KR20030032613A - Transdermal delivery patch of matrix type - Google Patents

Abstract

PURPOSE: A transdermal patch agent containing nonvolatile menthol derivatives as a promoter for transdermal absorption and a solubilizing aid is provided. It is dried at high temperature within a short time, has excellent skin permeability, low skin irritation and excellent stability. CONSTITUTION: The transdermal patch agent comprises a drug protecting layer, a matrix layer containing an active drug and a peeling layer which is released before attachment to the skin, wherein the matrix layer includes 1 to 30% by weight of nonvolatile menthol derivatives as a promoter for transdermal absorption, 40 to 95% by weight of a pressure sensitive adhesive and 1 to 25% by weight of an active drug and additionally 30% by weight of a solubilizing aid.

Description

Transdermal delivery patch of matrix type

The present invention relates to a matrix type transdermal patch.

Recently, many studies have been conducted on drug delivery systems in order to provide efficiency, safety, and patient convenience of drug administration.

Conventionally, drugs have been mainly administered by oral or injection, but in the case of oral administration, drugs that are easily metabolized in the liver by the first-pass effect of the drug may be inactivated before reaching the systemic circulation system. , The absorption rate in the body is not constant, and if the half-life of the drug is short, the frequency of administration should be frequent, so long-term administration has the disadvantage of causing side effects of gastrointestinal disorders. In addition, the injection has been pointed out the disadvantages such as pain during injection or the possibility of mixing foreign substances. Therefore, studies to formulate a transdermal drug to reduce such side effects have been actively conducted.

Transdermal administrations include topical dosage forms and patching agents. However, topical agents are applied directly to the skin without the drug protection layer that seals the active ingredients, so the amount of application of the drug on the user's clothes or once applied is not constant, and it is troublesome to apply it several times a day. . On the contrary, the patch formulation has a constant application amount when attached and does not have the inconvenience of having the drug adhere to clothes or attach several times a day.

Patch types are largely divided into a reservoir type and a matrix type. Among them, the patch in the form of a matrix is easy to apply to any part of the body depending on the nature of the drug protection layer material and adhesive components used, research on this has been vigorous in recent years.

Most patching agents, including matrix type patching agents, use transdermal absorption accelerators to promote absorption of the drug when the drug is difficult to pass through the skin keratin. These percutaneous absorption accelerators directly affect the absorption barrier of the skin without irritating or damaging the skin, thereby improving the skin penetration of the drug. Currently used or reported transdermal absorption accelerators include fatty acids such as oleic acid and linoleic acid, surfactants such as tween, alcohols such as ethanol and propylene glycol, or terpenes such as glycol and menthol.

U.S. Patent No. 4,933,184 describes the use of volatile menthol derivatives as transdermal absorption accelerators to promote skin permeation effects. However, volatile menthol derivatives have high skin irritation and, due to volatility, have a disadvantage in that the manufacturing time is long because the temperature should be maintained at about 50 to 60 ° C. during the manufacturing process.

Accordingly, in order to reduce the manufacturing time, Korean Patent Laid-Open No. 1999-29556 introduces a method of dividing the constituents of the patch into volatile and nonvolatile components. That is, only the non-volatile components of the pharmaceutical composition are selected and applied to one side of the drug protection layer and the release layer and dried at high temperature to form an adhesive layer, and then a high viscosity solution containing menthol, which is a volatile component, is applied on the dried adhesive layer. By penetrating into the pressure-sensitive adhesive layer at room temperature to form a volatile transdermal absorption accelerator layer, and by laminating the pressure-sensitive adhesive layer on top of the volatile transdermal absorption accelerator layer to prepare a matrix transdermal administration agent. However, such a process greatly shortened the drying time of the matrix type transdermal administration agent, but the process is cumbersome.

On the other hand, nonvolatile menthol derivatives have been used in external preparations such as cosmetic compositions.

In Korean Patent No. 201424, 3-L-Methoxypropane-1,2-diol, which is one of nonvolatile menthol derivatives, was used as a dissolving agent to promote absorption by liquefying drugs. 3-L-mentoxypropane-1,2-diol was used as a plasticizer.

International Patent Publication Nos. 00/62737 and 00/42983 used menthyl lactate, one of the other nonvolatile menthol derivatives, as a cooling agent in cosmetic compositions. International Publication Nos. 96/14840 and 97/42944 Menthyl lactate was used for the purpose of eliminating transdermal pain.

US Pat. No. 5,713,131 used menthyl pyrrolidone carboxylate, one of the other nonvolatile menthol derivatives, as a cooling agent for shaving, and in British Patent No. 1,567,496, a skin protective cosmetic composition, International Patent Publication No. 00/16738. Insect insect repellent, US Patent No. 6,048,549 was used as a skin irritant composition.

Since these non-volatile menthol derivatives have already been used successfully for the skin as external preparations, research as an alternative means for solving the problems of volatile menthol derivatives as transdermal absorption accelerators is required.

An object of the present invention is to provide a matrix transdermal patch containing a nonvolatile menthol derivative as a transdermal absorption accelerator.

The present invention relates to a matrix transdermal patch, characterized in that it contains a nonvolatile menthol derivative as a transdermal absorption accelerator.

In the present invention, the nonvolatile menthol derivative is selected from menthyl pyrrolidone carboxylate, 3-L-menthoxypropane-1,2-diol, menthyl lactate, menthyl ethoxyacetate and menton glycerine acetal.

The matrix type transdermal patch according to the present invention comprises a drug protection layer, an effective drug-containing matrix layer, and a peeling layer removed before adhesion to the skin, wherein the matrix layer is a transdermal absorption accelerator, 1-30 wt% of a nonvolatile menthol derivative, a pressure-sensitive adhesive It contains 40 to 95% by weight and 1 to 25% by weight of the active drug.

In addition, the matrix layer may further comprise up to 30% by weight of a dissolution aid.

Hereinafter, the component which comprises a matrix layer in the matrix type transdermal dosing patch of this invention is demonstrated.

The nonvolatile menthol derivative used as the percutaneous absorption accelerator of the present invention is used within the range of 1 to 30% by weight of the composition. The nonvolatile menthol derivative of the present invention assists in the passage of the stratum corneum of the drug and promotes intracellular penetration of the drug by reversibly destroying the intercellular fat layer. If the percutaneous absorption accelerator is less than 1% by weight, the percutaneous absorption promoting action is mild to promote the skin keratin passage of the effective drug, and if it exceeds 30% by weight, it is difficult to obtain a stable formulation by significantly lowering the adhesive strength of the patch. The percutaneous absorption accelerator of the present invention can be selected from nonvolatile menthol derivatives such as menthyl pyrrolidone carboxylate, 3-L-menthoxypropane-1,2-diol, menthyl lactate, menthyl ethoxyacetate and menthyl glycerine acetal Can be.

The pressure-sensitive adhesive used in the matrix layer composition of the present invention is used within the range of 40 to 95% by weight of the composition, it is preferable to apply a light pressure to the skin and leave no residue when removed. As the pressure-sensitive adhesive of the present invention, it is preferable to use an acrylic pressure-sensitive adhesive, a rubber elastomer and a silicone pressure-sensitive adhesive. As the acrylic pressure-sensitive adhesive, an acrylate polymer or a copolymer of acrylate and vinyl acrylate may be used, and a carboxyl group and a hydroxyl group may be included as a functional group (for example, National Starch Co., Ltd. product name: DT-87-4098, 87- 2516, 87-2100, 87-2052, etc.). Examples of the rubber elastomer include polyisobutylene (for example, National Starch Co., Ltd .: DT-87-6430, Exxon Chemical, Vistanex, etc.), styrene-isoprene-styrene block copolymer (for example, Japan Synthetic Rubber Co., Ltd .: JSR5000, JSR5100, etc. ) Can be used. As the silicone pressure-sensitive adhesive, polydimethylsiloxane (for example, Dow Corning's trade name: X7-2900, etc.) can be used.

The effective drug used in the matrix layer composition of the present invention is used within the range of 1 to 25% by weight of the composition. If the effective drug content is less than 1% by weight, the skin absorption rate is significantly reduced due to the decrease in drug concentration, whereas if it is contained in excess of 25% by weight, the drug precipitates out of the adhesive layer due to insufficient solubility of the drug in the patch.

The effective drug is ibuprofen, indomethacin, ketoprofen, pluviprofen, pyroxicam, ketorolac, diclofenac, mefenamic acid, salicylic acid and their pharmaceutically acceptable which have antipyretic, analgesic, anti-inflammatory effects salt; Dexamethasone, hydrocortisone, prednisolone, betamethasone, triamcinolone acetonide, holosinolone acetonide, and pharmaceutically acceptable salts thereof, of the adrenal cortex hormone family; Propranolol, atenolol, pindolul, timolol, bufranolol, metoprolol, alprenolol, oxprenolol and pharmaceutically acceptable salts thereof; Nifedipine, verapamil, diltiazem and their pharmaceutically acceptable salts of calcium blockers; Other cardiovascular drugs such as clonidine, enalapril, prazosin, nitroglycerin, isosorbate dinitrate; Female hormones estradiol, ethynylestradiol, progesterone and pharmaceutically acceptable salts thereof; Testosterone of androgenic hormone and pharmaceutically acceptable salts thereof; Local anesthetics, tetracaine, dibucaine, lidocaine, and pharmaceutically acceptable salts thereof; Antihistamines diphenhydramine, maleic acid diphenhydramine, chlorpheniramine, ketotifen and their pharmaceutically acceptable salts; Synthetic drugs buprenopine, fentanyl, sufentanil and pharmaceutically acceptable salts thereof; Bronchodilators salbutamol or terbutalin; Most drugs known to be applicable to other patches, such as nicotine, are used as anti-smoking aids.

In order to increase the concentration of the effective drug in the matrix layer of the present invention, the dissolution aid may further comprise up to 30% by weight of the composition. Dissolution aids are used to prevent the formation of drug crystals in the patch after drying if the drug concentration is high. Dissolution aids used in the present invention include triacetin, isopropyl alcohol, sorbitan monooleate, propylene glycol, butylene glycol, dimethylacetamide, propylene carbonate, diethylethanolamine, diethylamine, triethylamine, N -Methyl morpholine, benzammonium chloride, etc. can be used 1 type or in mixture of 1 or more types.

The drug protection layer used by the conventional patch preparation is used as a drug protection layer which comprises the matrix type transdermal administration patch of this invention. For example, a material having good permeability to air or moisture such as nonwoven fabric, cotton cloth, woven fabric, polyethylene terephthalate, polyurethane, polyethylene, polypropylene, aluminum treated polyethylene, or a multilayer laminate film may be used. If necessary, the nonwoven fabric or cotton cloth may be laminated with a plastic film having no moisture permeability.

The release layer constituting the matrix transdermal patch of the present invention is a silicone coated drug impermeable removal film or paper release paper commonly used in the manufacture of the patch, the material of the film is specifically aluminum, cellulose, poly Ester, polyethylene, polypropylene, etc. can be used, You may laminate these films as needed.

The manufacturing method of the matrix-type transdermal patch patch of this invention is demonstrated.

The drug preparation tank is mixed with an active drug, a pressure-sensitive adhesive solution, a transdermal absorption accelerator, and a dissolving aid to stir to uniformly mix all the components, and then coated on a silicon coated polyethylene terephthalate (PET) film or a paper peeling paper with a uniform thickness. And dry. At this time, the drying temperature of the dryer is set to (1 zone) 30 to 40 ° C, (2 zones) 40 to 60 ° C, (3 zones) 80 to 100 ° C, and (4 zones) 100 to 120 ° C. Too high a temperature from the beginning, the solvent evaporates quickly to form a hole to prevent this. After drying, the film is laminated with a PET film or a nonwoven fabric to prepare a matrix transdermal patch.

The matrix type transdermal patch can be easily adjusted according to the patient's symptoms, age, weight, sex and the like in the dosage.

Hereinafter, the present invention will be described in more detail with reference to the following examples, which are intended to illustrate the present invention but are not intended to limit the scope of the present invention.

Example 1 : Manufacture of matrix transdermal patch

Put an acrylic pressure-sensitive adhesive (DT 87-2852) in a 150 liter preparation tank, add fentanyl and stir until the drug is completely dissolved, and then add menthyl pyrrolidone carboxylate and propylene glycol at room temperature for 3 hours at 100 rpm. Stirred. The drug-containing adhesive solution was filtered through a 35 mesh sieve, bubbles were removed, and then applied to the liquid dam of the coating dryer. The drug-containing adhesive solution added to the liquid dam was coated on a silicon-coated polyethylene terephthalate (PET) film with a thickness of 400 μm. The coated drug-containing adhesive solution was dried at a rate of 7 m / min. At this time, the drying temperature of the dryer was set to (zone 1) 30 占 폚, (zone 2) 40 占 폚, (zone 3) 80 占 폚, and (zone 4) 100 占 폚.

After drying, the film was laminated with a polyethylene terephthalate (PET) film and wound up.

The composition of the final metric layer is as follows.

Fentanyl 5 wt%

85% by weight of acrylic pressure sensitive adhesive (DT 87-2852)

Menthyl pyrrolidone carboxylate 5% by weight

5% by weight of propylene glycol

Example 2 : Manufacture of matrix transdermal patch

Put an acrylic pressure-sensitive adhesive (DT 87-6430) in a 150-l preparation tank, add diclofenac diethylammonium, stir until the drug is completely dissolved, and add menthyl pyrrolidone carboxylate and propylene glycol for 3 hours at room temperature. And stirred at 100 rpm. The drug-containing adhesive solution was filtered through a 35 mesh sieve, bubbles were removed, and then applied to the liquid dam of the coating dryer. The drug-containing adhesive solution added to the liquid dam was coated with a thickness of 500 μm on a paper release sheet. The coated drug-containing adhesive solution was dried at a rate of 3 m / min. At this time, the drying temperature of the dryer was 40 degreeC (1 zone), (2 zones) 60 degreeC, (3 zones) 100 degreeC, and (4 zones) 120 degreeC.

After drying, it was laminated with a nonwoven fabric and wound up.

The composition of the final metric layer is as follows.

5% by weight of diclofenac diethylammonium

75% by weight of acrylic pressure sensitive adhesive (DT 87-6430)

Menthyl pyrrolidone carboxylate 10% by weight

10% by weight of propylene glycol

Example 3 : Manufacture of matrix transdermal patch

Polyisobutylene pressure-sensitive adhesive (DT 87-4098) was added to a 150-liter tank, stirred with indomethacin until complete dissolution of the drug, followed by addition of menthyl pyrrolidone carboxylate and propylene glycol at room temperature for 3 hours. While stirring at 100 rpm. The drug-containing adhesive solution was filtered through a 35 mesh sieve, bubbles were removed, and then applied to the liquid dam of the coating dryer. The drug-containing adhesive solution added to the liquid dam was coated with a thickness of 300 μm on a paper release sheet. The coated drug-containing adhesive solution was dried at a rate of 10 m / min. At this time, the drying temperature of the drier was (zone 1) 35 占 폚, (zone 2) 50 占 폚, (zone 3) 90 占 폚, and (zone 4) 110 占 폚.

After drying, it was laminated with a nonwoven fabric and wound up.

The composition of the final metric layer is as follows.

Indomethacin 5 wt%

75 wt% of polyisobutylene pressure sensitive adhesive (DT 87-4098)

Menthyl pyrrolidone carboxylate 15% by weight

5% by weight of propylene glycol

Experimental Example 1 : Skin permeability measurement

A skin permeation test was performed on Sprague-Dawley rat skin using the matrix-type transdermal administration patch prepared in Examples 1-3.

1) Extraction of Mouse Skin

Male Sprague-Dawley rats weighing 250 ± 20 g were anesthetized with ether, and the dorsal hair was removed with an electroepilator (TGC Inc., Model 900, Japan) and skin was extracted with an area of 3 cm × 3 cm. The subcutaneous fat was carefully removed so as not to damage the extracted skin, and it was stored on the glass plate at -20 ° C. until it was used for the experiment to prevent contamination. The shelf life did not exceed three days.

2) Skin Permeability Measurement

After dissolving the extracted rat skin at room temperature, soak it in physiological saline for about 30 minutes, mount it in a Franz diffusion cell, and place the cell in a diffusion cell drive console (Diffusion cell drive console; Fine Scientific Instrument, Model FCD8-900A). ), And using a constant temperature circulating pump (Fine Scientific Instrument, Model FT-101) while maintaining the temperature of the receptor layer at 37 ± 0.5 ℃, using a star-head magnetic bar Constant rotation at 600 rpm.

0.1 M pH 7.2 phosphate buffer was used as the receptor layer, the receptor layer volume was 11.5 ml, and the area of the skin in contact with the receptor layer was 1.77 cm 2.

The matrix type transdermal patchs prepared in Examples 1 to 3 were adhered to the exposed portions of the skin. At 1, 2, 4, 6, 8, 10, and 24 hours after adhesion, 0.2 ml of receptor layer was collected from the sampling port using a microsyringe, and then the concentration of the drug was measured by high-performance liquid chromatography. The skin penetration rate in the state was obtained.

A matrix-type transdermal patch was prepared in the same manner as in Examples 1 to 3 as the control group, without using only a transdermal absorption accelerator.

The results are shown in Table 1.

Skin penetration rate (㎍ / ㎠ / hr) Example 1 3.28 ± 0.53 Example 2 2.35 ± 0.74 Example 3 1.83 ± 0.02 Control group 1 1.21 ± 0.45 Control 2 1.03 ± 0.55 Control group 3 0.82 ± 0.02

As shown in Table 1, the matrix transdermal administration of the matrix type transdermal patch prepared in Examples 1 to 3 containing the nonvolatile menthol derivative of the present invention as a transdermal absorption accelerator does not include the transdermal absorption accelerator. It can be seen that the skin penetration rate is significantly increased compared to the patch.

Experimental Example 2 : Skin irritation measurement

Using a matrix transdermal patch prepared in Examples 1 to 3, rabbit skin was subjected to a primary irritation test.

The dorsal hairs of six mature white rabbits weighing 2.5-3.5 kg were removed so as to be approximately 10 cm in length with an electric hair remover (TGC Inc., Model 900, Japan).

The skin of the depilated rabbit is divided into right and left, and the left side is divided into the administration compartment and the right side as the control compartment, so that the healthy skin or abrasion skin is distributed diagonally to each other. 2 healthy skins of 2.5cm × 2.5㎝ and 2 abrasion skins It was set as.

The abrasion skin was made using the tip of the syringe needle, so that the epidermis was injured but the dermis was injured so that it would not bleed.

The amount obtained by attaching the matrix-type transdermal patch prepared in Examples 1 to 3 on the back skin of the depilated rabbit, and determining the erythema and edema for 24 hours and 48 hours after application, according to the skin irritation determination criteria. The sum of the scores was used as the stimulus score at each time, and the average value of the stimulus scores at each time was used as the primary skin stimulation index (PII value).

As a comparative sample, 5% by weight of diclofenac diethylammonium, 75% by weight of an acrylic pressure-sensitive adhesive (DT 87-6430), 10% by weight of menthol and 10% by weight of propylene glycol were prepared in the same manner as in Example 2.

The results are shown in Table 2.

Skin irritation (PII level) Example 1 0.0 Example 2 0.0 Example 3 0.0 Comparative Sample 1.0

※ Skin irritation criteria

0: erythema, edema-none 1: extremely light erythema, edema

2: obvious erythema, edema 3: moderate to strong erythema, edema

4: strong red erythema, edema

※ Primary skin irritation index (PII level)

0.0 to 0.5: non-irritating, 0.6 to 2.0: weakly irritating

2.1 to 5.0: moderate irritant, 5.1 to 8.0: strong irritant

As can be seen from Table 2, it can be seen that the matrix-type transdermal patch of the present invention has no skin irritation.

The matrix type transdermal patch containing the nonvolatile menthol derivative of the present invention greatly shortens the manufacturing process by drying at a high temperature for a short time, and speeds up the production process, and also has excellent skin permeability and low skin irritation. There is an effect, and there is also an effect that shows excellent aging stability.

Claims (10)

In the transdermal patch comprising a drug protection layer, an effective drug-containing matrix layer and a peeling layer removed before skin adhesion, the matrix layer is characterized as containing a nonvolatile menthol derivative, a pressure-sensitive adhesive and an effective drug as a transdermal absorption accelerator. Matrix transdermal patch The matrix type transdermal patch according to claim 1, wherein the matrix layer contains 1 to 30% by weight of a nonvolatile menthol derivative, 40 to 95% by weight of a pressure-sensitive adhesive, and 1 to 25% by weight of an effective drug as a transdermal absorption accelerator. The transdermal absorption accelerator according to claim 1 or 2, wherein the transdermal absorption accelerator used in the matrix layer structure is menthyl pyrrolidone carboxylate, 3-L-menthoxypropane-1,2-diol, menthyl lactate, menthyl ethoxyacetate. And menton glycerin acetal, a matrix type transdermal patch The matrix type transdermal patch according to claim 1 or 2, wherein the pressure sensitive adhesive used in the matrix layer structure is selected from an acrylic pressure sensitive adhesive, a rubber elastomer and a silicone pressure sensitive adhesive. The drug used in the composition of the matrix layer is ibuprofen, indomethacin, ketoprofen, pluviprofen, pyroxicam, ketorolac, diclofenac , Mefenamic acid, salicylic acid and pharmaceutically acceptable salts thereof; Dexamethasone, hydrocortisone, prednisolone, betamethasone, triamcinolone acetonide, holosinolone acetonide, and pharmaceutically acceptable salts thereof, of the adrenal cortex hormone family; Propranolol, atenolol, pindolul, timolol, bufranolol, metoprolol, alprenolol, oxprenolol, and pharmaceutically acceptable salts thereof, of beta blockers; Nifedipine, verapamil, diltiazem and calcium pharmaceutically acceptable salts thereof; Other cardiovascular drugs such as clonidine, enalapril, prazosin, nitroglycerin, isosorbate dinitrate; Female hormones estradiol, ethynylestradiol, progesterone and pharmaceutically acceptable salts thereof; Testosterone of androgenic hormone and pharmaceutically acceptable salts thereof; Local anesthetics, tetracaine, dibucaine, lidocaine, and pharmaceutically acceptable salts thereof; Antihistamines diphenhydramine, maleic acid diphenhydramine, chlorpheniramine, ketotifen and their pharmaceutically acceptable salts; Synthetic drugs buprenopine, fentanyl, sufentanil and pharmaceutically acceptable salts thereof; Bronchodilators salbutamol or terbutalin; Matrix transdermal patch, characterized in that selected from the group consisting of nicotine used as a smoking cessation aid The matrix type transdermal patch according to claim 1 or 2, further comprising up to 30% by weight of a dissolution aid. 7. The method of claim 6 wherein the dissolution aid is in triacetin, isopropyl alcohol, propylene glycol, dimethylacetamide, propylene carbonate, diethylethanolamine, diethylamine, triethylamine, N-methyl morpholine and benzammonium chloride Matrix type transdermal patch, characterized in that at least one selected. As a transdermal absorption accelerator, 1-30% by weight of a nonvolatile menthol derivative, 40-95% by weight of a pressure-sensitive adhesive, and 1-25% by weight of an effective drug are mixed and stirred so that all components are uniformly mixed, followed by silicone-coated polyethylene terephthalate ( PET) A method of manufacturing a matrix transdermal patch by coating a film or paper release paper with a certain thickness and drying it, and then laminating it with a PET film or a nonwoven fabric. The method of claim 8, further comprising up to 30% by weight of a dissolving aid. The drying temperature according to claim 8 or 9, wherein the drying temperature is (zone 1) 30 to 40 ° C, (zone 2) 40 to 60 ° C, (zone 3) 80 to 100 ° C, (zone 4) 100 to 120 ° C. Process for producing a matrix type transdermal patch