JP2618256B2 - Anti-inflammatory analgesic external preparation - Google Patents

Description

Description: FIELD OF THE INVENTION The present invention relates to an anti-inflammatory analgesic external preparation, and more particularly, to enhance percutaneous absorption of a non-steroidal anti-inflammatory analgesic drug as an active ingredient contained in the external preparation. The present invention relates to an anti-inflammatory and analgesic external preparation which improves bioavailability and is excellent in stability of a medicinal component, physical stability of an external preparation, safety and usability.

[Conventional technology]

Currently available non-steroidal anti-inflammatory analgesic external preparations include gel cartilage, solution, cream and the like. Among them, gel cartilage agents are particularly widely used as external preparations containing medicinal ingredients such as indomethacin, ketoprofen, flubinac, piroxicam, etc. because of their excellent transdermal absorbability.

On the other hand, studies have been made to enhance the transdermal absorbability of non-steroidal anti-inflammatory analgesic drugs, and 1-dodecylazecycloheptan-2-one, for example, is known as a transdermal absorption enhancer.

[Problems to be solved by the invention]

However, gel cartilage has a large amount of lower alcohols (ethanol, ethanol,
Since it contains isopropanol and the like and polyhydric alcohols (propylene glycol, polyethylene glycol 300, polyethylene glycol 400) and the like as essential components, there is a problem in terms of safety that it has irritation to the skin. In addition, when the gel cartilage is applied to the skin, the means of sealing the applied surface is not used in normal use, so the lower alcohol in the base volatilizes immediately, and crystals of the medicinal component precipitate, resulting in the medicinal component There is also a problem that the transdermal absorbability of the drug is hindered.

In order to solve these problems, the dosage form may be a cream prepared by emulsifying an oil phase and an aqueous phase using a nonionic surfactant, for example, JP-A-60-209515 and JP-A-62-298526. Is disclosed. However, in these techniques, the medicinal component is limited to ketoprofen, and there are problems in transdermal absorbability and stability of the medicinal component.

Regarding the external preparation of suprofen, Japanese Patent Application Laid-Open No.
Although disclosed in 203011, it is not satisfactory in percutaneous absorbability. By the way, regarding the means of improving the transdermal absorbability of a medicinal ingredient by blending a transdermal absorption promoter,
The percutaneous absorption enhancer cannot be said to be satisfactory in terms of skin safety and the effect of promoting percutaneous absorption, and has not yet been put to practical use.

[Means for solving the problem]

Under these circumstances, the present inventors have conducted various studies to solve the above-mentioned problems, and as a result, when a specific base component is added to a nonsteroidal anti-inflammatory analgesic drug, not only transdermal absorbability but also stability and safety are improved. The present inventors have also found that an excellent external preparation can be obtained and completed the present invention.

That is, the present invention relates to a non-steroidal anti-inflammatory analgesic drug as a medicinal component, a hydrophilic polymer as a base component, a sucrose fatty acid ester of HLB 10 or more, and 1 to 10% by weight.
An anti-inflammatory and analgesic external preparation characterized by containing a polyhydric alcohol, a dicarboxylic acid ester, a pH adjuster and water and containing no lower alcohol.

The non-steroidal anti-inflammatory analgesic drug that can be incorporated in the external preparation of the present invention is not particularly limited as long as it has an anti-inflammatory analgesic action. Chemical name: 2- [4- (2-thienylcarbonyl) phenyl] propionic acid) is particularly preferred.

Examples of the hydrophilic polymer include a carboxyvinyl polymer. These carboxyvinyl polymers can be easily obtained as, for example, Carbopol 934, Carbopol 940, and Carbopol 941 manufactured by Guddoritz; Hibis Wako 104, Hibis Wako 105 manufactured by Wako Pure Chemical Industries, and the like.

As sucrose fatty acid esters, sucrose long-chain fatty acids are preferred. Such sucrose fatty acid esters include mono-, di-, and triesters based on the number of bound fatty acids. In the present invention, those having a large ratio of mono- and diesters, that is, those having an HLB of 10 or more are used. A sucrose fatty acid ester having an HLB of less than 10 is not preferable because it reduces the emulsifiability and physical stability of the external preparation.

Polyhydric alcohols are compounded for the purpose of assisting solubility, emulsifying ability, and percutaneous absorption of the active ingredient.For example, glycols such as propylene glycol, 1,3-butylene glycol, and polyethylene glycol are used. Is done. The average molecular weight of polyethylene glycol is 30
Those having about 0 to 400 are preferable.

The dicarboxylic acid ester is compounded in order to improve the solubility and transdermal absorbability of the active ingredient, and it is preferable to use a liquid at room temperature. Specific examples include diethyl succinate, diethyl adipate, ciisopropyl adipate, diethyl sebacate and the like.

The pH adjuster is blended to make the pH of the whole external preparation suitable for release of the active ingredient from the external preparation and percutaneous absorption. Specifically, the pH of the external preparation is 4 to 4. 7, especially 4.
It is preferred to use ones that can be between 3 and 6.0. For example, inorganic bases such as sodium hydroxide and potassium hydroxide, and organic bases such as arginine, triethanolamine and diisopropanolamine are used.

It is preferable that the above components are blended in the external preparation of the present invention in the following amounts. That is, the non-steroidal anti-inflammatory drug depends on its components, but it is generally preferable to add 0.1 to 5% by weight (hereinafter simply referred to as%). The content of the hydrophilic polymer is preferably 0.1 to 2%, particularly preferably 0.3 to 1%. The content of sucrose fatty acid ester is preferably 0.5 to 8%, particularly preferably 1 to 4%.
The content of the polyhydric alcohol is preferably 1 to 10%, particularly preferably 2 to 8%.
The dicarboxylic acid ester content is preferably 5 to 20%, particularly preferably 5 to 10%. The pH regulator is preferably 0.05 to 3%, particularly preferably 0.1 to 0.5%. Water is preferably 65-85%.

Further, in the external preparation of the present invention, a preservative, a preservative, a fragrance, and the like can be appropriately compounded as required in addition to the essential components.

 The external preparation of the present invention is produced, for example, as follows.

The sucrose sugar fatty acid ester is dissolved by heating with a polyhydric alcohol, and the dicarboxylic acid ester and a medicinal component are added and dissolved by heating to form an oil phase.

Separately, a hydrophilic polymer is dissolved in water, and the pH is adjusted with a pH adjuster to obtain an aqueous phase.

The external preparation of the present invention can be obtained by gradually adding the oil phase while stirring the aqueous phase and emulsifying and mixing.

〔Example〕

 Next, the present invention will be described in detail with reference to examples.

Example 1 Composition: Production method: 8 g of polyethylene glycol (PEG-300) is added to 4 g of sucrose fatty acid ester and dissolved by heating. Further, 8 g of diethyl sebagate, 1 g of sprofen and 0.2 g of butylparaben are added and dissolved by heating to obtain an oil phase.

Next, 0.6 g of Carbopol 940 is dissolved in 77.0 g of purified water, and the pH is adjusted with 1.4 g of 10% diisopropanolamine to obtain an aqueous phase. While stirring the aqueous phase, the oil phase was gradually added to obtain an external preparation of the present invention.

Example 2 Composition: Production method: Performed according to Example 1.

Comparative Example 1 Based on the analysis results of a commercially available gel cartilage, suprofen was used as a medicinal ingredient, and the other components were adjusted to be the same as the commercially available gel cartilage.

1 g of suprofen is dissolved in 35 g of isopropyl alcohol and 4 g of diisopropyl adipate.

Next, 1.2 g of Carbopol 940 is dissolved in 45.80 g of purified water, and 5 g of propylene glycol and 5 g of PEG-300 are uniformly mixed.

Was gradually added with stirring to adjust the pH with 3 g of 10% diisopropanolamine to obtain a gel cartilage agent.

Comparative Example 2 An external preparation was obtained in the same manner as in Example 2 except that the sucrose fatty acid ester was changed from polyoxyethylene (20) to sorbitan monooleate.

Comparative Example 3 Example 2 was repeated except that the sucrose fatty acid ester was replaced with polyoxyethylene (60) hydrogenated castor oil.
An external preparation was obtained in the same manner as described above.

Test Example 1 Test on Percutaneous Absorption <Diffusion Cell Test Method> An external preparation containing a medicinal ingredient (sample) was placed on a sink type diffusion cell using a depilated guinea pig back skin film or silicone film from which hair had been removed. ) Is applied, and a certain amount is sampled from the receptor side at 37 ° C using a phosphate buffer aqueous solution of pH 7.4 at the receptor side, and the active ingredient is quantified by high performance liquid chromatography to determine the transdermal absorption amount. .

The apparatus used for the test is shown in FIG. 1 and FIG. First
The figure shows a normal diffusion cell with the donor side sealed. In contrast, FIG. 2 shows an open system on the donor side. Usually, after the external preparation is applied to the skin, the skin surface is not sealed. Therefore, it can be said that the apparatus shown in FIG. 2 reflects the actual use state more than the apparatus shown in FIG.

<Results> (1) FIGS. 3 to 6 show the results of comparison between the external preparation of Example 1 and the external preparation of Comparative Example 1.

FIG. 3 and FIG. 4 show the results when the sealed system device of FIG. 1 is used. FIGS. 5 and 6 show the results when the open system of FIG. 2 is used.

As a result, the external preparation of Comparative Example 1 showed high transdermal absorbability in the sealed system, but significantly reduced in the open system. On the other hand, the external preparation of Example 1 showed superior transdermal absorbability in the open system reflecting the actual use state, though the transdermal absorbability in the sealed system was lower than that of Comparative Example 1.

(2) FIG. 7 shows the results of comparison between the external preparation of Example 2 and the external preparations of Comparative Examples 2 and 3 using the open system shown in FIG.

As a result, as compared with the external preparation of Comparative Example 2 or 3, the external preparation of Example 2 showed extremely excellent transdermal absorbability.

Test Example 2 Stability test 30 g of the external preparation of Example 1 was filled in a glass bottle, stored at a predetermined temperature, and the remaining amount of the medicinal component, appearance, and pH were measured over time. As a result, as shown in Table 1, the external preparation of the present invention was excellent in stability.

Test Example 3 Test on skin irritation A patch test was performed on the skin of the back of 48 healthy boys. As a result of performing a closed patch for 48 hours on the base component obtained by removing only sprofen from the external preparation of Example 2, no skin reaction was observed. Never

 Therefore, the external preparation of the present invention is highly safe.

Examples 3 to 7 In the same manner as in Example 1, external preparations shown in Table 2 were obtained.
Table 2 also shows the results of a diffusion test performed using the open system shown in FIG. 2 in the same manner as in Test Example 1.

(Effect of the invention) The anti-inflammatory analgesic external preparation of the present invention promotes transdermal absorption of a nonsteroidal anti-inflammatory analgesic drug as a medicinal ingredient, improves bioavailability, and stability of the medicinal ingredient,
It is excellent in physical stability, safety and usability of an external preparation.

[Brief description of the drawings]

FIG. 1 is a schematic diagram of a sealed diffusion cell device used in a transdermal absorption test of Test Example 1, and FIG. 2 is a schematic diagram of a similar open diffusion cell device. FIG. 3 (using guinea pig skin membrane) and FIG. 4 (using silicone rubber membrane) show the diffusion amount and time when a transdermal absorption test was performed for the external preparation of Example 1 using the apparatus shown in FIG. FIG. FIG. 5 (using guinea pig skin membrane) and FIG. 6 (using silicone rubber membrane) show the diffusion amount and time when a transdermal absorption test was performed on the external preparation of Example 1 using the apparatus shown in FIG. FIG. FIG. 7 is a drawing showing the relationship between the amount of diffusion and time when a transdermal absorption test was performed on the external preparation of Example 2 using the apparatus of FIG.

──────────────────────────────────────────────────の Continued on the front page (51) Int.Cl. ⁶ Identification code Agency reference number FI Technical indication location A61K 47/14 A61K 47/14 EG (56) References JP-A-59-48413 (JP, A) JP-A-59-70612 (JP, A)

Claims (2)

(57) [Claims] 1. A nonsteroidal anti-inflammatory analgesic drug as a medicinal component, and a hydrophilic polymer, HLB10 as a base component
An anti-inflammatory analgesic external preparation comprising the above-mentioned sucrose fatty acid ester, 1 to 10% by weight of a polyhydric alcohol, a dicarboxylic acid ester, a pH regulator and water, and not containing a lower alcohol. 2. The anti-inflammatory analgesic external preparation according to claim 1, wherein the non-steroidal anti-inflammatory analgesic drug is suprofen.