JPS59175419A - Drug for external application - Google Patents

Abstract

PURPOSE:To prepare an external drug having excellent adhesivity, by laminating a carrier substrate layer to a sticking layer obtained by adding a drug component to a polymer composition prepared by the addition polymerization of an acrylic polymer having stickiness at normal temperature to a polymer derived from a hydrophilic unsaturated monomer. CONSTITUTION:A polymer composition obtained by the addition polymerization of (A) an acrylic polymer having stickiness at normal temperaure to (B) a polymer having a glass transition temperature of >=273 deg.K and prepared by the (co)polymerization of a monomer mixture containing a hydrophilic unsaturated monomer (e.g. vinyl acetate, acrylic acid, 2-methoxyethyl acrylate, etc.), is laminated with a carrier substrate to obtain the objective external drug. Since the external drug has high internal cohesivity, it is not necessary to apply a crosslinking treatment even in the case of adding a large amount of an agent to promote the release of the drug, and the diffusion of the drug can be performed smoothly when the hydrophilic part of the stem polymer is swollen with sweat, etc.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to an external member that is applied directly to a part of the body in order to treat a diseased part of the body or administer a drug to the circulatory system.

Conventionally, this type of externally used member has been known to have a layer of a polymer material that is sticky at room temperature and contains a drug dissolved therein, laminated on a carrier such as a plastic film or nonwoven fabric. Since the drug is dissolved and incorporated into the polymer material layer, the drug does not transfer sufficiently to the skin surface to which it is applied, resulting in poor drug release properties and failure to obtain the desired pharmacological effect.

For this reason, attempts have been made to incorporate polyethylene glycol, liquid paraffin, phthalate ester plasticizers, and the like into the polymer material layer as release aid substances that promote drug transfer and skin absorption.

However, these release aids require the addition of large amounts [
- If not, not only will sufficient effects not be achieved, but addition will also exhibit a plasticizing effect, resulting in a decrease in the cohesive force of the adhesive polymer material layer. For this reason, when using the patch, adhesive polymeric substances may remain on the release paper when the release paper is peeled off, and adhesive polymeric substances may remain on the skin surface of the patient when it is applied to the body and then peeled off. remain,
The so-called adhesive residue phenomenon may occur, or when using the adhesive,
This method has disadvantages in that the adhesive polymeric substance protrudes from the side surface of the external member, causing contamination.

Furthermore, in order to avoid the lack of cohesive force of adhesive polymer substances as shown above, chemical crosslinking methods using crosslinking agents such as phenol resin-melamine resin, ynoneanate compounds, epoxy compounds, metal ions, etc., and r-ray Various radiation crosslinking methods using electron beams and the like have been attempted. However, in this case, there may be reactions between each reagent and drug, decomposition of the drug due to heating for crosslinking reactions, decomposition of the drug due to radiation, and poor skin adhesion due to improved cohesive force. Furthermore, considering these factors, it is troublesome to select the type and amount of crosslinking agent to be used and the radiation dose, leaving problems in terms of quality and productivity.

As a result of extensive research from this perspective, the present inventors have developed an acrylic polymer that has a glass transition temperature (Tf) of 273 or more and is sticky at room temperature to a polymer of a specific unsaturated monomer. The addition polymer composition obtained by addition polymerizing improves the release properties of the drug, and the addition of a relatively large number of release auxiliary substances 1. However, we have discovered that an acrylic polymer with high cohesive strength can be obtained without using any crosslinking agent.

That is, the present invention uses a polymer having a Tf of 273° or more obtained by polymerizing or copolymerizing an unsaturated monomer blend containing at least one type of unsaturated monomer having hydrophilic properties to an acrylic material having adhesiveness at room temperature. The present invention provides an external member comprising a support layer and an adhesive layer formed by adding a drug to an addition polymer composition obtained by addition polymerization of a system polymer.

According to the external member of the present invention, the ring polymer and 1. Since a polymer of unsaturated monomers with a TI of 273 or more is used, it gives the adhesive layer itself a high internal cohesive force and also contains a relatively large amount in the adhesive layer containing the polymer. Even if a phase release auxiliary substance is added, there is little decrease in cohesive force due to the plasticizing effect, resulting in poor quality.I- In terms of production, adhesive residue and glue extrusion do not occur even without performing crosslinking treatment, which requires intermittent cross-linking. issues such as this will be resolved.

The acrylic polymer that is added has good adhesion to the skin because it is sticky at room temperature, and because it is hydrophobic, it also has good adhesion to multi-lipid areas, preventing it from falling off or peeling off when applied. Does not occur. Therefore, the drug is sufficiently supplied to the skin surface of the body, and the desired pharmacological effect can be obtained.

Furthermore, since a polymer of unsaturated monomers having hydrophilic properties is used in the ring polymer, when this external member is applied to the skin surface of the body, moisture such as sweat is supplied and the ring polymer becomes hydrophilic. The sexual part swells, and this swelling facilitates drug diffusion and promotes drug supply.

Examples of the carrier used in the present invention include various plastic films, nonwoven fabrics, woven fabrics, metal foils, and laminated films of these and plastic films.

The unsaturated monomer having hydrophilicity that can give the polymer TI of 273 or more to be used in the present invention can be arbitrarily selected from commonly used monomers, but particularly preferred ones include: Vinyl acetate, dimethylaminoethyl acrylate, 2-methoxyethyl methacrylate, dimethylaminoethyl methacrylate, N-methylolacrylamide F%N-N-dimethylacrylamide, etc., and acrylic acid, methacrylic acid, itaconic acid, etc. 2-hydroxyethyl acrylate, 2-methoxyethyl acrylate, 2-methoxypropyl acrylate, etc. (all of which have a homopolymer TI of 273 or more), 2-hydroxyethyl acrylate, 2-methoxyethyl acrylate, 2-methoxypropyl acrylate, etc.
3). All of these have hydrophilic properties, and the TI of the homopolymer is 273.
If the TV of the homopolymer is lower than 2730, the Tf of the copolymer is 273 or higher by combining with 273 or higher. It is used at a ratio of

In the copolymer system, it is necessary to use at least one unsaturated monomer having hydrophilic properties. If the glass transition temperature of the copolymer is lower than 273, it will not be possible to obtain a material for external use with high cohesive strength.

Furthermore, although each of the monomers exemplified above all have hydrophilic properties, it is also possible to combine monomers such as the above examples that have hydrophilic properties with monomers that do not have wood-philic properties. In short, it is sufficient that the copolymer has a TI of 273° or more. Examples of unsaturated monomers that do not have hydrophilicity include styrene and the ah form of histo, acrylonitrile, methacrylonitrile, vinyl acetate, acrylic acid alkyl ester,
Examples include methacrylic acid alkyl esters.

In the present invention, any acrylic polymer that is adhesive at room temperature may be used as long as it is conventionally known as a base polymer for acrylic adhesives.

Generally, an ester of acrylic acid and an alcohol having 12 or less carbon atoms is used as the main monomer, a modifying monomer is added to this, and a homopolymer or copolymer of the unsaturated monomer is added. The desired addition polymer is obtained by post-polymerization. Examples of the above-mentioned modifying monomer include vinyl chloride,
Vinyl acetate, propion-vinyl, mono- or diester of maleic acid, acrylic acid, methacrylic acid, crotonic acid, maleic acid, itaconic acid, 2-hydroxyethyl acrylate, 2-hydroxypropyl acrylate, e2-hyfuroxyethyl methacrylate, N-N-dimethylaminoethyl acrylate, N-N-dimethylaminoethyl methacrylate, N-tert-butylaminoethyl acrylate, bis(N-N-dimethylaminoethyl)
Marpit.

Examples include acrylamide, methacrylamide, N-methylol acrylamide, and glycidyl acrylate.

In the present invention, the addition polymerization initiation reaction of acrylic monomers as described above can be carried out using energy such as light or electron beams, but it is usually better to carry out using a general radical polymerization initiator.

Such initiators include azo compounds and various organic peroxides.

Examples of azo compounds include azobisisobutyronitrile and azobisdimethylvaleronitrile, and examples of organic peroxides include benzoyl peroxide, cumene high F lobar oxide, di-tert-butyl peroxide, tert-butyl peroxybenzoate, Lafroyl peroxide, ketone peroxide, tert-
Examples include butyl peroxy 2-ethylhexanoate, methyl ethyl ketone peroxide, and cyclohexanone peroxide. The amount of polymerization initiators such as these azo compounds and organic peroxides to be used is 0 to 1 to 5, preferably 0.05 to 5, based on the acrylic monomer.
The amount may be about 3% by weight.

The addition polymer composition obtained by the above method has excellent skin adhesion and high internal cohesive strength, and has both hydrophobic and hydrophilic properties, so it has excellent drug dissolution ability. When mixed with a drug and applied to the skin surface of the body, it promotes the diffusion of the drug and ensures sufficient transfer to the skin surface.

The drugs used in the present invention are those that can be dissolved in the adhesive addition polymer composition and transferred to or absorbed into the body, such as corticosteroids, anesthetics,
antihistamines, antibacterial substances, antifungal agents, analgesic anti-inflammatory agents,
These include keratin softeners, vitamins, antispasmodics, etc., as well as antihypertensive agents, antibiotics, central nervous system agents, vasodilators, sedatives, antispasmodics, sex hormones, and antidiabetic agents. . The appropriate amount of these drugs is selected to obtain the desired treatment or administration effect depending on the type of drug.

To give specific examples, examples of corticosteroids include prezonisolone acetate, prezonisolone, hydrocortide acetate, hydrocortide, dexamethacin, fluocinolone acetonide, petamethasone, beclomethasone propionate, fludroxycortide, fluocinonide, and the like. Anesthetics include pensicaine, lidocaine, and ethyl aminobenzoate; antihistamines include diphenhydramine hydrochloride, isocybenzyl hydrochloride, and diphenylimidazole; antibacterial agents include penzarconicum chloride and nitrofurazone; and antifungal agents include pensarconicum chloride and nitrofurazone. Examples of analgesic and anti-inflammatory agents include indomethacin, diclofenacunatrichum, flurbibro-7ene, methyl salicylate, glycol salicylate, salicylic acid amide, and sodium salicylate.

In addition, salicylic acid, vitamin A1 atropine, scopolamine hydrobromide, scopolamine, and the like can be mentioned as keratin softeners, vitamins, and anti-inflammatory agents. Furthermore, antihypertensive agents such as reserpine and clonidine as systemic adjuvants, -c! Antibiotics such as icin, chloramphenicol, cephalexin, tetracycline, neomycin sulfate, oxytetracycline, penicillin, central nervous system agents such as palpyrate, diazepam, nitrazebam, flunitrazebam, chlorpromazine, nitroglycerin, isosorbite Examples include vasodilators such as cinitrate and nifedipine.

Next, the release assisting substance used in the present invention can be simply defined as one that promotes the release of the drug to the body surface, but this includes the solubility and diffusion of the drug within the polymer material layer. Things that have the function of improving sexual performance, as well as the ability to retain water in the stratum corneum, soften the stratum corneum, permeate the stratum corneum (loosening it), act as penetration aids and pore-stretching agents, and change the interface condition of the skin. Those that have functions that improve transdermal absorption, those that have both of the above functions, or those that have functions that enhance the pharmacological effects of drugs in addition to these functions.
k! , '& also includes a wide range of expressions such as 1-.

Specific examples and 12 of these substances that assist release include t
Glycols such as diethylene glycol, propylene glycol, and polyethylene glycol (mainly drug-soluble), oils and fats such as olive oil, squalene, and lanolin (mainly drug-diffusing), urea, and fine urea derivatives such as allantoin (mainly water-retaining in stratum corneum) dimethyldecyl phosphooxide, methyl octyl sulfoxide, dimethyl lacrylamide, dodecyl pyrrolidone, isosorbitol dimethyl acetamide, dimethyl sulfoxide, dimethyl formamide and other polar solvents (mainly permeable to the stratum corneum), salicylic acid (mainly permeable to the stratum corneum), softening property), Ami7e (mainly penetration aid)
, benzyl nicotinate (mainly used as a hand pore opener), sodium lauryl sulfate (mainly used to change the surface texture of the skin), and Saroful (used in combination with drugs that have good transdermal absorption). Other plasticizers such as diisofluoride adipate, heptatarate, diethyl sebacate, hydrocarbons such as liquid paraffin, various emulsifiers, ethoxylated stearyl alcohol, higher ester ethers of glycerin, isopropyl myristate, ethyl raffinate, etc. can be mentioned.

The content of the above-mentioned release auxiliary substance is generally 3 to 5 % of the entire adhesive layer.
It can be about 0% by weight. Even when such a large amount is used, no significant decrease in the cohesive force of the drug-containing adhesive layer is observed. However, if this amount is too large, the cohesive force will be extremely reduced, the pharmacological effect will not be significantly improved, and there is a risk that the adhesion will fail.

The external member of the present invention is prepared by dissolving and mixing the above-mentioned addition polymer composition, drug and, if necessary, a release aid in an appropriate σ) solvent, and then blending the mixture with other optional components if necessary. A drug-containing adhesive layer is applied on one or both sides of the carrier to form a drug-containing adhesive layer on the carrier. It is formed by providing ν.

According to this external member, as already mentioned, pharmacological effects can be exhibited significantly without any glue cutting or other blanks occurring during pasting and use.

The present invention will be explained in more detail below with reference to Examples, but the present invention is not limited to these examples, and various modifications can be made without departing from the technical idea of the present invention. In the Examples, "part" means heavy odor, and the retention power, effective blood concentration, drug solubility, and adhesive residue were measured by the following method.

<Holding force> A test piece with a length of 1 cm and a width of 10 on 77') was prepared from each external member, and this was pasted on a Bakelite plate with a length of 2 wt., a load of 300 F was applied in the shear direction, and a test piece of 40 The time taken for cohesive failure to fall was measured in a constant temperature chamber at ℃.

Effective blood concentration〉 A test piece of 4 mm x 4 m was prepared from each external use member, and this was pasted on the hair removal site on the back of all cynomolgus monkeys, and after 2 hours,
Five liters of blood was collected from the arm. Extract this blood by shaking with an organic solvent 1. After drying, it was dissolved in methanol and quantitatively determined by gas chromatography. At the same time, a comparison was made with the case of oral administration.

<Drug solubility> After storing the external use members shown in each example at room temperature for one month, the adhesive surface was observed under a microscope. The presence or absence of precipitation of drug crystals was investigated.

Adhesive Remaining> For each external member, it was determined whether or not any adhesive remained on the release sheet when the release sheet was removed from the adhesive surface during use. Furthermore, it was determined whether or not there was any adhesive residue on the skin surface when the adhesive was applied to the side of the upper arm and removed 24 hours later.

Example 1 50 parts of 2-methoxyethyl acrylate, 1 part of acrylic acid
A monomer mixture consisting of 0 parts was polymerized in ethyl acetate in the presence of 0.2 parts of azobisisobutyronitrile at an elevated temperature of 60°C to obtain a copolymer.

To 100 parts of the obtained copolymer, 200 parts of 2-ethylhexyl acrylate, 10 parts of acrylic acid, and 5 parts of benzoyl peroxide were added, and the temperature was raised to 70°C to carry out post-addition addition polymerization. A polymer composition was obtained. 20 parts of olive oil, 20 parts of dimethyl sulfoxide, and 3 parts of scopolamine hydrobromide were mixed with 100 parts of the addition polymer composition obtained by Icl-coating as described above, and the mixture was coated on the surface of a polyethylene film to a thickness of 100 μm and dried to form a drug-containing mixture. A member for external use was obtained.

The retention strength of the obtained Yukou member was 420 minutes, and no adhesive residue was observed on the release sheet or on the skin surface to which it was applied. Furthermore, the drug amount reached an effective blood concentration of 1, the drug solubility was good, and no crystal precipitation was observed.

Example 2 0.0 parts of azobisisobutyronitrile was added to 100 parts of vinyl acetate.
Three parts of the mixture were added and polymerized in toluene at a temperature of 60° C. to obtain homopolymer (1).

To 100 parts of the obtained homopolymer, 150 parts of isononyl acrylate, 5 parts of acrylic acid, and 2 parts of azobisisobutyronitrile were added, and the temperature was raised to 60°C to perform post-addition addition polymerization. A polymer composition was obtained. 100 parts of the addition polymer composition thus obtained were mixed with 30 parts of polyethylene glyco-I C60 (1 (molecular weight: about 600)) and 0.5 parts of fluorenonide, and 50 μm f$ vC was applied to the surface of the polyester film. It was dried to obtain a drug-containing member for external use.

The resulting external member had a retention strength of 690 minutes, and no adhesive remained on the release sheet or the skin surface to which it was applied. Furthermore, the drug reached an effective blood concentration, exhibited sufficient pharmacological effects, had good drug solubility, and no crystal precipitation was observed.

patent applicant Nitto Electric Industry Co., Ltd. Representative Sanbe Hijikata

Claims (1)

[Claims] An acrylic polymer that is sticky at room temperature is added to a polymer having a glass transition temperature of 273 or higher, which is obtained by polymerizing or copolymerizing an unsaturated monomer blend containing at least one type of unsaturated monomer having hydrophilic properties. An external member comprising a support layer and an adhesive layer containing a drug in an addition polymer composition subjected to addition polymerization.