JPS601123A - Drug for external use - Google Patents

Abstract

PURPOSE:To provide the titled drug resistant to the separation of water in use, and containing a freeze-dried O/W-type emulsion containing a physiologically active substance such as physiologically active polypeptide, protein, steroid for external use, etc. in a stable and uniformly dispersed state. CONSTITUTION:The objective drug for external use is prepared by freeze-drying an O/W-type emulsion containing a physiologically active substance and an additive for drug preparation. A conventional base for external use, e.g. soybean oil, squalane, etc. is used as the oily substance for the base. The ratio of the oily substance to the aqueous solution is preferably 1:9-3:7. It is necessary to use a surface active agent, a polymer (e.g. MC, gelatin, etc.) and a vehicle (e.g. mannitol, glycine, etc.) as the additive for drug preparation. The obtained drug is free of water and can be stored stably for a long period. It has the advantages of both the oily base and the creamy base, i.e. it is tack-free and can be washed off with water in the form of emulsion.

Description

[Detailed description of the invention] The present invention relates to physiologically active polypeptides and proteins.

The present invention relates to a new external preparation obtained by freeze-drying an O/W type emulsion containing an active ingredient such as a topical steroid and additives for the preparation.

The main bases of conventionally known external preparations are oil bases, cream bases, and water-soluble bases.

There are gel bases, etc., and each has its own characteristics such as stability, dispersibility, expression of efficacy, and safety of the active ingredient.

Bases are selected based on factors such as suitability for production and usability.

On the other hand, physiologically active substances such as water-soluble proteins are unstable in aqueous solutions, and it is also difficult to disperse and dissolve them in oily bases, so it is not possible to use conventional bases to prepare them for external use. could not.

Therefore, the inventors of the present invention have conducted extensive studies regarding the development of substances that are difficult to use as external preparations using conventional formulations and/or manufacturing methods. It is thought to be used after being dissolved, and although it is well known that it can be used as an injection, it was unexpected that it would be used as an external preparation9. On the contrary, the present inventor has discovered that the product obtained by freeze-drying an O/W emulsion with a formulation in which both the oil phase and the water phase are liquid at room temperature can be applied as an external preparation without condensing during use. et al. completed the invention under the heading.

The external preparation obtained by the present invention has a white lumpy appearance,
The active ingredients are stable and uniformly dispersible, and can be used as a regular ointment by applying pressure.

The fine patterning is achieved by uniformly dispersing oil droplets with a size of several tens of micrometers or less in the supporting excipient, which is an aqueous phase in an emulsion state.
It is fixed. The external preparation of the present invention has the following characteristics.

■Since it does not contain water, the active ingredients can be stored in a stable state for a long period of time.

■It is also possible to add active ingredients after making the emulsion during manufacturing to avoid deactivation of unstable active ingredients such as bioactive proteins due to heat and shearing.

A stable formulation can be prepared quickly.

■It has both the advantages of an oil-based base and a cream-based base, and compared to oil-based bases, the amount of added oil and fat is small, so it is not sticky, and can be washed off as an emulsion with water, making it easy to use. good.

■Compared to cream bases, it is physically stable and does not lose its commercial value over a long period of time.

As mentioned above, it has superior characteristics compared to conventional external use bases.

The base material used in the present invention and the method for producing the external preparation of the present invention will be described in detail below.

Base oily substances include vegetable oils such as soybean oil and peanut oil, and animal-derived oils such as squalane.

It includes all mineral oils such as liquid paraffin that are liquid at room temperature and are commonly used as external bases. The mixing ratio of oily substance and aqueous solution is 0.5:9.5
~4=61, particularly preferably 1:9 to 3:7.

The additives in the formulation include all the additives normally used in this type of formulation, and the minimum necessary additions include surfactants, polymers, and excipients. The surfactant includes one or a combination of two or more commonly used surfactants such as polyoxyethylene sorbitol, tan fatty acid ester, sorbitan fatty acid ester, polyethylene glyfur fatty acid ester, and polyoxyethylene hydrogenated castor oil derivative. Also.

Bio-related surfactants such as egg yolk, phospholipids such as soybean lecithin, and bile acids may also be used. The amount added is preferably 5 to 25% ('/,) based on the oily substance.

Examples of polymers include methylcellulose, aqueous cellulose derivatives such as sodium carboxymethylcellulose, and sodium alginate.

Natural polymers such as gum arabic powder and gelatin.

Contains one type or a combination of two or more types of synthetic polymers such as polyvinyl alcohol and sodium polyacrylate. The amount is preferably 1% or less based on the total amount.

Excipients include mannitol and maltose.

Examples include sugars, amino acids such as glycine, and urea. The amount is about 8-12% of the total amount, but 6
Around % is optimal.

Incidentally, the composition ratio of each added component is not particularly limited and can be appropriately determined by a conventional method, and an example thereof will be shown in the Examples below.

The following is a manufacturing method for preparing an external preparation by forming a mixture of the above-mentioned components into a uniform emulsion and freeze-drying it.

First, physiologically active substances and surfactants depend on their solubility.
Soluble in oil or water as appropriate. In addition, polymers and excipients are dissolved in water. Other additives are also dissolved in oil or water as appropriate depending on their solubility. Then, the aqueous solution and oil solution are combined, and this mixed solution is emulsified by a conventional method such as mechanical stirring with a homogenizer or the use of ultrasonic waves. Note that at this time, a more stable emulsion can be produced by performing a heating operation.゛Again. A physiologically active substance that is decomposed by applying heat may be added after the emulsion is prepared. After dispensing the emulsion thus prepared into containers, the emulsion was transported into a 1-emotional dryer and rapidly frozen.

Dry under reduced pressure and prepare for external use.

In addition, it is also possible to add appropriate additives to the thus obtained external preparation to prepare a final preparation, if necessary.

Next, the present invention will be specifically explained with reference to Examples.

Example 1 Betamethacin valerate 0.19, 5pan 60 0.
59 is dissolved in 10 parts of squalane. Also, glance
801.5g, carboxymethylcellulose sodium 0.15g, mannitol 6g, methylparaben 0.1
Then, heat and dissolve 0.1 g of butyl paraben in 90 g of water. Add the aqueous solution to the oil solution and stir at high speed with a homogenizer to prepare a homogeneous 0/W type emulsion. Divide this emulsion into 5-unit containers and transport them into a freeze dryer. Temperature: -40°C After quickly freezing the mixture, it is dried under reduced pressure using a vacuum pump overnight to prepare an external preparation.

The preparation obtained in this example was in the form of a white lump and was stable for more than 2 years at room temperature.

Example 2 Liquid paraffin 109. Mix 5 parts of lauryl alcohol to obtain an oily component, and add 0.5 L of loropheniramine maleate and 0.52 parts of methyl salicylate. Furthermore, 8 g of Nikkor BL9EX, 0.15 g of sodium carboxymethyl cellulose, and 8 g of maltose were dissolved in water by heating.

Add the oily component to make the total amount 100-. Below is.

An external preparation was produced using the same method as in Example 1.

Claims (1)

[Claims] External preparation containing a freeze-dried O/W emulsion containing a physiologically active substance