JPH04300833A - Prostaglandin e1-containing fat emulsion-loaded aerosol - Google Patents

Abstract

PURPOSE:To obtain an aerosol of prostaglandin E1s (PGE1s) for external use, capable of keeping chemical stability of the PGE1s without inflicting pain on patients and capable of physiologically conforming to skin surfaces without damaging neogenetic skin surfaces, etc. CONSTITUTION:An aerosol for external use comprising a fat emulsion of PGE1s containing one or more compounds selected from PGE1 and its derivatives (PGE1s) at a concentration of 0.1-500mug/ml, preferably 1-100/mug/ml in the fat emulsion. Since the aforementioned aerosol has various advantages in that high pharmacological effects can be expected with a small amount of aerosol; the aerosol can directly be administered to affected parts without touching the affected parts and various treatments can be carried out according to conditions of the affected parts, the aerosol can be utilized for various diseases such as burn, skin ulcer, bed sore and alopecia and its administration is extremely easy and effective. The aforementioned fatty emulsion is mainly composed of preferably 5-50% soybean oil, phospholipids in an amount of 1-50 pts.wt., preferably 5-30 pts.wt. based on 100 pts.wt. soybean oil and an adequate amount of water.

Description

[Detailed description of the invention]

0001

[Industrial Application Field] The present invention relates to prostaglandin E1
and its derivatives (hereinafter abbreviated as PGE1). More specifically, the present invention relates to an external spray that can be sprayed onto affected areas in the form of a mist of a fat emulsion containing PGE1.

0002

[Prior Art] PGE1 species exist in small amounts in the body and have a wide variety of physiological effects, such as vasodilatory effects, angiogenic effects, platelet aggregation inhibitory effects, and epithelial regeneration promoting effects, and are effective as therapeutic agents for peripheral blood flow disorders. An injection is already commercially available. By the way, if PGE1 can be used as a topical agent, it will be possible to treat pressure ulcers, alopecia, sensitivity to cold, stiff shoulders, etc. by its vasodilatory action for the purpose of locally intensive treatment without systemic side effects, and its action to promote epithelial regeneration. The development of practical formulations is eagerly awaited, as the treatment of burns and the like due to the angiogenic effect and the treatment of skin ulcers and the like due to the vasodilatory and platelet aggregation inhibiting effects can be made easier and more effective.

[0003] Conventionally, external preparations have generally been in the form of ointments or creams, but in such dosage forms PGE
Category 1 is unstable, and furthermore, when applied to the skin surface that is the treatment area, the topical preparation may not be physiologically compatible with the skin surface, or the application of the topical preparation may cause pain to the patient and cause damage to the new skin surface, etc. It often causes damage and delays healing.

[0004] Although PGE1 is chemically unstable, it can be stabilized by incorporating it into a fat emulsion.
An injection formulation of this drug has been proposed. However, since this fat emulsion is a low viscosity fluid, it can be administered as an injection, but as it is, it is difficult to effectively administer it as an external preparation.

[0005]

SUMMARY OF THE INVENTION Accordingly, an object of the present invention is to provide a preparation that allows effective external administration of PGE1. In particular, the object of the invention is to
It is an object of the present invention to provide an external preparation of PGE1 class that maintains the chemical stability of class E1, does not cause pain to patients, is physiologically compatible with the skin surface, and does not damage new skin surfaces.

[0006]

[Means for Solving the Problems] The present inventors have conducted extensive research to achieve the above object, and have found that the above problems can be solved by using a fat emulsion containing PGE1 as a spray agent. This discovery led to the completion of the present invention. That is, the external preparation of the present invention is characterized by containing a fat emulsion containing at least one selected from PGE1.

[0007] Regarding the present invention, PGE1 is PGE1
There is no particular limitation as long as it has activity, but PGE
It may also be a derivative with greater lipophilicity than 1 . P.G.
Examples of the E1 type include PGE1, PGE1 alkyl ester (Japanese Patent Application Laid-Open No. 59-216820), PGE1
GE1 alkoxycarbonyl alkyl ester or P
GE1 Acyloxyalkyl ester (JP-A-59-
206399), 7-thia PGE1 (JP-A No. 5
8-110562) and the like.

The fat emulsion of the present invention preferably contains 5 to 50% soybean oil and 1 phospholipid per 100 parts by weight of soybean oil.
-50 parts by weight (preferably 5-30 parts by weight) and an appropriate amount of water. In addition, if necessary, further emulsification aids [e.g. up to 0.3% (W/V) of carbon atoms 6
~22, preferably 12 to 20 fatty acids or physiologically acceptable salts thereof], stabilizers [e.g.
% (W/V) or less, preferably 0.1% (W/V)
cholesterol in the following amounts or phosphatidic acid in an amount of 5% (W/V) or less, preferably 1% (W/V) or less], a polymeric substance [e.g. 5 parts by weight (preferably 0.5 to 1 part by weight) of dextran, vinyl polymer, nonionic surfactant, gelatin, hydroxyethyl starch, etc.), isotonic agent (
For example, glycerin, glucose, etc.) can also be added.

[0009] The content of PGE1 in a fat emulsion can be increased or decreased as appropriate depending on the form and use of the fat emulsion, but it is generally 0.1 to 500 μg/ml, preferably 1 to 100 μg/ml in the emulsifier. The soybean oil used in the production of the fat emulsion is generally a high-purity refined soybean oil, which is obtained by further refining the refined soybean oil by, for example, steam distillation (purity: triglycerides,
Contains 99.9% or more as diglycerides and monoglycerides).

Phospholipids are purified phospholipids such as egg yolk lecithin and soybean oil lecithin, and can be prepared by a conventional fractionation method using an organic solvent. That is, for example, crude egg yolk phospholipids are dissolved in cold n-hexane-acetone, and while stirring,
Purified phospholipids can be obtained by gradually adding acetone, filtering and collecting insoluble matter, repeating this operation one more time, and then distilling off the solvent. It mainly consists of phosphatidylcholine and phosphatidylethanolamine, and also contains other phospholipids such as phosphatidylinositol, phosphatidylserine, and sphingomyelin. Further, if necessary, phospholipids can be separated and purified using a chromatography column to use phosphatidylcholine as the main component.

[0011] The fatty acid having 6 to 22 carbon atoms as an emulsification aid may be any fatty acid that can be added to pharmaceuticals. The fatty acid may be linear or branched, and it is preferable to use linear stearic acid, oleic acid, linoleic acid, palmitic acid, linolenic acid, myristic acid, or the like. As these salts, physiologically acceptable salts such as alkali metal salts (sodium salts, potassium salts, etc.), alkaline earth metal salts (calcium salts, etc.), etc. can be used.

[0012] Cholesterol and phosphatidic acid as stabilizers may be of any type as long as they can be used medicinally. Examples of the vinyl polymer used as the polymer substance include polyvinylpyrrolidone, polyvinyl alcohol, and the like. In addition, as a nonionic surfactant, polyalkylene glycol (for example, average molecular weight 1
,000 to 10,000, preferably 4,000 to
6,000 polyethylene glycol), polyoxyalkylene copolymers (e.g., average molecular weight 1,000
~20,000, preferably 6,000 ~10,00
0 polyoxyethylene-polyoxypropylene copolymer), hydrogenated castor oil polyoxyalkylene derivatives (for example, hydrogenated castor oil polyoxyethylene-(20)-ether, hydrogenated castor oil polyoxyethylene-(20)-ether, hydrogenated castor oil polyoxyethylene-(20)-ether, hydrogenated castor oil polyoxyethylene-(20)-ether, hydrogenated castor oil polyoxyethylene-(100)) -ether, etc.), castor oil polyoxyalkylene derivatives (for example, castor oil polyoxyethylene-(20)-ether, castor-oil polyoxyethylene-(40)-ether, castor-oil polyoxyethylene-(100)-ether, etc.), and the like.

Particularly preferred compositions of the fat emulsion used in the present invention include, for example, the following. PGE1 class 1
~100μg refined soybean oil
50-500mg highly purified lecithin
5-50mg concentrated glycerin
5-50mg distilled water
Appropriate amount total
1ml

The fat emulsion according to the present invention is produced, for example, by the following method. That is, a predetermined amount of PGE1, soybean oil, phospholipids, and other additives mentioned above are mixed and heated to form a solution, and the mixture is homogenized using a commonly used homogenizer (e.g., high-pressure jet homogenizer, ultrasonic homogenizer, etc.). It can be produced by treating a water-in-oil dispersion, then adding the necessary amount of water thereto, and homogenizing it again with the homogenizer to convert it into an oil-in-water emulsion. Depending on manufacturing circumstances, stabilizers,
Additives such as isotonic agents may be added (Japanese Patent Laid-Open No. 58-22
2014 Publication).

The external spray of the present invention is prepared by adding known additives to the thus produced fat emulsion itself or to the fat emulsion.

The external spray of the present invention is preferably filled into a sprayer having the following structures 1 to 5. 1. It has an injection port. 2. Air does not flow back into the container from the injection port. 3. It is a sealed container. 4. The volume of the container changes depending on the volume of the emulsion. That is,
If an emulsion is used, the volume of the container will be reduced by the amount used, and no hollow space will be formed inside the container. 5. The emulsion is sprayed from the injection port by mechanical pressure. In other words, instead of being injected by the pressure of the injected gas,
Spray at the time of use by mechanical pressure.

As an example of a spray container that satisfies the above conditions, "Airless Pump for Medication" (manufactured by Top Co., Ltd.) is commercially available, but is not limited thereto.

By filling the above-mentioned closed container, oxidation of PGE1 and lecithin by air can be prevented, and the stability of the emulsion can be maintained for a long time in the state at the time of filling. Furthermore, since air is not allowed to flow back into the container during spraying, bacterial contamination can be prevented.

Methods for applying the external spray according to the present invention to patients include, for example, spraying it directly onto the affected area, or applying it to the affected area after spraying it, or spraying it onto gauze or sheet-like materials and applying it onto the affected area. There are methods such as pasting.

[0020] The dosage of the drug of the present invention varies depending on the pathological condition, the size of the affected area, etc., but is usually 1 ng as PGE1 class.
/kg body weight to about 10 mg/kg body weight. Further, as for usage, it is applied to the affected area about once to several times a day.

[0021]

EXAMPLES The present invention will be specifically explained below using experimental examples and examples, but the present invention is not limited thereto. Experimental Example 1 Stability test over time of a spray filled with a PGE1-containing fat emulsion A spray consisting of 7 ml of the PGE1-containing fat emulsion produced in Example 1 was aseptically dispensed using an airless pump (Co., Ltd.).
(manufactured by Top Co., Ltd.) and tested for total spray volume, appearance, pH, peroxides, free fatty acids, emulsion particle size, and residual PGE1 content. The results are shown in Table 1 (refrigerated storage).

[0022]

[Table 1]

[0023] From the above results, it was confirmed that this drug has excellent stability over time.

Experimental Example 2 Sterility test during long-term storage of PGE1-containing fat emulsion-filled spray The spray of Experimental Example 1 was aseptically administered using an airless pump ((
A sterility test was conducted on the remaining liquid after filling the liquid into a container (manufactured by Top Co., Ltd.) and spraying over time based on the general test method "sterility test method, direct method" described in the Japanese Pharmacopoeia. The results are shown in Table 2 as the number of samples showing bacterial growth/number of test samples.

[0025]

[Table 2]

[0026] From the above results, it was confirmed that this agent can prevent bacterial contamination.

Example 1 50 mg of PGE1, 20 g of purified egg yolk lecithin and 2.4 g of oleic acid were added to 100 g of purified soybean oil, and the mixture was heated to about 50°C.
The mixture was dissolved and dispersed under heating. Next, 25 g of Japanese Pharmacopoeia glycerin and distilled water were added to make a total volume of 1 liter, and the mixture was coarsely emulsified using a homomixer. This was emulsified by passing it through a Manton-Gaulin type homogenizer 10 times under pressure of 120 kg/cm 2 in the first stage and a total pressure of 500 kg/cm 2 . As a result, a homogenized extremely fine PGE1-containing fat emulsion was obtained. The average grain size of this emulsion is 0.2 to 0.4 μm, and 1
It did not contain particles larger than μm. This was aseptically filled into a spray container consisting of an EO gas sterilized nozzle and pump part, a dry heat sterilized main glass part, and a high-pressure steam sterilized rubber stopper part. The particle size after spraying was 10 μm or more, and a large number of PGE1-containing fat emulsions were present therein, and there were no changes such as collapse or deformation of individual particles.

Example 2 10 mg of PGE1, 18 g of purified egg yolk lecithin and 1 g of oleic acid were added to 100 g of purified soybean oil and dissolved and dispersed under heating at about 50°C. Next, Japanese Pharmacopoeia glycerin 25
g and distilled water were added to make a total volume of 1 liter, and the mixture was coarsely emulsified using a homomixer. After rough emulsification, the same operation as in Example 1 was performed to obtain a homogenized extremely fine PGE1-containing fat emulsion. Furthermore, this emulsion was aseptically filled into an airless pump spray container for administration. Similar to Example 1, there were no physicochemical changes regarding the spray particles.

Example 3 2.5 mg of PGE1 and 18 g of purified egg yolk lecithin were added to 100 g of purified soybean oil and dissolved and dispersed under heating at about 50°C. Next, 22 g of Japanese Pharmacopoeia glycerin and distilled water were added to make a total volume of 1 liter, and the mixture was coarsely emulsified using a homomixer. After rough emulsification, the same operation as in Example 1 was performed to obtain a homogenized extremely fine PGE1-containing fat emulsion. Furthermore, this emulsion was aseptically filled into an airless pump spray container for administration. Similar to Example 1, there were no physicochemical changes regarding the spray particles.

Clinical Example 1 The spray of Example 1 was directly sprayed on a patient (female, 67 years old, in the ischial and sacral areas) in the early stages of pressure ulcers. As a result, there was no pain to the patient during administration. , a good healing effect was obtained.

Clinical Example 2 After spraying the spray of Example 2 onto a collagen sheet, this sheet was used to treat a second degree burn (male, 8 years old, right foot). As a result, there was no pain during the treatment. An effect of promoting epithelial regeneration was observed during the healing process, and complete healing occurred after 7 days, resulting in clean skin formation.

[0032]

Effects of the Invention The spray containing the fat emulsion containing PGE1 of the present invention is an external pharmaceutical preparation that can be expected to have high pharmacological effects with a small amount of spray. Further, the spray of the present invention can be administered directly to the affected area without touching it, and various treatments can be performed depending on the condition of the affected area. The preparation of the present invention, which has many such advantages, can be used for many diseases such as burns, skin ulcers, bedsores, and alopecia, and its administration is extremely easy and effective.

Claims (1)

[Claims] 1. An external spray comprising a fat emulsion containing at least one selected from prostaglandin E1 and its derivatives.