JPH078784B2 - Hydrophilic transdermal preparation - Google Patents

Description

TECHNICAL FIELD The present invention relates to a hydrophilic transdermal preparation containing a transdermal drug.

[Prior Art] Conventionally, as a simple means for transdermal administration of drugs, tapes, plaster agents, gelatin, polyvinyl alcohol, polyacrylic acid containing a transdermal drug in a natural or synthetic rubber system, an acrylic system, etc. A poultice containing a water-soluble polymer such as a salt and a transdermal drug in water as a medium is widely used.

[Problems to be Solved by the Invention] However, the administration means using these tapes, plasters and poultices has the following problems.

1) Tape, plaster agent: a) Since heat and solvent are used as a manufacturing method, the content of drug,
There is a problem of heat deterioration of rubber and the like, and there is a problem of industrial pollution in the case of the solvent method.

b) Due to its high adhesive strength, it tends to pull hair during peeling, cause redness, touch, etc.

c) Since it is an oily base, it impairs skin respiration and causes contact with the skin.

2) Pap: a) Since the adhesive strength is weak, an auxiliary means for sticking to the skin is required. Further, since it contains water, it is difficult to control the adhesive strength with time.

b) Since it contains water, there is a problem in stable retention of the drug such as hydrolysis.

c) Since volatile acid water is used, it is difficult to control the dose of the drug contained in a trace amount.

Therefore, the appearance of an ideal patch that can satisfy the following characteristics is desired.

1. A physiologically safe administration means that is familiar to the skin.

2. With proper self-adhesiveness, elimination of physical factors such as feeling caused by excessive adhesion.

3. Obtained by a simple manufacturing method in terms of production efficiency, cost, pollution, etc.

4. Uses water-soluble polymer, maintains adhesive strength, stabilizes drug, and maintains dose control.

In view of the above points, the present invention has been intensively studied for the purpose of providing a hydrophilic transdermal preparation having these properties, and as a result, a transdermal preparation that can be constituted by eliminating the presence of water, The inventors have found that the above objects can be achieved and have completed the present invention.

[Means for Solving Problems] That is, the hydrophilic transdermal preparation of the present invention comprises a water-soluble polymer having a carboxyl group and / or a hydroxyl group and soluble in a polyhydric alcohol, a cross-linking agent thereof, and It is characterized in that it contains a percutaneously absorbable drug in a base containing a polyhydric alcohol, and is a substantially anhydrous transdermal preparation.

The water-soluble polymer used in the present invention has a carboxyl group and / or a hydroxyl group in its molecule and is soluble in a polyhydric alcohol, for example, methyl vinyl ether maleic anhydride copolymer, isobutylene- Examples thereof include maleic anhydride copolymers, carboxy-modified polyvinyl alcohol, carboxymethyl cellulose, and the like. Among them, methyl vinyl ether maleic anhydride copolymers and isobutylene maleic anhydride copolymers are particularly preferable.

As the cross-linking agent for the water-soluble polymer, those which act on the functional groups such as carboxyl group and hydroxyl group of the water-soluble polymer to make it cross-link insoluble, and conventionally known ones can be used. For example, a compound having at least two epoxy groups in the molecule, specifically polyethylene glycol diglycidyl ether, ethylene glycol diglycidyl ether, glycerin diglycidyl ether, glycerin triglycidyl ether, propylene glycol diglycidyl ether, glycerol polyglycidyl Examples include ether. Other cross-linking agents are polyvalent metal compounds, such as aluminum hydroxide, aluminum chloride, calcium hydroxide, calcium chloride, magnesium hydroxide, aluminum silicate, calcium phosphate, magnesium aluminate, aluminum glycinate, hydrotal. Site, potassium aluminum sulfate and the like.

The preferred amount of these cross-linking agents is 0.1 to 30 parts by weight, more preferably 1 to 10 parts by weight per 100 parts by weight of the water-soluble polymer.
Parts by weight. If the compounding amount of the cross-linking agent deviates from this range, there arises a problem that cohesiveness and shape retention are deteriorated or tackiness is lost and the composition becomes hard.

Further, as the polyhydric alcohol used in the present invention, ethylene glycol, diethylene glycol, triethylene glycol, polyethylene glycol, propylene glycol, polypropylene glycol, glycerin, 1,3
-Butylene glycol 1,4-butylene glycol and the like can be mentioned, and among them, glycerin, 1,3-butylene glycol and ethylene glycol are particularly preferable.

A preferred blending ratio (weight ratio) of the polyhydric alcohol and the water-soluble polymer is 10: 0.5 to 5.0, more preferably 10: 1.
2 to 2.5. If the compounding ratio of both deviates from this range,
There is a problem that shape retention and cohesive force are reduced, and workability is reduced.

As the base component of the hydrophilic transdermal preparation of the present invention, in addition to the essential components consisting of the above water-soluble polymer, its cross-linking agent and polyhydric alcohol, conventionally known antioxidants, softeners, tackifiers A suitable amount of compounding agents such as an agent, an antiaging agent, and an inorganic filler is appropriately mixed.

Further, the transdermal drug used in the present invention is not particularly limited, for example, salicylic acid, methyl salicylate, glycol salicylate, 1-menthol, camphor, peppermint oil, nicotinic acid benzyl ester, ibuprofen,
Piroxicam, ketoprofen, indomethacin, suprofen, loxoprofen, diclofenac sodium, flurbiprofen, and their ester derivatives, skin stimulants and analgesics, hydrocortisone acetate, dexamethasone, dexamethasone acetate, betamethasone acetate, betamethasone acetate, betamethasone valerate, prednisolone. , Corticosteroids such as fluocinonide and fluocinolone acetonide, local anesthetics such as ethyl aminobenzoate, procaine hydrochloride, lidocaine hydrochloride, propranolol hydrochloride, pindolol, carteolol hydrochloride,
Β-blockers such as timolol maleate, coronary vasodilators such as nitroglycerin, isosorbite nitrate, nifedipine, diltiazem hydrochloride and dipyridamole, bronchial asthma therapeutic agents such as procaterol, isoproterenol hydrochloride and theophylline, diphenhydramine hydrochloride, chlormaleate Phenylamine, antihistamines such as clemizole hydrochloride, salbutamol sulfate, procaterol hydrochloride, sodium cromoglycate, tranilast, antitussive expectorants such as ketotifen, antihypertensive agents such as clonidine, other antibacterial agents, prostaglandins, hormones, herbal extracts, etc. One or two or more of these medicinal components are appropriately mixed and used.

As the support of the transdermal preparation of the present invention, for example, a film or sheet of polyethylene, polypropylene, polybutadiene, ethylene vinyl acetate copolymer, polyvinyl chloride, polyester, nylon, polyurethane or the like, or a porous body or a foam thereof. Further, it is selected from paper, cloth, non-woven fabric and the like.

Next, the method for producing the transdermal preparation of the present invention may be a conventionally practiced method, but as an example thereof, after mixing and dissolving the polyhydric alcohol and the water-soluble polymer in a kneader, the drug contained And a cross-linking agent are added and dispersed evenly, and then spread directly onto a tape or sheet support.
Alternatively, it can be manufactured by spreading it on a paper, a film or the like that has been once subjected to a peeling treatment, and then pressure-bonding and transferring it to a support to be used.

[Examples] Hereinafter, the present invention will be described in more detail with reference to Examples and Test Examples.

Example 1 Isobutylene maleic anhydride copolymer (trade name; Isoban, manufactured by Kuraray Co., Ltd.) 18 parts by weight Glycerin 82 parts by weight was mixed with a matrix in a kneader at 60 ° C. for 40 minutes, and then 100 parts by weight of the above composition was added. On the other hand, 2.6 parts by weight of 1-menthol, 1.5 parts by weight of peppermint oil and 1.0 part by weight of dl-camphor were added and mixed, and then 1.4 parts by weight of ethylene glycol diglycidyl ether as a cross-linking agent were added and mixed, and then the nonwoven fabric had a thickness of 500 μm. And then cut into a desired size by covering with a release paper, and then a hydrophilic transdermal preparation (patch)
And

When this patch was applied, a good refreshing sensation was maintained, it adhered well without peeling during application, and there was no pulling of hair during peeling, redness after peeling, and no feeling.

Example 2 Methyl vinyl ether maleic anhydride copolymer (trade name; Gauntlet, GAF) 15 parts by weight 85 parts by weight of glycerin are mixed in a kneader at 60 ° C. for 30 minutes, and then the above composition is obtained.
To 100 parts by weight, 2.5 parts by weight of methyl salicylate and 2.5 parts by weight of l-menthol were added and mixed, and then 1.3 parts by weight of ethylene glycol diglycidyl ether as a cross-linking agent was added and mixed, so that the thickness of the nonwoven fabric was 500 μ. Then, it was covered with a release paper and cut into a desired size to give a hydrophilic transdermal preparation (patch).

When this patch was applied, a good refreshing sensation was maintained, it adhered well without peeling during application, and there was no pulling of hair during peeling, redness after peeling, and no feeling.

Example 3 Methyl vinyl ether maleic anhydride copolymer (trade name; Gauntlet, GAF Co.) 12 parts by weight 1,3-butylene glycol 88 parts by weight are mixed in a kneader at 50 ° C. for 40 minutes, and then the above composition is obtained.
To 100 parts by weight, 2 parts by weight of ketoprofen were added and mixed, and then 1.0 part by weight of aluminum hydroxide as a cross-linking agent was added and mixed, and then spread on a non-woven fabric so as to have a thickness of 300 μ, and further with release paper. It was covered and cut into a desired size to prepare a hydrophilic transdermal preparation.

Example 4 Isobutylene maleic anhydride copolymer (trade name: Isovan, manufactured by Kuraray Co., Ltd.) 22 parts by weight 78 parts by weight of glycerin are mixed at 55 ° C. for 40 minutes in a kneader, and then the above composition is obtained.
After adding and mixing 5 parts by weight of ketotifen to 100 parts by weight, and then adding and mixing 0.66 parts by weight of glycerol polyglycidyl ether as a cross-linking agent, spread it on a polyester film to 200 μm, and cover with release paper. It was cut into a desired size to prepare a hydrophilic transdermal preparation.

Example 5 Isobutylene maleic anhydride copolymer (trade name; Isovan, manufactured by Kuraray Co., Ltd.) 14 parts by weight 86 parts by weight of glycerin are mixed in a kneader at 50 ° C. for 35 minutes, and then the above composition is obtained.
Add and mix 8 parts by weight of clonidine to 100 parts by weight,
After that, 1.4 parts by weight of ethylene glycol diglycidyl ether as a cross-linking agent was added and mixed, then spread on a polyester film to a thickness of 100 μ, further covered with release paper and cut into a desired size, and hydrophilic transdermal administration It was made into a formulation.

Example 6 Methyl vinyl ether maleic anhydride copolymer (trade name; Gauntlet, manufactured by GAF) 20 parts by weight 80 parts by weight of glycerin are mixed in a kneader at 50 ° C. for 30 minutes, and then the above composition is obtained.
3 parts by weight of estradiol was added and mixed with 100 parts by weight, and then 1.8 parts by weight of alumina magnesium hydroxide was added and mixed as a cross-linking agent, and then spread on a polyester film to a thickness of 200 μ, and further release paper. And cut into a desired size to prepare a hydrophilic transdermal preparation.

Example 7 Methyl vinyl ether maleic anhydride copolymer (trade name; Gauntlet, manufactured by GAF) 15 parts by weight 85 parts by weight of glycerin are mixed in a kneader at 50 ° C. for 30 minutes, and then the above composition is obtained.
After adding and mixing 11.5 parts by weight of isosorbite nitrate to 100 parts by weight, and then adding and mixing 3 parts by weight of hydrotalcite as a cross-linking agent, a polyester film with a thickness of 15
It was spread to 0 μm, covered with release paper, and cut into a desired size to give a hydrophilic transdermal preparation.

Reference Example 1 Methyl vinyl ether maleic anhydride copolymer (trade name; Gauntlet, GAF) 15 parts by weight Glycerin 20 parts by weight Water 65 parts by weight are mixed in a kneader at 60 ° C. for 30 minutes, and then the above composition is obtained.
2.5 parts by weight of methyl salicylate was added to 100 parts by weight of the mixture, and then 1.3 parts by weight of ethylene glycol diglycidyl ether as a cross-linking agent was added and mixed.
The same process was carried out.

Reference Example 2 Isobutylene maleic anhydride copolymer (trade name; Isovan, manufactured by Kuraray Co., Ltd.) 14 parts by weight Glycerin 25 parts by weight Water 61 parts by weight are mixed in a kneader at 50 ° C. for 35 minutes, and then the above composition is obtained.
Add and mix 8 parts by weight of clonidine to 100 parts by weight,
After that, 1.4 parts by weight of ethylene glycol diglycidyl ether as a crosslinking agent was added and mixed, and then treated in the same manner as in Example 5.

Reference Example 3 Sodium polyacrylate 8 parts by weight Carboxyvinyl polymer 1.5 parts by weight Glycerin 20 parts by weight Water 70.5 parts by weight is mixed at 60 ° C., then clonidine 8 parts by weight is added to 100 parts by weight of the above composition, and then a crosslinking agent. Then, 1.1 parts by weight of aluminum hydroxide was added and mixed, and then treated in the same manner as in Example 5.

Test Example 1 Adhesion Test Using a tack tester (Picuma Tuck Tester, manufactured by Toyo Seiki Co., Ltd.), the patches of Examples 1-2 and a commercially available anti-inflammatory analgesic patch (Comparative Example 1: water-soluble polymer such as gelatin) Of water) was compared in adhesive strength. The results are shown in Table 1 below.

From Table 1, it is clear that the patches of Examples 1 and 2 have excellent adhesive strength as compared with the commercially available poultice of Comparative Example 1.

Test Example 2 Skin Irritation Test For 30 test subjects, three kinds of patches of Examples 1-2 and commercial anti-inflammatory analgesic tape (Comparative Example 2: Synthetic rubber tape) were applied to the back for 48 hours and after peeling. The degree of skin irritation was determined by observing the degree of skin change after 1 hour and 24 hours.

The results are shown in Table 2. The skin irritation criteria are as follows.

No change; -Weak redness; ± Clear redness; + Severe feel; As is clear from Table 2, the patches of Examples 1 and 2 are
Compared with the commercially available anti-inflammatory analgesic tape of Comparative Example 2, the expression rate of skin irritation is remarkably low, and the usefulness as a highly safe patch is sufficiently demonstrated.

Test Example 3 (Drug Stability Test, Dose Control Test) Using Example 2, Example 5, Reference Example 1, Reference Example 2 and Reference Example 3, a drug stability test and a dose control test were performed. The test method is as follows.

Was measured and expressed as a drug stability rate.

Was measured and expressed as a dose control rate.

The results are shown in Table 3.

As is clear from the above results, Example 2 containing no water
Compared to Reference Examples 1 to 3 containing water, due to the volatilization of water during production and the influence of water over time, Nos. 5 and 5 are very unstable in both the dose control rate and the drug residual rate. This proves its usefulness.

[Effects of the Invention] In the hydrophilic transdermal preparation of the present invention as described above,
The following effects are achieved.

1.Because it is a hydrophilic base, it is a physiologically safe administration means that is familiar to the skin.

2.Because of proper self-adhesiveness, there is no occurrence of contact due to physical factors such as hair pulling and exfoliation of keratin.

3. Obtained by a manufacturing method that is fully satisfactory from the viewpoints of production efficiency, cost, pollution, etc.

4. Since water-soluble polymer is used and no water is used, sufficient maintenance of adhesive strength, stabilization of drug and dose control can be achieved.

Therefore, the hydrophilic transdermal preparation of the present invention can be used in a wide variety of applications.

Claims (1)

[Claims] 1. A water-soluble polymer having a carboxyl group and / or a hydroxyl group and soluble in a polyhydric alcohol, and a base containing the crosslinking agent and the polyhydric alcohol,
A substantially anhydrous hydrophilic transdermal preparation, which comprises a transdermal drug.