JPH02178228A - Suppository composition - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a suppository composition containing hydrocortisone acetate.

Hydrocortisone acetate is widely used as a systemic and topical adrenocortical hormone agonist in external eye drops, ointments, and hemorrhoid preparations. However, it is known that general esterified steroids undergo rearrangement reactions and hydrolysis reactions and decompose not only in liquid preparations but also in ointments (see the following literature), and are particularly affected by hydrogen ion concentration. It has been known.

(1)^, D, Marcus, J, Am, Pharm
, As5oc,, 49.383 (2) Takashi Watanabe - Pharmacology, 29.267 (1969) (3) Takashi Yamamoto et al. Pharmaceutical Journal, 91.855.863゜871, 877 (19
71) In addition, even during soil use, the degree of hydrophilicity of the base itself,
Even if the base itself is nonaqueous, it is known that similar decomposition occurs in the base as shown in Table 1 below due to the combination of active agents, active ingredients, or other additives. .

As a countermeasure to this problem, it is possible to stabilize the particles by coating the surface of the hydrocortisone acetate particles or dissolving and dispersing them with a hydrophobic substance, but such treatments are not necessarily effective in order to fully demonstrate the medicinal efficacy. This is especially problematic when the purpose is to directly affect the affected area.

(Left below) Note) PEG: Polyethylene glycol CMCC Carboxymethylcellulose MC: Methylcellulose The present invention provides a soil base material in which hydrocortisone acetate can be stably blended.

2141 Wamata The base composition of the present invention is characterized in that a fatty acid triglyceride having a hydroxyl value of 15 or less is used as a base material in the base composition containing hydrocortisone acetate.

The present invention will be explained in more detail below.

The stability of hydrocortisone acetate in a suppository composition depends on the hydroxyl value of the fatty acid triglyceride used as a base, and stability is improved if the hydroxyl value is about 25 or less. The hydroxyl value is more preferably 20 or less, and even more preferably 15 or less. When the hydroxyl value is 15 or less, the stability is significantly improved and the medicinal efficacy is more than maintained.

As the fatty acid triglyceride, higher fatty acids, particularly glycerin esters of saturated or unsaturated fatty acids having 12 to 18 carbon atoms, are preferred.

The base composition of the present invention has fatty acid triglyceride as the main component, but if necessary, lecithin, wax,
Beeswax, hydrogenated oil, lauric fat, cinnamon fat, liquid paraffin, etc. may also be blended.

The fatty acid triglycerides of the present invention are present in suppository compositions containing 8
It is preferable to blend 0 to 98% by weight.

The active ingredient, hydrocortisone acetate, is generally incorporated into suppository compositions in an amount of about 0.1 to 10%.

Next, the manufacturing method for doyo will be explained.

Doyo is manufactured by filling a container made of vinyl chloride, aluminum, etc. with molten doyo raw materials, solidifying it by blowing cold air from the outside, and then sealing the container. During this cooling, the volume of the doyo was reduced, and the doyo 31 had a depressed portion 33 at its end as shown in FIG. 3, but in the past, it was often sold and used in this state.

However, such a sunken doyo causes problems such as inconvenience of insertion and irritation to the affected area during insertion.

Therefore, by slowing down the cooling rate and preventing rapid volume reduction,
Efforts have been made to prevent the doyo from sinking, but this manufacturing method significantly reduces the production capacity of the doyo.

According to the studies conducted by the present inventors, during the doyo manufacturing process, by filling a container with molten doyo raw materials and treating the end of the doyo with hot air immediately before assimilation or after cooling and solidifying, the collapse of the doyo can be significantly reduced. was found to be reduced.

FIG. 2 is an explanatory diagram showing an example of a manufacturing apparatus used in the above method. When the container 25 is filled with the soil material according to a conventional method and cooled, the soil material solidifies within the container 25. Then, by sealing the seal portion 25a, a doyo can be obtained. After cooling, just before sealing, the hot air supply nozzle 23 is lowered to blow hot air intensively to the end of the doyo, and only the end of the doyo is heated. By melting the soil, you can obtain soil that is less likely to cave in.

When the air cylinder 11 is driven in FIG. 2, the arm 13
moves downward, and the hot air supply nozzle 23 descends directly above the container 25 filled with soil material (not shown).

The solenoid valve 17 opens and pressurized air flows from the intake port 15 into the heating chamber 19.
The soil material is heated to a predetermined temperature by the heater 21 and solidified in the container 25, and hot air is blown onto it. Thereafter, the seal portion 25a of the container 25 is quickly sealed.

When an oil-based base is used as the base for the doyo and a container made of vinyl chloride is used, a temperature of 35 to 100 °C is sufficient for the hot air blown to the end of the dojo, but preferably 50 to 80 °C. At temperatures above 80°C, vinyl chloride may be deformed and re-sag due to a sudden drop in temperature. On the other hand, if the temperature is below 50° C., the air blowing time becomes long and productivity is reduced. Air blowing conditions are temperature 50-60℃, 5
~10 seconds is optimal. As this oily base, the oil and fat composition bases shown in Table 1 in the above-mentioned "Prior Art" column can be used.

In addition, the emulsion base materials shown in Table 1-1 can also be produced using vinyl chloride as a container, but when using a mixture of an oil-based base and a water-soluble base, the hot air temperature must be 5 to 10 degrees higher than the melting point of the mixed base.
It is desirable to set the temperature to a temperature higher than ℃.

On the other hand, when producing doyo using an aluminum container, it is optimal to set the hot air temperature to a temperature 5 to 10° C. higher than the melting point of the doyo raw material, and to blow the air for 5 to 10 seconds. As this base or mixed base, any of the hydrophobic bases and hydrophilic bases shown in Table 1-1 can be used.

According to the above manufacturing method, it is possible to prevent the distal end portion from collapsing which occurs during the manufacturing process, and it is possible to eliminate inconvenience during insertion and discomfort after insertion.

Furthermore, since it is not necessary to take a long cooling time during filling and cooling to prevent caving, the cooling time can be shortened and productivity can be improved.

According to the present invention, by using a base mainly composed of fatty acid glyceryl ester with a low hydroxyl value, the stability of the base ingredient containing hydrocortisone acetate is significantly improved. Hydrocortisone acetate has side effects such as skin atrophy, delayed wound healing, purpura, flushing, steroid elastosis, milia, and pigment abnormalities. Therefore, in order to prevent these side effects, extremely limited amounts are used. However, since hydrocortisone acetate is stably blended, it has become possible to maintain the accuracy of the blended amount over a long period of time. In addition, the drug may be used for the purpose of absorption in addition to local action, and in this case, the initial pass effect is small, so the stable drug of the present invention has great pharmaceutical value.

Nuni Spasm - Mother-in-law - 5 mg of hydrocortisone acetate was dissolved and dispersed in 1500 mg of fatty acid esters with different hydroxyl values, filled in a polyvinyl chloride container, tested at room temperature, and heated at 35°C to 75°C.
An accelerated test under % relative temperature was conducted for 8 months, and hydrocortisone acetate was analyzed by high performance liquid chromatography before and after the test to determine the residual rate of hydrocortisone acetate.

The results are shown in FIG. 1. When the hydroxyl value of fatty acid triglyceride was 25 or less, the stability was significantly improved, and when it was 15 or less, the survival rate was 90% or more.

The abbreviations in FIG. 1 indicate the sample symbols of the base material.

The base material sample is Pharmasol (manufactured by NOF) N type,
A type, B type, and T type were used, and these were mixed and prepared as shown in Table 2 below.

Table-2 Prepare the main ingredient compositions of the following formulation examples 1 to 4, 35"C-7
After conducting a forced test at 5% RH for 8 months, the residual rate was measured, and the results are shown together with prescription examples.

1 Rate 97.4% Hydrocortisone acetate Zinc oxide Resorcinol Lidocaine mg 00mg mg 0mg ■ 3 Rate 98.0% Hydrocortisone acetate Tocopherol acetate Allantoin Lecithin Liquid paraffin nidoline 0mg mg mg mg mg Eight total 400mg Mu total 000mg Example 1 Rate 96.5 %) Hydrocortisone acetate Zinc oxide wax Beeswax Methyl ephedrine Hydrochloride Divucaine hydrochloride Total mg 50mg 0mg mg 3+ng B 000mg ■ 4 Rate 95.5%) Hydrocortisone acetate Bismuth gallate Castor oil mg 50mg 0mg Total 500mg Alliance-" L-Kai conventional equipment and Using the apparatus of the present invention shown in FIG. 2, pots having the following formulations A to E were manufactured, and the depressed volume of the end portion was evaluated. Note that the cooling temperature during manufacturing was kept constant at 20°C.

The results are summarized in Table 3 below together with the hot air blowing conditions of the present invention. Here, the depression volume is Fig. 4 (longitudinal cross-sectional view)
The halftone dot portion 33 is shown in FIG.

Prescription A (100 servings) Alleviatin 5-10g Witepsol H-15135g Prescription B Prescription 4 servings) Aspirin 37.0g Cocoa butter 74.0g Prescription C (io
o pieces) Cocaine hydrochloride 2.0g Bismuth gallate 20.0g Purified lanolin
10.0g Witepsol
200.0g Formula D (for 100 pieces) Ethyl aminobenzoate 20.0g Roth extract 5.0g Tannic acid
10.0g Cocoa Butter Formula F (100 servings) Aminophylline Macrogol 1500 Macrogol 4000 131.0g 50.0g 90.0g 20.0g

[Brief explanation of the drawing]

FIG. 1 is a graph showing the relationship between the residual rate of hydrocortisone acetate and the hydroxyl value of the base material.9 FIG. 2 is an explanatory diagram showing an example of a soil manufacturing apparatus. FIG. 3 is a perspective view showing the depression of the end portion of the soil. FIG. 4 is an explanatory diagram showing the depressed volume. 11... Air cylinder 15... Intake port 19... Heating chamber 23... Hot air supply nozzle 25a... Seal portion 33... Concave portion 13... Arm 17... Solenoid valve 21... ... Heater 25 ... Container 31 ... Doyo 35 ... Volume of depression 2nd 3rd 4th

Claims (1)

[Claims] 1. A suppository composition containing hydrocortisone acetate as an active ingredient, characterized in that the base is mainly triglyceride of a fatty acid with a hydroxyl value of 25 or less.