JPH0311017A - Pharmaceutical composition containing prostaglandin e1 - Google Patents

Abstract

PURPOSE:To obtain a pharmaceutical composition which is externally applicable and useful in treatment for burn and bed sore by using prostaglandin E1 or its derivative, and a collagen sheet. CONSTITUTION:The subject composition contains at least one selected from prostaglandin E1 (abbreviated to PGE1) and its derivatives and a collagen sheet. The PGE1 derivative is suitably emulsifiable with lipid, can be made into liposome or soluble in water. The emulsifier is preferably 5 to 50W/V% of soybean oil, 1 to 50 pts., preferably 5 to 30 pts., per 100 pts. of soybean oil, of phospholipid and an appropriate amount water. The content of the PGE1 or its derivative in the lipid emulsion can be varied depending on the form and use of the emulsion, but in general an extremely trace amount, e.g. 100 to 0.1mug/ml.

Description

[Detailed Description of the Invention] [Industrial Application Field] The present invention relates to prostaglandin L (hereinafter referred to as PGE), which has many actions such as vasodilatory action, platelet aggregation action, angiogenic action, and epithelial regeneration promoting action. The present invention relates to a pharmaceutical composition capable of being formulated for external use, in which at least one active ingredient selected from collagen sheets and derivatives thereof (particularly PGE in the form of a fat emulsion, and derivatives thereof) is present in or on the surface of a collagen sheet.

[Prior Art] PGE and its derivatives exist in small amounts in living bodies and are known to have a wide variety of physiological effects, and efforts were first made to develop therapeutic agents for peripheral blood flow disorders.

If PGE and its derivatives could be used as external preparations, their ability to promote epithelial regeneration would make it possible to treat burns, and their vasodilatory effects would enable the treatment of thin skin. P in the form of
GE and its derivatives are extremely useful, and the development of practical formulations thereof is eagerly awaited.

On the other hand, PGEI and its derivatives have very poor stability, but they can be stabilized by incorporating them into a fat emulsion.

However, since this fat emulsion is a low viscosity fluid, although it can be administered as an injection, other forms of administration,
In particular, it is extremely difficult to administer as an external preparation.

Conventionally, as external preparations, ointments and creams such as JJi are used, but when such external preparations are applied to the skin surface that is the treatment area, it cannot be said that the external preparations are physiologically compatible with the skin surface. It often causes damage to the new skin and delays its healing.

Further, it is not possible to prepare such a dosage form while maintaining the state of a fat emulsion, and therefore, an external preparation made of a fat emulsion containing a PGE derivative has not yet been put to practical use.

Therefore, in order to make the action of the fat emulsion containing PGE+ and its derivatives more widespread, for example, to make it possible to administer it as an external preparation, the fluidity of the fat emulsion must be stopped and fixed in some way.

[Problem to be solved by the invention]

Accordingly, an object of the present invention is to provide a pharmaceutical composition or preparation that can be administered externally using PGE or its derivatives. In particular, the object of the present invention is to use PGE,
An object of the present invention is to provide a pharmaceutical composition or a preparation in which a fat emulsion containing a derivative thereof can be administered externally.

[Means to solve the problem]

In order to achieve such an object, the present inventor has conducted repeated research and found that all of the above problems can be solved by combining PGE, its derivative, and a collagen sheet, and has developed the present invention. I was able to complete it.

That is, the gist of the present invention is as follows (1), particularly (2).

(1) A pharmaceutical composition comprising at least one selected from prostaglandin E1 and its derivatives and a collagen sheet.

(2) The pharmaceutical composition according to (1) above, which comprises a collagen sheet and a fat emulsion containing at least one selected from prostaglandin E1 and its derivatives.

Regarding the present invention, the PGE+fi conductor is PGE, and there is no particular limitation as long as it has activity. In particular, those that can be made into a fat emulsion, those that can be made into liposomes, or those that are water-soluble are preferable. For example, JP-A-59-206349
PGE described in JP-A-59-216820,
Derivatives and the like are preferably used.

In the present invention, the fat emulsion preferably contains 5 to 50% soybean oil.
w/v%, 1 to 50 parts (preferably 5 to 30 parts) of phospholipid per 100 parts of soybean oil, and an appropriate amount of water. In addition, if necessary, an emulsification aid [for example, an amount of up to 0.3% (w/v) of carbon atoms 6 to 2]
2, preferably 12 to 20 fatty acids or physiologically acceptable salts thereof], stabilizers (e.g. 0.5
% (W/V) or less, preferably 0.1% (W/V) or less, or phosphatidic acid in an amount of 5% (W/V) or less, preferably 1% (W/V) or less. etc.] polymeric substances [for example, PC, E, 0.1 to 5 parts by weight (preferably 0.5 to 1 part by weight) of albumin, dextran, vinyl polymer, nonionic surfactant per 1 part by weight agent, gelatin, hydroxyethyl'R powder, etc.]
, isotonic agents (eg, glycerin, glucose, etc.), etc. can also be added. The content of PGE and its derivatives in a fat emulsion can be increased or decreased as appropriate depending on the form of the emulsion and its use, but it is generally sufficient to include a very small amount, for example 100 to 0.1 μg/Inl, in the emulsion.

Here, the soybean oil is preferably high-purity refined soybean oil, preferably high-purity refined soybean oil obtained by further refining the refined soybean oil, for example, by a steam distillation method (as pure nitriglyceride, diglyceride, and monoglyceride). 99.9% or more).

Phospholipids are purified phospholipids such as egg yolk lecithin and soybean lecithin, and can be prepared by a conventional fractionation method using an organic solvent. That is, for example, crude egg yolk phospholipid is dissolved in cold n-hexane-acetone, acetone is gradually added under stirring, insoluble matter is collected by filtration, and this operation is repeated one more time, and then the solvent is distilled off. Purified phospholipids can be obtained by It mainly consists of phosphatidylcholine and phosphatidylethanolamine, and also contains other phospholipids such as phosphatidylinositol, phosphatidylserine, and sphingomyelin.

Fatty acids having 6 to 22 carbon atoms as emulsification aids can be used as long as they can be added to pharmaceuticals. This fatty acid may be linear or branched, and linear stearic acid, oleic acid, linoleic acid, valmitic acid, lylunic acid,
It is preferable to use 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.) can be used.

Cholesterol and phosphatidic acid as stabilizers may be of any type as long as they can be used for pharmaceutical purposes.

As the albumin, vinyl polymer, and nonionic surfactant used as the polymeric substance, the following are preferable:
That is, it is preferable to use human-derived albumin from the viewpoint of antigenicity. Examples of vinyl polymers include polyvinylpyrrolidone.

In addition, as a nonionic surfactant, polyalkylene glycol (for example, an average molecular weight of 1000 to +000
0, preferably 4000 to 6000 polyethylene glycol), polyoxyalkylene copolymers (e.g.
Average molecular weight 1000-20000, preferably 6000
~toooo polyoxyethylene-polyoxypropylene copolymer), hydrogenated castor oil polyoxyalkylene derivatives (for example, hydrogenated castor oil oxypolyethylene-(
40) - Ether, same (20) - Ether, same (1
00) to ether), castor oil polyoxyalkylene derivatives (e.g. castor oil polyoxyethylene-(
20) - Ether, same (40) - Ether, same (1
00)-ether), etc. can be used.

A preferred composition of the fat emulsion used in the present invention is as follows.

PGE or its derivatives 0.1-100 ug Refined soybean oil 50-500 mg Highly purified egg yolk lecithin 5-50 mg Oleic acid
1-10mg4 Glycerin 5-50
An example is 1 tel of mg water for injection, total appropriate amount.

The fat emulsion related to the present invention is produced, for example, by the following method.

namely, soybean oil, phospholipids, and PCBs in predetermined amounts.

(derivatives thereof) and other additives mentioned above,
A water-in-oil dispersion is prepared by heating to form a solution and homogenizing it using a commonly used homogenizer (for example, a pressure injection homogenizer, an ultrasonic homogenizer, etc.), and then adding the required amount of water to this. In addition, it can be produced by homogenizing again using the homogenizer to convert it into an oil-in-water emulsion. Depending on the manufacturing convenience, additives such as stabilizers and isotonic additives may be added after the production of the fat emulsion (Japanese Patent Laid-Open No. 58-222014).

Furthermore, PGE and its derivatives can be used in the present invention as such, as an aqueous solution thereof, or a liposome solution thereof. Here, the aqueous solution and liposome solution are as follows, for example.

(a) Water solution The aqueous solution is exemplified by a form consisting of PC;E (a derivative thereof), a polyoxyethylene-polyoxypropylene copolymer, and a suitable aqueous solvent.

Examples of the aqueous solvent include distilled water for injection, physiological saline, electrolyte solution, and buffer solution.

(b) Liposome solution The liposome solution includes PC; E, (derivative thereof),
A form consisting of a polyoxyethylene-polyoxypropylene copolymer or a phospholipid and a suitable aqueous solvent is exemplified.

Examples of phospholipids include mixtures of (1) soybean oil phospholipids or egg yolk phospholipids (2) phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, or sphingomyelin (2).

Examples of the aqueous solvent include those mentioned in (a) above.

There are no particular limitations on the collagen used in the present invention,
Preferably, those derived from animal skin, especially cow (particularly young cow) dermis, are used. The collagen sheet is preferably spongy, and in particular, collagen extracted and purified from the dermis of young cows is desirably molded into a spongy (porous) shape by freeze-drying, but the spongy collagen sheet is not limited to this. It's not something you can do. The thickness of the collagen sheet is preferably 0.1 to 3 m, and the size may be determined as appropriate depending on the area of the affected area.

The pharmaceutical composition of the present invention usually contains PGE, derivatives thereof (
Preferably, an embodiment in which PGE or a derivative thereof itself, an aqueous solution thereof, a fat emulsion thereof, a liposome solution thereof) is included in the collagen sheet, an embodiment in which the above drug is attached to the surface of the collagen sheet, and an embodiment in which the above drug is attached. In this embodiment, the collagen sheet is included in the collagen sheet and attached to the surface of the collagen sheet.

Examples of methods for incorporating the drug into the collagen sheet or adhering it to the surface of the collagen sheet include a method in which a liquid-like drug as described above is sucked into a sponge-like collagen sheet by capillary action, and a method in which the drug is kneaded with collagen. Examples include a method of forming the collagen sheet into a sheet, and a method of spraying or applying the drug onto the collagen sheet. Alternatively, a preparation may be prepared in which a collagen sheet is impregnated with the drug and then water is removed by freeze-drying or the like, and in such a preparation, the drug is liquefied by body fluids during use. For example, in the case of a fat emulsion, a preparation from which water has been removed by freeze-drying or the like is re-emulsified with body fluids.

Pharmaceutical compositions of the invention are typically administered dermally.

The dosage varies depending on the pathological condition, the size of the affected area, etc.
Usually, the amount of PGE or its derivative is about 1ng/kg body weight to 10 μg/kg body weight.

Further, as for usage, it is applied to the affected area about once to several times a day.

〔Effect of the invention〕

With the pharmaceutical composition of the present invention, PGE, derivatives thereof (
In particular, it has become possible to administer the fat emulsion (fat emulsion) as an external preparation, and due to the pharmacological action of PGE, it is possible to effectively treat burns, thinning, etc., and it can also be administered locally for external use. This limits the site of action of the drug, making it possible to exert pharmacological action only in a specific site. Furthermore, when the pharmaceutical composition of the present invention is administered externally (transdermally), the pharmacological action of PGE lasts for a long time and exhibits a strong pharmacological action.

〔Example〕

Examples will be given to explain the present invention in more detail, but the present invention is not limited thereto.

Example 1 30g of refined soybean oil, 3.6g of lecithin, PGE900
ag, 0.15 g of sodium oleate, and 0.15 g of phosphatidic acid were added and dissolved by heating at 40-75°C. Add 200 d of distilled water to this, then
Add 7.5g of Japanese Pharmacopoeia glycerin and heat at 20-40°C.
The total volume was made up to 300 d with distilled water for injection, and the mixture was coarsely emulsified using a homomixer.

Using a Manton-Gallin type homogenizer,
Emulsification was carried out by passing the mixture 10 times under a pressure of 120 kg/cd per stage and a total pressure of 500 kg/cd. As a result, a homogenized fat emulsion containing very fine PGE was obtained. The average grain size of this emulsion was 0.2 to 0.4 .mu. and contained no grains larger than 1 .mu..

A sponge-like collagen sheet (5 cm x 5 cm) was impregnated with 2 d of the obtained PGE-containing fat emulsion.

Example 2 PGE, 5 μg refined soybean oil
toomg High quality egg yolk lecithin 18mg Oleic acid 2.4mg Concentrated glycerin 22.1mg Water for injection
Appropriate amount total ld After preparing a PGE-containing fat emulsion having the above composition according to Example 1, a preparation consisting of the pharmaceutical composition of the present invention was prepared.

On the other hand, the same amount of cyclodextrin inclusion P G
A petrolatum ointment containing E l was used as a control. ■° Burn injury (male, 11 years old, dorsal region of left foot) was treated with these type 2 agents after the blisters had burst.

Epithelial regeneration started around 4 days after treatment, and both
The thin film became completely epithelialized around the day.

However, when the wound is peeled off during healing, Vaseline ointment also peels off the previously formed film, but with the collagen sheet preparation of the present invention, only the collagen sheet can be quickly peeled off, allowing the wound to heal during healing. I was able to exchange the preparation without damaging it.

Example 3 The healing effects of a collagen sheet preparation with the emulsion composition of Example 1 and a gauze preparation containing fradiomycin sulfate (comparative control) on ■° burns (male, 4 years old, left forearm site) were investigated.

As a result, in the case of the collagen sheet preparation, epithelial regeneration began around the fourth day and was completely cured one week after the treatment. On the other hand, in the case of the gauze preparation, epithelial regeneration was slow and it took about two weeks for complete healing.

Example 4 A vaseline ointment (comparative control) containing a collagen sheet preparation having the emulsion composition of Example 1 and the same amount of cyclodextrin-clathrated PGE.

The healing effect on burns (female, 60 years old, left leg) was investigated.

As a result, in the case of the collagen sheet preparation, a clean epithelium was directly regenerated, but in the case of the vaseline ointment, a hard skin was formed first, and then a clean skin was formed underneath. Therefore, the former had better results regarding the healing process.

Example 5 A collagen sheet having the emulsion composition of Example 1 was used to treat ■° trauma (4-year-old female, right neck, back), but ■0
Although the healing speed was a little slower than that of the conventional method, a good healing effect was obtained.

Claims (2)

[Claims] (1) A pharmaceutical composition comprising at least one selected from prostaglandin E_1 and its derivatives and a collagen sheet. (2) The pharmaceutical composition according to claim (1), comprising a collagen sheet and a fat emulsion containing at least one selected from prostaglandin E_1 and its derivatives.