JPH1045579A - Plaster - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a plaster capable of effectively absorbing a medicine through skin or mucous membrane into a body by adding a medicine, a polyhydric alcohol and a water-absorbing filler to a tacky agent layer. SOLUTION: This plaster is obtained by laminating a tacky agent layer onto one side of a support and the tacky agent layer contains diclofenac sodium, a polyhydric alcohol (preferably glycerol) and a water-absorbing filter (preferably crosslinked polyvinylpyrrolidone). The polyhydric alcohol is preferably included in the tacky agent layer in a compatibilized state. The medicine is preferably blended in an amount of 0.1-30wt.% into the tacky agent layer and the water- absorbing filler is preferably blended in an amount of 0.5-20wt.% into the tacky agent layer. Thereby, a medicine developing various adverse effects such as gastrointestinal disorder when orally or rectally administered can parenterally effectively be administered.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a patch for transdermal administration of diclofenac sodium.

[0002]

2. Description of the Related Art Diclofenac sodium is a non-steroidal anti-inflammatory analgesic and is currently marketed as oral tablets and suppositories. However, when administered orally or rectally, various side effects such as gastrointestinal disorders have become a problem, and in order to reduce such side effects, transdermal absorption preparations in which diclofenac sodium is transdermally administered have been proposed. .

[0003] However, since the stratum corneum on the skin surface has a barrier function to prevent foreign substances from entering the body, even when a drug is administered using a patch, the drug hardly penetrates the skin.
Bioavailability is often low.

For this reason, Japanese Patent Application Laid-Open No. 61-280426 discloses a patch containing an organic acid to enhance the transdermal absorbability of diclofenac sodium. However, organic acids are generally known as substances that irritate the skin or mucous membranes.

[0005] Also, Japanese Patent Application Laid-Open No. 4-13617 discloses that
Although a patch containing a water-absorbing filler has been disclosed, sufficient performance regarding transdermal absorption has not been obtained.

[0006]

SUMMARY OF THE INVENTION The present invention solves the above-mentioned problems, and an object of the present invention is to provide a patch capable of effectively absorbing a drug contained therein through the skin or mucous membrane and into the body. It is in.

[0007]

The patch of the present invention is a patch in which a pressure-sensitive adhesive layer is laminated on one surface of a support, and the pressure-sensitive adhesive layer comprises diclofenac sodium, polyhydric alcohol and water-absorbent filling. It is characterized by containing an agent.

The pressure-sensitive adhesive is not particularly limited as long as it has a pressure-sensitive adhesive force capable of fixing the patch to the skin surface at room temperature for a long time. As such a pressure-sensitive adhesive, for example, a pressure-sensitive adhesive of an acrylic type, a rubber type, a silicone resin type or the like can be used, and among these, an acrylic type pressure-sensitive adhesive is particularly preferably used.

As the acrylic pressure-sensitive adhesive, due to its adhesiveness, etc., a (co) polymer of (meth) acrylic acid alkyl ester obtained from an aliphatic alcohol having 1 to 18 carbon atoms and (meth) acrylic acid and / Alternatively, a copolymer of the above (meth) acrylic acid alkyl ester and another functional monomer is preferable.

Examples of the alkyl (meth) acrylate include ethyl (meth) acrylate, butyl (meth) acrylate, isobutyl (meth) acrylate, hexyl (meth) acrylate, and octyl (meth) acrylate. , 2-ethylhexyl (meth) acrylate,
Examples include isooctyl (meth) acrylate, decyl (meth) acrylate, isodecyl (meth) acrylate, lauryl (meth) acrylate, stearyl (meth) acrylate, and the like.

Examples of the functional monomer include a monomer having a hydroxyl group, a monomer having a carboxyl group, a monomer having an amide group, a monomer having an amino group, and a monomer having a pyrrolidone ring. Examples of the monomer having a hydroxyl group include 2-hydroxyethyl (meth) acrylate, hydroxyethyl (meth) acrylate, hydroxyalkyl (meth) acrylate such as hydroxypropyl (meth) acrylate, and polyoxyethylene. (4) Lauryl ether and the like. Examples of the monomer having a carboxyl group include α, β-unsaturated carboxylic acids such as (meth) acrylic acid; monoalkyl esters of maleic acid such as butyl maleate; (anhydride) maleic acid, fumaric acid,
Crotonic acid and the like.

The monomers having an amide group include:
Examples thereof include alkyl (meth) acrylamides such as acrylamide, dimethyl acrylamide and diethyl acrylamide; alkyl ether methylol (meth) acrylamides such as butoxymethyl acrylamide and ethoxymethyl acrylamide; and diacetone acrylamide. As the monomer having an amino group,
For example, dimethylaminoethyl acrylate and the like can be mentioned. Examples of the monomer having a pyrrolidone ring include vinylpyrrolidone.

In order to improve the cohesiveness of the acrylic pressure-sensitive adhesive, it is preferable that a polyfunctional monomer is further contained if necessary. The addition of this polyfunctional monomer causes only slight cross-linking between the resulting polymers, which increases the internal cohesive strength of the adhesive. Therefore, the so-called glue residue phenomenon at the time of peeling the adhesive is almost eliminated irrespective of the properties of the attached skin and the amount of perspiration. Moreover, the addition of this polyfunctional monomer has no effect on the drug release or hypoallergenicity. The polyfunctional monomer is not particularly limited, and examples thereof include di (meth).
Examples thereof include acrylic acid ester, tri (meth) acrylic acid ester, and tetra (meth) acrylic acid ester.

Examples of the above-mentioned di (meth) acrylic acid ester include polymethylene glycols such as hexamethylene glycol and octamethylene glycol, and (meth)
A di (meth) acrylic acid ester obtained by binding with acrylic acid; a di (meth) acrylic acid ester obtained by binding polyalkylene glycols such as polyethylene glycol and polypropylene glycol with (meth) acrylic acid No.

Examples of the tri (meth) acrylate include trimethylolpropane tri (meth) acrylate and glycerin tri (meth) acrylate. Examples of the tetra (meth) acrylic acid ester include pentaerythritol tetra (meth) acrylic acid ester.

The above polyfunctional monomers may be used in combination of two or more kinds. If the amount of the polyfunctional monomer is small, the effect of improving the internal cohesive force by cross-linking is small, and if it is large, the adhesive obtained by the polymerization is apt to gel, and the diffusion and release of the drug are also affected. Is preferably used in a proportion of 0.005 to 0.5% by weight based on all monomers used for the production of

If necessary, a tackifier such as a rosin resin, a polyterpene resin, a coumarone-indene resin, a petroleum resin, or a terpene-phenol resin may be added to the acrylic pressure-sensitive adhesive.

The acrylic pressure-sensitive adhesive is polymerized by an ordinary known method. For example, the acrylic pressure-sensitive adhesive is prepared by blending the above monomers in the presence of a polymerization initiator and performing solution polymerization. However, the polymerization conditions are appropriately selected mainly depending on the type of the monomer.

As the acrylic pressure-sensitive adhesive, in particular, an alkyl (meth) acrylate having an alkyl group having 1 to 18 carbon atoms is polymerized at a rate of 45 to 97% by weight and vinylpyrrolidone at a rate of 3 to 55% by weight. Copolymers are preferably used.

Examples of the rubber-based adhesive include natural rubber, synthetic isoprene, polyisobutylene, polyvinyl ether, polyurethane, polyisoprene, polybutadiene,
Styrene-butadiene copolymer, styrene-isoprene copolymer, styrene-isoprene-styrene block copolymer rubber elastic body, for example, rosin resin, polyterpene resin, coumarone-indene resin, petroleum resin,
Tackifiers such as terpene-phenolic resins and, if necessary, softeners such as liquid polybutene, mineral oil, lanolin, liquid polyisoprene, liquid polyacrylate; fillers such as titanium oxide; aging prevention such as butylhydroxytoluene A product obtained by adding an appropriate amount of the agent or the like is used. In particular, one obtained by adding 50 to 200 parts by weight of a tackifier such as a petroleum resin to 100 parts by weight of a styrene-isoprene-styrene copolymer is preferably used.

As the silicone resin-based pressure-sensitive adhesive, one containing polyorganosiloxane or the like as a main component is used.

The drug used in the present invention is diclofenac sodium. When the compounding amount of the above-mentioned drug is small, sufficient permeability cannot be obtained and the therapeutic effect is deteriorated, and when it is large, a large amount of crystals are present in the pressure-sensitive adhesive layer and the sticking property is deteriorated. It is preferably 1 to 30% by weight, more preferably 1 to 20% by weight. The drug in the pressure-sensitive adhesive layer may be dissolved in the pressure-sensitive adhesive layer or may be dispersed as crystals.

The water-absorbent filler used in the present invention is a compound (usually a polymer) capable of absorbing water and swelling, has a low affinity for the pressure-sensitive adhesive and the drug, and is in the form of fine particles in the pressure-sensitive adhesive. Those that are dispersed are preferred. Examples of such a water-absorbing filler include cross-linked polyacrylic acid salt, cross-linked polyvinyl pyrrolidone, cross-linked crystalline cellulose, cross-linked carboxymethyl cellulose, cross-linked hydroxyalkyl cellulose (for example, cross-linked hydroxypropyl cellulose), cross-linked polyvinyl alcohol and the like. However, crosslinked polyvinylpyrrolidone is particularly preferable.

The above-mentioned crosslinked polyvinylpyrrolidone is prepared by copolymerizing N-vinyl-2-pyrrolidone and a polyfunctional monomer. Hexamethylene glycol di (meth) is a polyfunctional monomer used for copolymerization.
Di (meth) acrylates such as acrylate, ethylene glycol di (meth) acrylate and triethylene glycol di (meth) acrylate; tri (meth) acrylates such as trimethylolpropane triacrylate; tetra (meth) acrylates such as pentaerythritol tetramethacrylate Polyallyl compounds such as diethylene glycol bisallyl carbonate, triallyl glycerin and triallyl cyanurate; and polymaleimide compounds such as ethylene bismaleimide.

Other polyfunctional monomers other than those described above include cyclic acid amide compounds such as N, N'-divinylimidazoline, N, N'-divinylhexahydropyrimidenone, N-vinyl-3-ethylidene-pyrrolidone; Divinylbenzene, methylenebisacrylamide, ethylidenebisvinylpyrrolidone, divinylketone, butadiene, isoprene and the like can also be used.

When the amount of the polyfunctional monomer used in the copolymerization is reduced, the obtained crosslinked polyvinylpyrrolidone dissolves in the adhesive or extremely swells to maintain its particle structure in the adhesive layer. When the amount increases, the obtained crosslinked polyvinylpyrrolidone hardly swells with respect to the pressure-sensitive adhesive, and the drug release property of the pressure-sensitive adhesive layer cannot be increased.
-20% by weight is preferred.

The above-mentioned crosslinked polyvinylpyrrolidone is known under the name of crospovidone, and commercially available products thereof include "Coridone CL" manufactured by BASF, "Polyplasdone INF-10" manufactured by ISP. The method for producing crospovidone is described in US Pat. No. 375988.
0, 3933766 and 3689439.

If the amount of the water-absorbing filler is too small, a sufficient effect of releasing the drug cannot be obtained, and if the amount is too large, the adhesiveness of the adhesive patch decreases, and good adhesiveness cannot be obtained. Among them, 0.5 to 20% by weight is preferable.

Examples of the polyhydric alcohol include glycerin, ethylene glycol, polyethylene glycol, propylene glycol, dipropylene glycol and the like, and glycerin is particularly preferable. When the compounding amount of the polyhydric alcohol is small, a sufficient release effect of the drug cannot be obtained, and when the compounding amount is large, it bleeds out from the pressure-sensitive adhesive layer,
In the pressure-sensitive adhesive layer, 0.5 because good adhesiveness cannot be obtained.
~ 30% by weight is preferred.

As the above-mentioned support, those generally used as a support for patches can be used, and examples thereof include cellulose acetate, ethyl cellulose, polyethylene, polyurethane, polyethylene terephthalate, ethylene-vinyl acetate copolymer, and plastic. Resin films such as plasticized vinyl acetate-vinyl chloride copolymer, polyamide, plasticized polyvinyl chloride, and polyvinylidene chloride; aluminum sheets and the like; these may be used as a single-layer film or a sheet, or two or more kinds. May be used as a laminate. Further, materials other than aluminum may be used as a woven fabric or a non-woven fabric.

The thickness of the support is preferably 1000 μm or less, more preferably 2 to 150 μm.

The patch of the present invention can be prepared according to a conventional method for producing an adhesive tape. For example, a solvent coating method, a hot melt coating method, an electron beam curing emulsion coating method and the like can be used. The construction method is preferable. In the solvent coating, a pressure-sensitive adhesive is dissolved in a predetermined solvent, a drug and other additives are dissolved or dispersed in the predetermined solvent and added, and the resulting solution or dispersion is applied to one surface of the support. Then, by removing the solvent by drying, a patch having a pressure-sensitive adhesive layer having a predetermined thickness formed on the support can be obtained. Alternatively, the above solution or dispersion may be once applied onto a release paper, dried to form an adhesive layer, and then transferred to a support.

The release paper used in the patch of the present invention is not particularly limited, and examples thereof include those obtained by treating a polyethylene terephthalate film with silicon.

The thickness of the pressure-sensitive adhesive layer varies depending on the purpose of use, but when the thickness is thin, the amount of drug per unit area of the patch is insufficient, and when it is thick, the drug contained in the pressure-sensitive adhesive layer near the support is diffused to the skin. Since it becomes difficult to reach the surface and the drug cannot be effectively used, 20 to 200 μm is preferable.

[0035]

The patch of the present invention can enhance drug release and skin permeability by including a polyhydric alcohol and a water-absorbing filler in the adhesive layer.

[0036]

BEST MODE FOR CARRYING OUT THE INVENTION The present invention is described in more detail below with reference to Examples, but the present invention is not limited to these Examples.

[Preparation of adhesive solution] 2-ethylhexyl acrylate 65 mol% (302 g), N-vinyl-2
-Pyrrolidone 35 mol% (98 g) and 1,6-hexamethylene glycol dimethacrylate 40 mg were charged into a separable flask equipped with a stirrer and a cooling device, and 400 g of ethyl acetate was further added to adjust the monomer concentration to 50% by weight. This solution was heated to a temperature of 60 ° C. under a nitrogen atmosphere, and 2 g of lauroyl peroxide was added to 100 g of cyclohexane.
The solution dissolved in the above and 240 g of ethyl acetate were added little by little, polymerization was carried out for 12 hours, and the solid content was 35% by weight.
To obtain an acrylic adhesive solution.

(Examples 1 to 4 and Comparative Examples 1 to 3) With the composition shown in Table 1, an adhesive (the numerical values in the table indicate% by weight as solid content), diclofenac sodium ("D" in the table)
F "), glycerin (indicated by" GL "in the table) and crospovidone (" Polyplasdone INF- "manufactured by ISP).
10) (indicated by “CP” in the table), and the final solid content was 2
Ethyl acetate was added so as to be 8% by weight to obtain a coating solution which was uniform throughout.

This coating solution was applied to a release paper obtained by subjecting a polyethylene terephthalate film (hereinafter referred to as “PET”) having a thickness of 38 μm to silicon treatment to a thickness of 100 μm after drying.
m and dried in a gear oven at 60 ° C. for 30 minutes to form an adhesive layer. This is the thickness 31
An adhesive patch was prepared by sticking the laminated film of μm PET and ethylene-vinyl acetate copolymer on the PET side.

The patch obtained above was subjected to the following skin permeation test, and the results are shown in Table 1. After a hairless mouse (6 weeks old, male) was killed by cervical dislocation, the skin was immediately peeled off, the subcutaneous fat was removed, and the mouse was set in a Franz cell. 3.14 cm of the patch obtained above
A sample punched out into a ² (circle having a diameter of 2 cm) was stuck on the excised skin of a hairless mouse. The receptor liquid was placed in the receptor layer below the Franz cell and placed in a constant temperature bath kept at 37 ° C. after the start of the test. Twenty-four hours after the start of the test, a liquid was collected from the lower receptor layer, and the amount of drug in the liquid (amount of permeation through the skin) was measured by high performance liquid chromatography. In the test, n = 3 was set and the average value was taken as the skin permeation amount.

The receptor liquid was sodium hydrogen phosphate (5 × 10 ⁻⁴ mol), disodium hydrogen phosphate (2 × 10 ⁻⁴ mol), sodium chloride (1.5 × 10 ⁻⁴ ).
^-1 mol) and 10 mg of gentamicin were dissolved in distilled water, and the pH was adjusted to 7.
The mixture was adjusted to 2, and distilled water was added to make 1000 ml.

[0042]

[Table 1]

[0043]

The patch of the present invention is as described above,
The drug, diclofenac sodium, can be effectively transdermally or transmucosally absorbed.

──────────────────────────────────────────────────の Continued on the front page (51) Int.Cl. ⁶ Identification number Agency reference number FI Technical display location A61K 9/70 370 A61K 9/70 370 47/10 47/10 E 47/32 47/32 E 47 / 38 47/38 E // (A61K 47/10 47:32) (A61K 47/10 47:38)

Claims (4)

[Claims] 1. A patch having a pressure-sensitive adhesive layer laminated on one side of a support, wherein the pressure-sensitive adhesive layer contains diclofenac sodium, a polyhydric alcohol and a water-absorbing filler. . 2. The adhesive patch according to claim 1, wherein the polyhydric alcohol is contained in the pressure-sensitive adhesive layer in a compatible state. 3. The patch according to claim 1, wherein the polyhydric alcohol is glycerin. 4. The patch according to claim 1, wherein the water-absorbing filler is crosslinked polyvinylpyrrolidone.