JP3132837B2 - Medical adhesive - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a medical pressure-sensitive adhesive for transdermal or transmucosal administration of a drug using a blend polymer of a vinylpyrrolidone (co) polymer and a (meth) acrylic acid copolymer. More specifically, the release of the drug from the pressure-sensitive adhesive layer is effectively performed, the skin irritation is alleviated, the application for a long time is possible, and the adhesion and application properties are sharp even after repeated use. It relates to a medical adhesive that does not decrease.

[0002]

2. Description of the Related Art Conventionally, various acrylic adhesives and rubber adhesives have been widely used as medical adhesives for transdermal or transmucosal administration of drugs. However, these adhesives have strong adhesiveness to the skin, and when peeled off from the skin, they may peel off a part of the stratum corneum of the skin and cause damage, or may be a major cause of skin irritation. There were many. In addition, components constituting the pressure-sensitive adhesive often act directly on the skin to cause skin irritation.

[0003]

SUMMARY OF THE INVENTION The present invention solves the drawbacks of the conventional medical pressure-sensitive adhesives, and has as its object to absorb drugs transdermally and transmucosally from the pressure-sensitive adhesive. Can be used as a medical adhesive, the adhesive component itself has no skin irritating action, and can be applied to the skin surface for a long time without causing peeling, and peels from the skin An object of the present invention is to provide a medical adhesive that does not damage the stratum corneum at the time.

[0004]

The medical pressure-sensitive adhesive of the present invention comprises a blend polymer of a vinylpyrrolidone (co) polymer and a (meth) acrylic acid copolymer, a pharmaceutically acceptable softener and a carboxylic acid. Having two or three groups
It contains a weakly basic organic carboxylate as a main component, thereby achieving the above object. That is, the pressure-sensitive adhesive (pressure-sensitive adhesive component I) composed of a vinylpyrrolidone (co) polymer and a softening agent has no irritancy due to the component itself, and since the polymer is hydrophilic, the adhesiveness to the skin is too strong. And does not cause a phenomenon such as exfoliation of the stratum corneum. However, it is not preferable as a medical pressure-sensitive adhesive because of its low internal cohesive force, adhesive remaining on the skin at the time of peeling, and poor water resistance. The present inventors blended a (meth) acrylic acid copolymer with the pressure-sensitive adhesive component I,
Weakly basic organic having two or three carboxyl groups
It has been found that the addition of the carboxylate increases internal cohesion and moisture resistance while retaining the excellent properties of the pressure-sensitive adhesive component I, that is, good sticking property to the skin and non-irritating property to the skin, The present invention has been accomplished.

Vinylpyrrolidone (co) polymer The vinylpyrrolidone (co) polymer includes, for example,
Vinylpyrrolidone homopolymer, or one or more of vinylpyrrolidone and (meth) acrylic acid, methyl (meth) acrylate, ethyl (meth) acrylate, maleic anhydride, vinyl alcohol or vinyl acetate And a copolymer of Such vinylpyrrolidone (co) polymers include water and / or
Alternatively, it must be soluble in alcohol, and must have tackiness even if the internal cohesion is weakened by adding a softener. Further, the content of vinylpyrrolidone in the copolymer is determined so as to maintain excellent properties as the adhesive component I, that is, good sticking property to the skin and non-irritating property to the skin, and (meth) acrylic acid. 70 mol% or more, preferably 9 mol%, in order to increase internal cohesion and moisture resistance by blending the copolymer.
0 mol% or more is preferable.

(Meth) acrylic acid copolymer The above (meth) acrylic acid copolymer is, for example, one or two or more (meth) acrylic acids (salts) such as acrylic acid or methacrylic acid, and vinyl Alcohol, vinyl acetate, vinylpyrrolidone, maleic anhydride, methyl (meth) acrylate, ethyl (meth) acrylate,
Butyl (meth) acrylate, (meth) acrylic acid-2-
Copolymers with one or more monomers having no free carboxylic acid in the molecule, such as ethylhexyl, dimethylaminoethyl (meth) acrylate, and trimethylammonium ethyl (meth) acrylate are exemplified.
The (meth) acrylic acid copolymer is a copolymer containing 5 mol% to 90 mol% of (meth) acrylic acid. If the content of the (meth) acrylic acid is less than 5 mol%, the effect of increasing the internal cohesive force and moisture resistance of the pressure-sensitive adhesive cannot be obtained. Since it is difficult to obtain an agent, 5 mol% to 90 mol% is a preferable range, and furthermore, 20 mol% to 80 mol% is more preferable. The reason why the internal cohesive force and the water resistance of the pressure-sensitive adhesive of the present invention are remarkably enhanced by the addition of the (meth) acrylic acid copolymer is not specifically understood, but the carboxylic acid of the (meth) acrylic acid copolymer and It is thought that this is due to unexpected interaction with the pyrrolidone ring of the vinylpyrrolidone (co) polymer. Therefore, in order to obtain a desired effect by the addition of the (meth) acrylic acid copolymer, the (meth) acrylic acid copolymer does not need to exhibit tackiness by the addition of a softening agent, but the vinylpyrrolidone ( In order for the (co) polymer and the (meth) acrylic acid copolymer to interact, both must be compatible in the compounding solution and are soluble in water and / or alcohol having a pH of 4 or more. It is preferred that It is also possible to use a copolymer salt obtained by adding a monovalent or divalent metal salt to the copolymer as necessary and neutralizing the copolymer.

[0007] mixing ratio The content of (meth) acrylic acid copolymer in the blend polymer is not obtained the effect of increasing the internal cohesion and moisture resistance is less than 1 wt%, it exceeds 30 wt% polyvinyl Since the pyrrolidone (co) polymer loses the above-mentioned excellent properties, the range of 1 to 30% by weight is preferable, and the range of 5 to 25% by weight is more preferable.

Having two or three carboxyl groups
Weakly basic organic carboxylate As the weakly basic organic carboxylate having two or three carboxyl groups , for example, fumaric acid, maleic acid, citric acid, sodium salt, potassium salt of phthalic acid,
Calcium salts and the like. As these properties, 1
The pH of the aqueous solution is preferably in the range of 7 to 9. The amount added to 100 parts by weight of the blend polymer is from 0.1 to 20 parts by weight, preferably from 1 to 10 parts by weight.
If the amount exceeds the weight part, the adhesive becomes supersaturated, and crystal precipitation and the like easily occur.

[0009] As the softener softening agents are formulated in order to soften the polymer blend, for example, polyhydric alcohols, high boiling compounds, such as polyhydric alcohol derivative is preferable. Specifically, ethylene glycol, propylene glycol,
Examples include dipropylene glycol, polyethylene glycol, glycerin and the like. The amount of the softening agent added to 100 parts by weight of the blended polymer is 20 to 500 parts by weight, preferably 50 to 300 parts by weight.
If the amount is less than part by weight, the softening effect is not sufficient. If the amount is more than 500 parts by weight, bleed out from the polymer is liable to occur.

Drug The drug contained in the medical pressure-sensitive adhesive of the present invention is not particularly limited as long as it is a drug having transdermal absorbability, and one or two or more kinds may be appropriately compounded as necessary. Can be used. As the drug, that is, a medicinal component, for example, antipyretic analgesic analgesic, analgesic, steroidal anti-inflammatory drug, vasodilator, hypertension / arrhythmic agent, antihypertensive agent, antitussive expectorant, local anesthetic, hormonal agent, Asthma / nasal allergy treatment, antihistamine, anticoagulant, antispasmodic, cerebral circulation / metabolism improving agent, antidepressant / antianxiety agent, vitamin D preparation, oral hypoglycemic agent, anti-ulcer agent, sleeping pill, antibiotic, etc. No. Antipyretic anti-inflammatory analgesics include indomethacin, salicylic acid, aspirin, acetaminophen,
Examples include diclofenac sodium, ibuprofen, sulindac, naproxen, ketoprofen, flufenamic acid, ibfenac, fenbufen, alclofenac, phenylbutazone, mefenamic acid, piroxicam, flurbiprofen, bendazac and the like. Examples of the analgesic include pentazocine, buprenorphine hydrochloride, eptazosin hydrobromide, butorphanol tartrate and the like. Steroidal anti-inflammatory drugs include hydrocortisone, prednisolone, phlocinolone acetonide, phloxycortide, methylprednisolone,
Hydrocortisone acetate, triamcinolone acetonide,
Dexamethasone, hetamethasone acetate, diflucortron valerate, propionclohetazole, fluocinonide and the like can be mentioned. Examples of the vasodilator include diltiazem, verapamil, pentaerythritol tetranitrate, dipyridamole, isosorbide dinitrate, nifedipine, nitroglycene and the like. Examples of agents for hypertension and arrhythmia include propanolol, atenolol, pindolol, quinidine sulfate, adimarin, alprenolol hydrochloride, metoprolol tartrate, nadolol, timolol maleate, disopyramide and the like. Examples of antihypertensive agents include clonidine hydrochloride, captoril, prazosin hydrochloride, benbutrol sulfate, guanabenz acetate, guanfacine hydrochloride, guanabenz acetate, punazosin hydrochloride, elanapril maleate, alotinolol hydrochloride, bunitrol hydrochloride and the like. Examples of the antitussive expectorant include procaterol hydrochloride, terbutaline sulfate, fenoterol hydrobromide, tulobuterol hydrochloride, ambroxol hydrochloride, pyrobuterol hydrochloride, mabuterol hydrochloride, clenbuterol hydrochloride, trimethoquinol hydrochloride, formoterol fumarate and the like. 5-fluorouracil, 1-
(2-tetrahydrofuryl) -5-fluorouracil,
Mitomycin C and the like. Examples of the local anesthetic include benzocaine, procaine, lidocaine, tetracaine and the like. Hormonal agents include steroid hormones such as estrogen, estradiol, testosterone, progesterone, and prostaglandin; and peptide hormones such as insulin. Examples of the therapeutic agent for asthma and nasal allergy include ketotifen fumarate, azelastine hydrochloride, sodium cromoglycate and the like. Examples of the antihistamine include cycloheptadine hydrochloride, diphenhydramine hydrochloride, fenbenzamine, mequitazine and the like. Anticoagulants include heparin and the like. Antispasmodics include scopolamine, clofluperol and the like. Examples of the cerebral circulation metabolism improving agent include pinpocetine, flunadiline hydrochloride, nicardipine hydrochloride, brovincamine fumarate, dihydroergotoxin mesylate, ifenprodil tartrate, isoxsuprine hydrochloride and the like. Examples of the antidepressant / anxiolytic include maprotiline hydrochloride, etizolam, diazepam, bromazepam, amitriptyline hydrochloride, mianserin hydrochloride and the like. Vitamin D
Examples of the agent include α-calcidol, ergocasiferol and the like. Oral hypoglycemic agents include glibenclamide, gliclazide and the like. Examples of the anti-ulcer agent include grepobride malate, famotidine, glycopyrronium bromide and the like. Hypnotics include fanobarbital, amobarbital and the like. Examples of antibiotics include tetracycline and chloramphenicol. The amount of these drugs varies depending on the type of the drug, the purpose of use of the patch, and the like, but is usually contained in the adhesive in a ratio of 0.1 to 40% by weight. In addition, if necessary, an absorption enhancer that enhances the absorption of the drug, a skin irritation reducing agent that reduces irritation to the skin, a stabilizer that stabilizes the drug, and an excipient, if necessary, are added. And in that case, it is included in a patch using the pressure-sensitive adhesive of the present invention.

Production of Patch The patch using the medical pressure-sensitive adhesive of the present invention can be produced according to a usual method for producing a pressure-sensitive adhesive tape. For example, various coating methods such as a solution coating method, a hot melt coating method, and an emulsion coating method are employed. In particular, a solvent coating method is preferably used. In order to form the pressure-sensitive adhesive layer by the solvent coating method, for example, a pressure-sensitive adhesive solution of an appropriate solvent is applied to the surface of the support and dried. For coating, a coater such as a roll coater or a blade coater is used. Instead of applying the solution directly to the surface of the support, the solution may be applied to a release paper coated with a silicone resin or the like, and dried, and then brought into close contact with the support. Such a release paper is used to protect the surface of the adhesive layer of the patch until use. In a coating method other than the solvent coating method, it is recommended to arrange a release paper after the formation of the pressure-sensitive adhesive layer to protect the surface of the pressure-sensitive adhesive layer. The thickness of the pressure-sensitive adhesive layer of the patch varies depending on the use, but is usually 10 to 3000 µm. If it is less than 10 μm, the required amount of drug cannot be contained, and the adhesiveness is insufficient. If it exceeds 3000 μm, the drug contained in the pressure-sensitive adhesive layer near the support is not sufficiently diffused, and the drug release property is reduced.

[0012]

The medical pressure-sensitive adhesive of the present invention is constituted as described above and has a relatively low affinity for the skin because it is hydrophilic. Therefore, when peeling off the patch, the phenomenon of peeling off the stratum corneum or tearing off the hair on the surface is unlikely to occur, and therefore, there is little irritation to the skin and rash on the skin also occurs. hard. Further, since the pressure-sensitive adhesive layer is flexible, it can adhere to the skin surface and follow the expansion and contraction of the skin without difficulty, even though the affinity is low, so that the pressure-sensitive adhesive layer does not easily peel off from the skin surface. In addition, only the pressure-sensitive adhesive component I has low water resistance and internal cohesion, and when used as a patch, the composition of the pressure-sensitive adhesive layer protrudes to the outside of the support during sticking or the patch was peeled off. Sometimes the adhesive composition remained on the skin. On the other hand, the medical pressure-sensitive adhesive of the present invention is obtained by blending a (meth) acrylic acid copolymer with the pressure-sensitive adhesive component I and further having two or three carboxyl groups.
By adding a weakly basic organic carboxylate , the internal properties of the pressure-sensitive adhesive component I, that is, good cohesive strength and moisture resistance, while maintaining good adhesion to the skin and non-irritating properties to the skin are maintained. Has been raised. In addition, since the vinylpyrrolidone (co) polymer remains swollen by the softener and the internal cohesion and moisture resistance are enhanced, the drug can easily move through the adhesive base and is effective. Is released into the skin and absorbed percutaneously.

[0013]

DESCRIPTION OF THE PREFERRED EMBODIMENTS The present invention will be specifically described below with reference to examples and comparative examples. Example 1 Vinylpyrrolidone homopolymer (manufactured by BASF, Kollidon 3)
0) 75 parts by weight were uniformly dissolved in 200 parts by weight of ethanol to obtain a solution I. 25 parts by weight of methacrylic acid-ethyl acrylate copolymer [Euidragit L100-55 (methacrylic acid content 38-52%) manufactured by Rohm Pharma Co.] was dissolved in 50 parts by weight of ethanol to obtain a solution II. Solutions I and II above
And 250 parts by weight of polyethylene glycol 600 (manufactured by NOF CORPORATION, standard outside Japan) to obtain a colorless and transparent pressure-sensitive adhesive solution. 3N citric acid in this adhesive solution
a 10% aqueous solution of a was reduced to 5%
And a 5% ethanol solution of isosorbide dinitrate is added so that the isosorbide dinitrate in the adhesive becomes 10%, and the mixture is uniformly mixed with a dissolver.
Was adjusted to be an ethanol solution. This ethanol solution was applied on a surface silicone-treated polyethylene terephthalate (PET) release paper so that the thickness after drying became 100 μm, and dried at 60 ° C. for 1 hour to form an adhesive layer. A PET / ethylene-vinyl acetate copolymer (EVA) laminate film was adhered to this to obtain a patch of Example 1.

COMPARATIVE EXAMPLE 1 40 parts by weight of 2-ethylhexyl acrylate, 30 parts by weight of 2-ethylhexyl methacrylate and 30 parts by weight of butyl acrylate were used as a solvent, and lauroyl peroxide was used as a polymerization catalyst. .25 parts by weight, polymerization was carried out at 60 ° C., and the weight average molecular weight was 6.5 × 1.
0 ⁵ to give a solid content of 54% adhesive solution. To this adhesive solution, a 10% ethyl acetate solution of isosorbite nitrate is added so that the concentration of isosorbite nitrate in the adhesive becomes 15%, and the mixture is uniformly mixed with a dissolver, and adjusted to become an ethyl acetate solution having a nonvolatile content of about 30%. did. This ethyl acetate solution was applied on a surface-silicone-treated PET release paper so that the thickness after drying became 100 μm, and dried at 60 ° C. for 30 minutes to form an adhesive layer. A PE / EVA laminate film was bonded to this to obtain a patch of Comparative Example 1. Comparative Example 2 Using ethyl acetate as a solvent with 5 parts by weight of acrylic acid, 95 parts by weight of 2-hexyl acrylate and 0.02 parts by weight of hexanediol dimethacrylate, 0.25 parts by weight of lauroyl peroxide was used as a polymerization catalyst. Plus 60
Polymerization was carried out at a temperature of about 0 ° C. to obtain an adhesive solution having a weight average molecular weight of 1.05 × 10 ⁶ and a solid content of 58%. To this adhesive solution, a 10% solution of indomethacin in ethyl acetate was added so that the concentration of indomethacin in the adhesive was 10%, and the mixture was uniformly mixed with a dissolver to prepare an ethyl acetate solution having a nonvolatile content of about 30%. This ethyl acetate solution was applied on a surface-silicone-treated PET release paper so that the thickness after drying became 70 μm, and dried at 60 ° C. for 30 minutes to form an adhesive layer. A PE / EVA laminate film was bonded to this to obtain a patch of Comparative Example 2.

Each of the patches obtained in Example 1 and Comparative Examples 1 and 2 was subjected to a drug migration test to rabbits by the method shown in Experiment 1. Experiment 1 A patch test piece (area 10 cm ² ) was attached to the depilated back and abdomen of a rabbit (White New Zealand), and after 24 hours, the patch was peeled off and collected. The number of repetitions was four for each patch. In Example 1, these test pieces were extracted with ethyl acetate, and the remaining amount of each drug in the patch was measured by high performance liquid chromatography. The difference between the amount of drug in each patch before the test and the amount remaining after the test was defined as the amount of skin transfer for 24 hours. Comparative Example 1,
With respect to 2, these test pieces were subjected to an extraction treatment with ethanol, the remaining amount of each drug in the patch was measured by high performance liquid chromatography, and the amount of skin transfer was determined in the same manner as in Example. Table 1 shows the amount of drug transferred to the skin of rabbits for each patch.

[0016]

[Table 1]

As is clear from Table 1, the comparison between Example 1 and Comparative Example 1, the case of using the medical adhesive of the present invention, as compared with the case of using an acrylic pressure-sensitive adhesive of Comparative Example , It is recognized that the drug release property is equal or better. With respect to the patches obtained in Example 1 and Comparative Examples 1 and 2, an irritation test of the patches on rabbit skin was performed by the method shown in Experiment 2. Experiment 2 For the rabbit skin treated in the same manner as in Experiment 1, the patch was applied for 24 hours and then peeled off, and the erythema state of the skin was visually observed 1 hour and 48 hours later. In this test, edema and crust formation were not observed. The degree of erythema was evaluated according to the following five-point criteria of 0 to 4. 0: No erythema 1 ... Mild erythema barely discernable 2 ... Obvious erythema 3 ... Medium erythema 4 ... Strong erythema with a deep red color Average value (the sum of the scores in each time divided by the number of repetitions 4) The skin irritation index of the patch was used. Table 2 shows the obtained evaluation results.

[0018]

[Table 2]

As is clear from Table 2, skin irritation of the patch of Example 1 using the medical pressure-sensitive adhesive of the present invention was hardly observed at 1 hour and 48 hours, whereas acrylic Skin irritation of the patches of Comparative Examples 1 and 2 using the system-based adhesive was hardly observed after 48 hours, but after 1 hour, high irritation considered to be caused by damage to the stratum corneum was observed. The patch obtained in Example 1 and Comparative Examples 1 and 2 was subjected to a drug permeability test on the excised skin of hairless mice by the method shown in Experiment 3. Experiment 3 First, the diffusion cell 1 shown in FIG. 1 was prepared. Diffusion cell 1
Consists of an upper donor tank 3 and a lower cylindrical receptor tank 2 with a bottom. An opening 4 is provided at the center of the bottom wall of the donor tank 3, and the lower end of the donor tank 3 and the receptor tank 2 are provided.
The upper end is provided with an upper flange 5 and a lower flange 6, respectively. Then, by overlapping the upper flange 5 and the lower flange 6 so that they face each other, the donor tank 3 and the receptor tank 2 are airtightly and concentrically stacked. A sampling port 7 is attached to the side of the receptor tank 2 so as to protrude to the side, and a magnet stirrer 9 is inserted into the receptor tank 2. Hairless mouse (8 weeks old,
Male) was sacrificed by cervical dislocation, and the skin was immediately peeled off to remove subcutaneous fat to obtain a skin piece of about 5 cm × 5 cm. The skin piece 8 was narrowed between the side flange 5 and the lower flange 6 on the diffusion cell 1 so that the opening 4 of the donor tank 3 was completely closed by the skin piece 8. A test piece 10 punched in a circular shape having a patch area of 3.14 cm ^{2 was} applied to the upper surface of the skin piece 8. The receptor tank 2 was filled with a receptor solution prepared by the following method. Next, the diffusion cell 1 was placed in a thermostat maintained at a temperature of 37 ° C., and the receptor solution was stirred by a magnet stirring device. After the start of the test, 1 ml of the receptor liquid was sampled from the sampling port 7, and the amount of the drug permeated into the receptor liquid was measured by a high performance liquid chromatography. Table 3 shows the measured permeation amount for each patch. Preparation of receptor solution NaH ₂ PO ₄ (5 × 10 ⁻⁴ mol), Na ₂ HPO
₄ (2 × 10 ⁻⁴ mol), NaCl (1.5 × 10 ⁻⁴ mol) and 10 mg of gentamicin are dissolved in 500 ml of distilled water, and the pH of the resulting solution is adjusted to 7.2 with 0.1N NaOH aqueous solution. After that, the volume is adjusted to 1000 with distilled water.
ml.

[0020]

[Table 3]

As is clear from Table 3, similarly to the result of Experiment 1, as is clear from the comparison between Example 1 and Comparative Example 1, when the medical pressure-sensitive adhesive of the present invention was used, the acrylic of Comparative Example was used. As compared with the case where a system-based pressure-sensitive adhesive is used, it is recognized that it has a drug release property equal to or better than that of the case where a system-based pressure-sensitive adhesive is used.

[0022]

As described above, the patch comprising the medical adhesive according to the present invention can effectively absorb various drugs transdermally or transmucosally. In addition, the medical pressure-sensitive adhesive of the present invention is considered to be originally high in the diffusion rate of the drug in the pressure-sensitive adhesive because the blended polymer is in a swollen state due to the effect of the softener in the pressure-sensitive adhesive and is very flexible. However, when applied to the skin or mucous membrane, the drug absorbs water or secretion liquid evaporating from the skin or mucous membrane surface, lowers the viscosity, and increases the diffusion rate of the drug in the adhesive, so that the drug can be easily absorbed. It can diffuse and move through the adhesive, is effectively released from the adhesive, and is absorbed transdermally and transmucosally. Furthermore, since the medical pressure-sensitive adhesive of the present invention is hydrophilic, its affinity for skin is relatively weak.
Therefore, when peeling off the patch, a phenomenon such as peeling of the stratum corneum does not occur, and further, since hair on the body surface is not peeled off, there is little irritation to the skin, and skin irritation hardly occurs. Furthermore, the medical pressure-sensitive adhesive of the present invention is very flexible, so that it has a low affinity for the skin,
It can adhere to the skin surface and follow the expansion and contraction of the skin without difficulty. Therefore, it can be stuck for a long time without peeling off from the skin surface, and even if it is used repeatedly, the adhesiveness and sticking property do not suddenly decrease.

[Brief description of the drawings]

FIG. 1 is a perspective view showing a diffusion cell used in a drug permeability test on an isolated skin of a hairless mouse in Experiment 3.

[Explanation of symbols]

DESCRIPTION OF SYMBOLS 1 ... Diffusion cell, 2 ... Receptor tank, 3 ... Donor tank, 4 ...
Opening, 5: Upper flange, 6: Lower flange, 7: Sampling port, 8: Skin piece, 9: Magnetic stirrer, 1
0: Test piece.

Claims (2)

(57) [Claims] 1. A blend of a vinylpyrrolidone (co) polymer and a (meth) acrylic acid copolymer, a softener, and a weakly basic organic carboxylate having two or three carboxyl groups. A medical adhesive, wherein the vinylpyrrolidone (co) polymer is soluble in water and / or alcohol. 2. The method according to claim 2, wherein said carboxyl group is two or three.
The organic carboxylic acids that it contains are fumaric acid, maleic acid,
Acid selected from the group consisting of
The medical adhesive according to claim 1, characterized in that: