JPH07165586A - Steroid ointment for external use - Google Patents

Abstract

PURPOSE:To prepare a steroid ointment for external use containing sisomicin sulfate stabilized by a stabilizer. CONSTITUTION:This steroid ointment for external use contains a steroid compound and mixed powder of sisomicin sulfate. The mixed powder of sisomicin sulfate used in this invention is obtained by subjecting an aqueous solution containing 1 pt.wt. of sisomicin sulfate and 0.05-0.5 pts.wt. of a stabilizer to spraying drying or lyophilization. As the stabilizer, at leastone kind stabilizer is selected from a group consisting of sodium sulfite, ascorbic acid and an ascorbic acid salt. The steroid compound is typically betamethasone dipropionate.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a steroid external ointment containing an antibiotic, and more particularly to a steroid external ointment containing sisomycin sulfate stabilized by a stabilizer.

[0002]

2. Description of the Related Art External steroidal ointments containing steroidal anti-inflammatory agents such as corticosteroid compounds as main components are widely used mainly for the treatment of skin inflammation.
Since these steroidal anti-inflammatory agents generally have an immunosuppressive action, when they are used especially in patients with reduced resistance, bacterial infection is likely to occur together. In order to prevent such infection, antibiotics are generally mixed with steroidal anti-inflammatory drugs. Ointments are often exposed to oxygen and moisture in the air under normal use conditions. Therefore, when an antibiotic is mixed with a steroid external ointment and used, it is important to ensure the physicochemical stability of the antibiotic under the conditions of use.

Cissomycin sulfate is represented by the following chemical formula (I):

[0004]

[Chemical 1]

It is known that it is a sulfate of an aminoglycoside compound represented by and has a broad antibacterial spectrum against Gram-negative and positive bacteria. Cissomycin sulfate has a chemical structure similar to that of gentamicins, which are also aminoglycoside antibiotics, especially gentamicin C _1A . Gentamicin is chemically stable and has already been put to practical use as a component of an external ointment for steroids. On the other hand, sisomycin sulfate is very unstable because it is easily decomposed by oxidation, and requires refrigeration in the powder state.

Therefore, it has hitherto been considered that an unstable antibiotic such as sisomycin sulfate is unsuitable for use as a component of a steroid external ointment.

[0007]

DISCLOSURE OF THE INVENTION The present invention is intended to solve the above problems, and an object thereof is to provide a steroid external ointment containing sisomycin sulfate effectively stabilized by a suitable stabilizer. To provide.

[0008]

The present inventors have remarkably improved the stability of sisomycin sulfate in an ointment by mixing a suitable stabilizer having an antioxidant action with sisomycin sulfate in a specific manner. Found something to do,
The present invention has been completed.

The external steroid ointment of the present invention contains a steroid and a mixed powder of sisomycin sulfate, wherein the mixed powder of sisomycin sulfate is 1 part by weight of sisomycin sulfate (hereinafter referred to as SISO) and 0.05 to 0.5 part by weight. Obtained by spray-drying or freeze-drying an aqueous solution containing a stabilizer, the stabilizer being at least one stabilizer selected from the group consisting of sodium sulfite, ascorbic acid and sodium ascorbate. Therefore, the above object is achieved.

The steroid compound used in the steroid external ointment of the present invention is typically betamethasone dipropionate (hereinafter referred to as BMDP). BMDP
Is the following chemical formula (II):

[0011]

[Chemical 2]

It is a known corticosteroid compound represented by: However, in the present invention, other steroid compounds may be used alone or in combination with BMDP. The stabilizer used in the steroid external ointment of the present invention is selected from the group consisting of sodium sulfite, ascorbic acid and sodium ascorbate.

In the present invention, the above stabilizer is 0.05 to 0.5 parts by weight, preferably about 0.1 parts by weight per 1 part by weight of SISO.
Parts by weight are used. This weight ratio is selected on the basis of various factors such as the method of storing and using the steroid ointment to be obtained, and the type of steroid compound used. In the specification of the present application, the weight of SISO means the weight in terms of titer. The titer of SISO can be determined using any method known in the art. In the following examples of the present application, a fluorescent post-labeling method was used.
The titer of SISO was determined by HPLC.

In the present invention, SISO and a stabilizer are dissolved in an aqueous solvent to form an aqueous solution, and then spray-dried or freeze-dried to obtain a mixed powder of shisomycin sulfate (hereinafter referred to as SISO mixed powder). can get. Water is usually used as the aqueous solvent, but if necessary, a mixed solvent composed of water and an organic solvent miscible with water, such as water-ethanol, may be used. As the above-mentioned spray drying or freeze-drying method, any drying method known in the art can be used as long as it does not adversely affect the physicochemical properties of SISO and the stabilizer.

In the above SISO mixed powder, it is presumed that the mixing uniformity of SISO and the stabilizer at the microscopic level is extremely high. Therefore, when such a highly uniform SISO mixed powder is dispersed in an ointment base, the individual molecules of SISO are uniformly stabilized because they receive the antioxidant effect of the stabilizer uniformly. it is conceivable that. On the other hand, when using a method usually used in the production of ointments, for example,
When SISO and the stabilizer are directly mixed in the ointment base without using the dissolution and drying steps as described above,
It is believed that the stabilization of SISO as in the present invention is not obtained due to insufficient uniformity of mixing of SISO and stabilizer at a microscopic level.

The steroid external ointment of the present invention is usually
It is prepared according to the following steps. The above SISO mixed powder and a steroid compound such as BMDP are mixed with a suitable dispersion medium to obtain a dispersion liquid in which each component is uniformly dispersed. As the dispersion medium, liquid paraffin, polybran, vegetable oil, and other dispersion media known in the art can be used. The dispersion medium is usually used in an amount of 5 to 100 parts by weight based on the SISO mixed powder and the dispersoid such as BMDP. A steroid external ointment can be obtained by further mixing the dispersion obtained as described above into an ointment base so that the steroid compound and the like have a desired concentration. As the ointment base, white petrolatum, plastibase, and other ointment bases known in the art can be used. The step of mixing the dispersion medium and the ointment base is usually carried out under reduced pressure in order to prevent inclusion of bubbles generated by the mixing.

[0017]

EXAMPLES The present invention will be described below with reference to examples. These do not limit the invention.

Example 1 5 g of sodium ascorbate as a stabilizer was added to 100 g of SISO. Furthermore, add purified water so that the total weight becomes 2500 g,
A homogeneous aqueous solution was obtained. The pH of the aqueous solution was adjusted to about 6.5 with sodium hydroxide as needed. This aqueous solution was divided into appropriate metal trays and stored in a freeze dryer. Freeze the aqueous solution at -40 ° C and then perform primary drying.
0.1 mbar at 0 ° C for 15 hours, then secondary drying at 0.1 mbar, 40
A dried product was obtained by carrying out the treatment at 4 ° C. for 4 hours, and the SISO mixed powder was prepared by crushing the dried product.

The above SISO mixed powder (corresponding to SISO having a titer of 10 g) and 6.4 g of BMDP were mixed with 1000 g of liquid paraffin and stirred to obtain a uniformly dispersed suspension. Add 8975 g of white petrolatum to a closed stirrer equipped with a stirrer and capable of controlling the degree of vacuum and temperature,
After melting and softening at ~ 85 ° C, the mixture was cooled to 40 ~ 50 ° C with stirring. The liquid paraffin suspension described above was added to this white petrolatum, and the mixture was stirred under reduced pressure of about 750 mmHg to be uniformly dispersed. The dispersion was cooled to 25 to 35 ° C while further stirring under reduced pressure to obtain an ointment of Example 1 according to the present invention.

(Examples 2 to 7) The ointments of Examples 2 to 7 according to the present invention were prepared in the same manner as in Example 1 except that a predetermined amount of sodium sulfite or sodium ascorbate was used as a stabilizer. Obtained.

Table 1 shows the type and weight of the stabilizer used in each of the above Examples (weight (g) relative to SISO having a titer of 100 g).

[0022]

[Table 1]

In the above embodiment, by the freeze-drying method
SISO mixed powder is prepared, but SISO is prepared by spray drying method.
Even if a mixed powder is prepared, the effects of the present invention can be obtained similarly. When using the spray drying method, for example, an aqueous solution containing a SISO and stabilizer, co-current - using a fluid granulation-type spray dryer, blast temperature 100 to 180 ° C., air volume 250-300 ³
The desired SISO mixed powder can be obtained by drying under the conditions of / h and an aqueous solution supply rate of 1 to 1.5 kg / h.

Comparative Examples 1 to 5 By mixing 1000 g of liquid paraffin with 10 g of SISO, 6.4 g of BMDP and, if necessary, the stabilizer (1 g) shown in Table 2 by stirring. A uniformly dispersed suspension was obtained. Here, tocopherol, ascorbic acid, BHT (butylhydroxytoluene) or BHA (butylhydroxyanisole) was used as a stabilizer.

Into a closed stirrer equipped with a stirrer and capable of controlling the degree of vacuum and temperature, 8975 g of white petrolatum was charged, melted and softened at 80 to 85 ° C., and then stirred at 40 to 40 ° C.
Cooled to 50 ° C. The above liquid paraffin suspension was added to this white petrolatum and stirred under reduced pressure of about 750 mmHg to uniformly disperse each component. The dispersion was cooled to 25 to 35 ° C. while further stirring under reduced pressure to obtain ointments of Comparative Examples 1 to 5.

Table 2 shows the kinds of stabilizers used in each of the above comparative examples.

[0027]

[Table 2]

Using the ointments of Examples and Comparative Examples obtained above, the following experiments were conducted in order to confirm the effect of the stabilizer on the stability of SISO in the ointment.

(Experiment 1) The effect of the difference in the type of stabilizer and the drying process on the change in the content of SISO in the ointment was investigated.

The ointments of Examples 2 and 5 and Comparative Examples 1 to 5 were placed in a sealed container and stored at 100 ° C. The content of SISO in the ointment was measured before storage and after 8 hours. The relative change in the content was determined by setting the content of SISO in the ointment before storage to 100. The results are shown in Table 3.

[0031]

[Table 3]

As is apparent from Table 3, in the ointments of Examples 2 and 5 according to the present invention prepared by the freeze-drying method using sodium ascorbate or sodium sulfite as a stabilizer, The decrease in SISO content was negligible. On the other hand, in the ointments of Comparative Examples 2 to 5 prepared by using various stabilizers without using the freeze-drying process, the decrease in the content of SISO was caused by the comparison without using the stabilizers. It was about the same as in the case of the ointment of Example 1. In particular, from the results of Example 2 and Comparative Example 2, it is understood that even if sodium ascorbate is used at the same concentration, the effect of stabilizing SISO is significantly different depending on the presence or absence of the freeze-drying step.

[0033]

INDUSTRIAL APPLICABILITY According to the present invention, a steroid external ointment containing SISO (sisomycin sulfate) stabilized by sodium sulfite, ascorbic acid and / or sodium ascorbate can be obtained. This has traditionally limited its scope due to its instability.
Can be used as a component of a steroid external ointment.

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Claims (3)

[Claims] 1. A steroid external ointment containing sisomicin sulfate mixed powder, wherein the sisomicin sulfate mixed powder comprises 1 part by weight of sisomycin sulfate and 0.05 to 0.5 part by weight of an aqueous solution spray-dried. Alternatively, a steroid external ointment obtained by freeze-drying, wherein the stabilizer is at least one stabilizer selected from the group consisting of sodium sulfite, ascorbic acid and sodium ascorbate. 2. The topical steroidal ointment of claim 1, wherein the aqueous solution comprises 1 part by weight of sisomycin sulfate and about 0.1 part by weight of the stabilizer. 3. The ointment for external use of steroid according to claim 1, wherein the steroid compound is betamethasone dipropionate.