyl alcohol, cetyl alcohol, stearyl alcohol, oleyl alcohol, isostearyl alcohol, and dimerization by Guerbet method. Alcohol, ethylene glycol, propylene glycol, butylene glycol, hexylene glycol, dodecanediol, hexadecanediol, octadecanediol, neopentyl glycol, glycerin, trimethylolethane, trimethylolpropane, 1,3,5, pentanetriol, erythritol, penta Examples include erythritol, diglycerin, triglycerin, polyglycerin, dipentaerythritol, sorbitol, sorbitan, sorbide, glucose, fructose, mannose, xylose, methyl glucoside, trehalose, seuucrose, and ethylenediamine. The amount of alkylene oxide added is in the range of 5 to 200 moles of ethylene oxide, propylene oxide, or butylene oxide per functional group of the above compound. If the amount of alkylene oxide added is less than the above range, the ability to uniformly mix polyethylene glycol and triglyceride will be insufficient, and if the amount added is too much than the above range, the melting point and viscosity of the compound will become significantly high, resulting in a small This is inconvenient for producing suppositories because it is difficult to handle. The fatty acids required to esterify part or all of the hydroxyl groups of the compound represented by general formula (1) are fatty acids having 6 to 22 carbon atoms, including caproic acid, caprylic acid, capric acid, lauric acid, and myristic acid. , palmitic acid, stearic acid, oleic acid,
Examples include arachidic acid, behenic acid, 2-ethylhexanoic acid, and isostearic acid. The compound represented by the general formula (1) or a compound obtained by esterifying some or all of the hydroxyl groups of the compound has a stronger ability to dissolve or disperse medicinal ingredients compared to polyethylene glycol and triglyceride, and further It has the great feature of being able to mix uniformly in any ratio. The compound of general formula (1) or its esterified product has a melting point of 10 to 70°C, and by selecting the polyethylene glycol and triglyceride to be blended, a suppository base composition having an arbitrary melting point can be prepared. The suppository base composition of the present invention is a mixture of the three components, polyethylene glycol, triglyceride, and the compound represented by the general formula (1), in specific proportions. Among the three components, polyethylene glycol is 95% by weight triglycerides
If the amount of the compound represented by formula (1) exceeds 80% by weight, the disadvantages of each of the three components will appear, which is undesirable, and the effect of mixing them will not appear. Also, the amount of the compound represented by general formula (1) is 3
If it is less than % by weight, the polyethylene glycol and triglyceride will not be mixed uniformly and will separate, which is not preferable. Since the suppository base composition of the present invention contains both hydrophilic and lipophilic components, it is applicable to both highly polar medicinal ingredients and weakly polar medicinal ingredients.
Since it can be prepared with any melting point between 30 and 60°C, it has a wide range of applications, and the moldability and stability over time of suppositories are very good. In the present invention, the suppository base composition includes reduced viscosity during manufacture, adjustment of melting point, improved lubricity during insertion,
Water, propylene glycol, glycerin, propylene glycol fatty acid ester, sucrose fatty acid ester, sorbitan fatty acid ester, polyoxyethylene alkyl ether, polyoxyethylene polyhydric alcohol fatty acid ester, oil-soluble polyester are used for the purpose of promoting the release of medicinal ingredients. It is also possible to blend oxyalkylene glycol derivatives and the like. Examples will be shown below and explained in more detail. % indicates weight %. Examples 1 to 18, Comparative Examples 1 to 8 The components shown in Table 1, polyethylene glycol, triglyceride, and the compound represented by the general formula (1) above, were mixed and melted in the proportions shown in Table 2 to form a suppository base. Adjusted things. Each suppository base composition was then subjected to a compatibility test using the method described below. (Test method and judgment method) Pour 100 g of the suppository base composition into a 300 ml beaker and add 60 g of the suppository base composition.
Warm to ℃ and stir until homogeneous. When the composition becomes homogeneous, stop stirring and cool the beaker to 20°C to solidify the suppository base composition. Then, the solidified product is observed and judged based on the criteria shown below. 〇: Compositions that were recognized to have solidified in a uniform state ×; Compositions that were recognized to have separated into two or more layers or solidified in a non-uniform state Table 2 shows the tested compositions and test results. show. From the results in Table 2, it was confirmed that all the products of the present invention using the compound represented by the general formula (1) solidified while maintaining a uniform state, and had good compatibility. (Temporal stability test of suppositories) 5 g of medicinal ingredients shown in Table 3 and 75 g of suppository base composition
Each of the mixed compositions was melted at 70°C, and the resulting melted products were thoroughly mixed and filled into a 2.5 g suppository container pack to obtain suppositories. The stability over time of each suppository was measured when each suppository was stored at 5℃, 20℃, and 35℃ for 2 weeks, and when 24 hours at 5℃ and 24 hours at 40℃ were repeated for 2 weeks alternately. The measurement results were judged based on the following criteria. The results obtained are shown in Table 3. 〇; Those that maintained a uniform state immediately after production ×; Those that had crystals of medicinal ingredients growing and the suppositories were uneven × ×; Most of the medicinal ingredients separated From the results in Table 3, the products of the present invention: It was found that it always maintained a uniform state in the temperature range of 5 to 70°C, and had good stability over time.

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[Table] Residues are shown.

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Claims (1)

[Scope of Claims] 1. 5-95% by weight of polyethylene glycol with an average molecular weight of 200-20,000, 2-80% by weight of fatty acid triglyceride having 6-22 carbon atoms, a compound represented by the general formula (1), or a hydroxyl group of the compound. A suppository base composition comprising 3 to 80% by weight of a partially or entirely esterified compound. A [(C _o H _2o O) _a H] _n ... (1) where A is the residue of a compound having 1 to 8 active hydrogens, a = 5 to 200, n = 2 to 4, m = 1 ~
It is 8.