JPH01110623A - Protective film forming type medicine - Google Patents

Abstract

PURPOSE:To obtain a protective film-forming preparation which contains the drug, polyvinyl alcohol and a solvent, thus forms a flexible protective film on the skin surface readily, when it is applied whereby the active ingredients of the drug release for a long time with percutaneous absorption increased. CONSTITUTION:The subject preparation is produced by using, as essential components, 0.01-20wt.% of the drug, 3-30wt.% of polyvinyl alcohol, and 0.1-80wt.% of a solvent, and, when needed, a humectant, and a solubilizer and formulating them into a preparation. The drug is at least one selected from an anti-inflammatory analgesic, steroid, antifungal, antibiotic, coronary vasodilator, anticonvulsant, antiarrhythmic. The polyvinyl alcohol has 10,000-200,000mol.wt., 1-70cps viscosity rating, 10-100% saponification degree. The solvent is at least one selected from water, lower alcohols, and glycols.

Description

DETAILED DESCRIPTION OF THE INVENTION Field of Industrial Application The present invention is a protective film-forming preparation, more specifically, an external preparation containing a pharmacologically active substance, which can be applied to the skin surface to quickly dry. The present invention relates to a preparation that forms a flexible protective film, allows medicinal ingredients to be continuously released through the film, and can be absorbed transdermally.

Conventionally, ointments, which are one of the external preparations, can be rubbed into the skin surface to allow medicinal ingredients to be absorbed locally or throughout the body, and are widely used in surgical, dermatological, and other clinics. However, because the drug exists in a rubbed state, there are problems in that it may contaminate clothing or be wiped off by contact with clothing, and it is difficult to apply when the drug is volatile.
The release of the drug and the sustained percutaneous absorption are not satisfactory.

The present inventors have carried out extensive research in order to solve the problems of such ointments and to provide an external preparation that continuously increases the transdermal absorption of drugs, and found that using polyvinyl alcohol as a film-forming agent, If you combine this with a drug and a solvent,
After application to the skin surface, a flexible protective film with excellent quick-drying properties is formed, and long-term transdermal absorption of the drug is achieved through this film, and it is also easily peeled off by contact with clothing. The present invention was completed based on the discovery that this is not the case.

That is, 1 the present invention provides a drug, polyvinyl alcohol (P
The present invention provides a protective film-forming preparation characterized by comprising VA) and a solvent.

The drugs used in the present invention are not particularly limited as long as they are systemically or locally acting, and include anti-inflammatory analgesics (indomethacin, diclofenac or its salts, ibuprofen,
phenylbutacin, oxyfebutazone, mepirizole, aspirin, etengamide, aminopicillin, zenacetin, etc.), steroids (cortisone acetate, hydrocortisone, hydrocortisone acetate, dexamethacin,
Dexamethacin acetate, triamcinolone, triamcinolone acetonide, prednisolone, prednisolone acetate, betamethacin, betamethacin sodium phosphate, methylprednisolone, methylprednisolone acetate, etc.)
Antibacterial agents (chlortetracycline, oxytetracycline, streptomycin, kentamycin, dihydrosprebutomycin, bacitramine, erythromycin.

ampicillin, penicillin, cephalosporin, etc.)
Antibiotics (oxytetracycline hydrochloride, kanamycin, chloramphenicol, 1ffi!gentamicin,
Tetracycline, sodium fusidate, fradiomycin sulfate, sulfadiazine, sulfamethoxazole, sulfisomidine, etc.), coronary vasodilators (insorbide nitrate, nitroglycerin, nifedipine, ethaphenone hydrochloride, oxyphethrine hydrochloride, etc.), antispasmodics (furo propion, butropium bromide, amantadine hydrochloride,
Trospium chloride, etomidrine, methipidium bromide,
N-methylscopolamine methyl sulfate, phloroglucin, piropeftin hydrochloride, frifinium bromide, cemonium iodide, mazaticol hydrochloride, eperisone hydrochloride, etc.),
Examples include antiarrhythmic agents (acebutolol hydrochloride, alprenolol hydrochloride, indeolol hydrochloride, oxbrae 70-ol hydrochloride, carteolol hydrochloride, propranolol hydrochloride, pindolol, dinpyramide, etc.), and at least one of these is used.

PVA in the present invention has a molecular weight of 10,000 to 2
00000, viscosity rating (measured at 20°C, 4% aqueous solution) 1
~70 cps and a saponification degree of 10-100% may be used.

Regarding the saponification degree of PVA, generally speaking, the lower the saponification degree, the higher the solubility in alcohol, and the higher the saponification degree, the higher the solubility in water. Saponification degree 50%
PVA of less than 10% does not dissolve in water alone, but dissolves in a water/alcohol mixed system or alcohol, and the formed film is flexible and can be applied to bends. On the other hand, saponification degree is 50%
Although the above-mentioned PVA is easily soluble in water, its solubility in alcohol is low, and the formed film is strong and increases the protective function of the skin, but it is difficult to apply to curved parts.

Therefore, it is preferable to use an appropriate combination of a saponification degree of less than 50% and a saponification degree of 50% or more,
This makes it possible to form a flexible and strong film, which can be applied to a wide range of areas such as bent parts.Solvents used in the present invention include, for example, water, lower alcohols (ethanol, furopanol, isofuro, pyrualcohol, etc.), glycols (propylene Glycol, ethylene glycol, 1,
3-butanediol, etc.), and at least one of these is used. Particularly preferred are water and ethanol.

The protective film-forming preparation according to the present invention contains the above-mentioned drug, PVA, and solvent as essential components, and optionally includes a moisturizing agent and a solvent.
It is composed of a system containing a solubilizing agent. The content of essential components in the preparation of the present invention (in the total amount of the preparation) is usually 0.01
~20% (wt%, between Fi>c preferably 0.05
-10%), PVA3-30% (preferably 5-25%)
) and solvent 0.1-80% (preferably 5-70%)
It should be selected so that it falls within the range of . If the PVA content is less than 3%, it will be difficult to form a film, and if it is formed, it will be weak; if it exceeds 30%, the main drug will precipitate and the film will become too hard and lose its ability to adhere to the skin. There is a tendency to

Examples of the moisturizing agent include propylene glycol,
Glycerin, polyethylene glycol.

Polyhydric alcohols such as ethylene glycol and sorbitol are preferred, and at least one of these can be used. The content should normally be selected to be 30% or less of the total amount of the preparation.

Examples of solubilizers include crotamiton, esters of dicarboxylic acids having 1 to 8 carbon atoms (dioctyl succinate, diisostearyl malate).

Diisobutyl adipate, diisopropyl adipate,
dioctyl adipate, etc.), lower alcohols, medium chain fatty acid triglycerides, glycols, etc., and at least one of these can be used. The content is usually selected to be 0.1 to 10% of the total amount of the preparation.

In addition, in the formulation of the present invention, alcohol (especially ethanol) acts as an absorption enhancer, increasing transdermal absorption of the drug,
Also, its transpiration action removes heat from the inflamed area, creating a cooling sensation.

According to the formulation of the present invention having the above configuration, the following advantages can be achieved.

i) Even if the drug is volatile, it can be used freely, and its volatile action additionally improves transdermal absorption.

++) It has excellent drug release and transdermal absorption, and has a sufficiently long-lasting effect.Furthermore, there is no risk of skin damage during or after application, and it can be applied evenly to curved areas, etc. After application, it quickly becomes a single film,
This has good skin adhesion and is easy to peel off. Thus, it can be said that the formulation of the present invention has both the rubbing effect of an ointment and the sustained transdermal absorption effect of a poultice.

■) When applied to bacterial skin disease areas, the formation of a protective film prevents the affected area from expanding, contributing to shortening the treatment period.

Next, the present invention will be explained in more detail with reference to Examples.

Example 1 PVA (degree of saponification 70-90%) ・14 Glycerin 2 Polytruvay)-80 (manufactured by Dai-ichi Kogyo Seiyaku Co., Ltd., Tween 80)
... 0.5 Ethanol ... Gentamicin 20 sulfate ... 0.1 (potency) Methyl parahydroxybenzoate ... 0.
1 Bara n-propyl hydroxybenzoate...0.
05 Sterile water... Remaining needle 100 PVA is gradually added to about 50 y of cold (5-20°C) sterile water to dissolve and disperse it, and then the PVA is completely dissolved while keeping the temperature at 70°C. After cooling, add glycerin, Tween
After adding and mixing 80 and gentamicin sulfate, a previously prepared ethanol solution of methyl hydroxybenzoate and n-propyl hydroxybenzoate was gradually added and thoroughly kneaded. Finally, sterilized water is added to make a total volume of 100p to prepare a preparation for external use.

Example 2 PVA (Saponification degree less than 50% River 1゜P
VA ('7' 70-90%)-41,3-butanediol... 2 Sterile water
・・・ 2゜Methyl hydroxybenzoate 0.1゜N-propyl hydroxybenzoate ・・・0.05 Tetracycline hydrochloride 3 (potency) Ethanol ・・・Remaining total
100 PVA (saponified 1i 70-90%) is added to 20 y of cold sterilized water, PVA is completely dissolved using the same method as in Example 1, and after cooling, 1,3-butanediol and tetracycline hydrochloride are added. This solution was gradually added to a solution in which PVA (saponification degree less than 50%), methyl hydroxybenzoate, and n-propyl hydroxybenzoate were dissolved and kneaded in ethanol (appropriate amount), and after thorough mixing, ethanol was added. In addition, an external preparation is obtained as whole Biooy.

Example 3 Ingredients
yPVA (saponification degree less than 50%)...
3PVA (saponification degree 70-90%)... 1
1 crotamiton...2.5
Prednisolone... 0.3 Chloramphenicol... 2 (titer) Fradiomycin sulfate... 0.5 (
Titer) Ethylenediamine four-bar dNa...0
．． 01 Ethanol... 2
0 Methyl parahydroxybenzoate ... 0
．． 1 unit n-propyl hydroxybenzoate... 0.05 Sterile water... balance total
100 Add PVA (degree of saponification 70-90%) to cold sterilized water (appropriate amount), completely dissolve PVA using the same method as in Example 1, and after cooling, add Na1 chloramphenicol and fradiomycin sulfate to ethylenediaminetetraacetic acid. Add and mix, then add crotamiton solution of prednisolone, and under further stirring, add methyl hydroxybenzoate to ethanol in advance,
A solution prepared by dissolving and kneading n-propyl hydroxybenzoate and PVA (saponification degree of less than 50%) is added, and finally sterilized water is added to give a total volume of 100 y to obtain an external preparation.

Example 4 Component 2 PVA (degree of saponification 70-90%) ... 3PV
A (Saponification degree less than 50%) 18 Kanamycin sulfate 0.5 (potency) Polyethylene glycol (PEG400) Isopropyl myristate 1.5 Methyl hydroxybenzoate 0.1 N-propyl hydroxybenzoate... 0.05 Sterilized water... 20 Ethanol... Total remaining 100 Add 20 y of cold sterilized water KPVA (degree of saponification 70-90%) and prepare PVA using the same method as in Example 1. Completely dissolve and after cooling, add and mix PEG400 and kanamycin sulfate, then add this to ethanol (appropriate amount) in advance, PVA (saponification degree less than 50%), methyl hydroxybenzoate,
After adding n-propyl hydroxybenzoate and isopropyl myristate to a solution in which they are dissolved and kneaded, ethanol is added to obtain a whole flooy preparation for external use.

Example 5 Ingredients
yPVA (saponification degree less than 50%)...
30 Propylene glycol...
5Fradiomycin sulfate...0.3
5 (potency) Methyl hydroxybenzoate... 0.1 N-propyl hydroxybenzoate... 0.05 Sterilized water... 10 Ethanol... Remainder total 100 Add fradiomycin sulfate and propylene to sterile water After adding glycol and mixing and dissolving it, mix it with ethanol (
methyl rose hydroxybenzoate, n-propyl rose hydroxybenzoate and PVA (saponification degree 50%)
After gradually adding t4) to the solution, ethanol is added to bring the total amount to 100y to obtain a preparation for external use.

Example 6 Ingredients! PVA (Saponification degree 70-90%)・13PVA (Saponification degree 95% or more) Streptomycin disulfate 0.5 (potency) Gramicidin hydrochloride S 0.2 (
Potency) Chlorpheniramine maleate...0.1
Hydrocortisone acetate...0.2 Crotamiton...3 Glycerin...2 Ethanol
・-・ 10 Methyl para-hydroxybenzoate ・・・ 0.1 n-propyl para-hydroxybenzoate ・ 0.05 Sterilized water ・ Total balance 1
00 Two types of PVA were added to cold sterilized water (appropriate amount), PVA was completely dissolved using the same method as in Example 1, and after cooling, streptomycin sulfate, gramicidin S hydrochloride and glycerin were added and mixed.

After gradually adding a solution of chlorpheniramine maleate, hydrocortisone acetate, crotamiton, methyl hydroxybenzoate, and n-propyl hydroxybenzoate dissolved in ethanol, sterilized water was added to bring the total volume to 1.
An external preparation is obtained as 00y.

Example 7 PVA (degree of saponification 70-90%) 15 sulfate 7 Radiomycin... 0.2 (potency) Bacitramine 250 units 1.3-
Butanediol...3 Stearyl alcohol...2Cetyl alcohol...1Methyl parahydroxybenzoate...0.1N-butyl parahydroxybenzoate...0.025 N-propyl parahydroxybenzoate・・・ 0.025 1 ethanol ・・・ 10 sterilized water ・・・ Remainder total 10
0 Add PVA to cold sterilized water (appropriate amount) and completely dissolve PVA using the same method as in Example 1. After cooling, add fradiomycin sulfate, bacitramine and 1,3-butanediol and mix. 1 Then, to this, Add the stearyl alcohol and cetyl alcohol solution and mix. To this mixed solution, a solution prepared by dissolving methyl hydroxybenzoate, n-butyl hydroxybenzoate, and n-propyl hydroxybenzoate in ethanol is gradually added, and then sterile water is added to make a total volume of 100 y to obtain a preparation for external use. .

Formulation testing (1) Antibacterial activity test This will be carried out in accordance with the general laws listed in the Japan Anti-Corporation Act as shown below.

Japanese Antibiotic General Test Method: According to the same cylinder plate method described in the potency test method, using the culture medium specified in the drug monograph and the test bacteria, the preparations of Examples 1 to 7 (100 μ each) were preliminarily applied to the test bacteria. was added dropwise to the inoculated medium, and after culturing at 35°C for 20 hours, the diameter of the inhibition circle was measured. The results are shown in Table 1.

Table 1 (n=5) (2) Stability test Stability, which has an important meaning in pharmaceuticals, is also conducted according to the potency test method listed in the 1-day antibody.

The results are shown in Table 2.

Table 2 (ratios with the initial value as 100) (3) Skin irritation test Regarding local irritation, which is often a problem in clinical use of external preparations, ■ Drogie for rabbits.
The test will be conducted in accordance with the law and in accordance with the methods and criteria of the Japanese Patch Test Research Group on healthy adult males. The results are shown in Tables 3 and 4, respectively (commercial products A and B
Table 3 (Rabbit, cumulative score, n=7)

Claims (1)

[Claims] 1. A protective film-forming preparation comprising a drug, polyvinyl alcohol, and a solvent. 2. The preparation according to item 1 above, wherein the drug is a systemically or locally acting drug, and the content thereof is 0.01 to 20% by weight based on the total amount of the preparation. 3. The formulation according to item 1 or 2 above, wherein the drug is at least one selected from the group of anti-inflammatory analgesics, steroids, antibacterial agents, antibiotics, coronary vasodilators, antispasmodics, and antiarrhythmic agents. . 4. Polyvinyl alcohol has a molecular weight of 10,000 to 200
000, viscosity rating 1~70cps and saponification degree 10~
100%, and the content thereof is 3 to 30% by weight based on the total amount of the preparation, according to any one of items 1 to 3 above. 5. The preparation according to item 4 above, which uses a mixture of a polyvinyl alcohol having a saponification degree of less than 50% and a saponification degree of 50% or more. 6. Items 1 to 5 above, wherein the solvent is at least one selected from the group of water, lower alcohols, and glycols, and the content thereof is 0.1 to 80% by weight based on the total amount of the preparation.
2. The formulation according to any one of paragraphs 1-1. 7. The formulation according to item 1 above, which contains a humectant and/or a solubilizer. 8. No. 7 above, wherein the humectant is at least one selected from polyhydric alcohols such as propylene glycol, glycerin, polyethylene glycol, ethylene glycol, and sorbitol, and the content thereof is 30% by weight or less based on the total amount of the preparation. Preparations as described in section. 9. The solubilizing agent is at least one selected from the group of crotamiton, esters of dicarboxylic acids having 1 to 8 carbon atoms, lower alcohols, medium-chain fatty acid triglycerides, and glycols, and the content thereof is in the total amount of the preparation. 0.1~1
8. The formulation according to item 7 above, which contains 0% by weight.