KR19980067255A - Transdermal Administration System of Hydrophilic Drugs - Google Patents

Abstract

The present invention provides a hydrogel matrix of hydrophilic and ionic drugs; Sulfoxides such as dimethyl sulfoxide, hexylmethyl sulfoxide, decylmethyl sulfoxide, octadecanoic acid, capric acid, lauric acid, linoleic acid, stearic acid, oleic acid, fatty acids such as lauryl alcohol, Fatty acids alcohols such as oleyl alcohol, sorbitan monooleate, sorbitan monolaurate, sorbitan monopalmitate, sorbitan monostearate, isopropyl myristate, isopropyl palmitate, PEG monolaurate An adhesive layer comprising at least one absorption promoter and a drug selected from a warm surfactant, N-methylpyrrolidone and 2-pyrrolidone; The present invention provides a transdermal administration system for a hydrophilic and ionic drug comprising a back layer and a release layer, and a method for preparing the same. And skin adaptability is excellent.

Description

Transdermal Administration System of Hydrophilic Drugs

The present invention relates to a novel transdermal administration system and a method for producing the same, which introduce a polymer matrix layer and a pressure-sensitive adhesive layer to enable continuous administration of an ionic drug and increase the drug transmittance using an absorption accelerator.

Transdermal administration systems that have a systemic effect of absorbing drugs through the skin;

1. The drug absorbed through the gastrointestinal tract prevents metabolism of the drug (loss or reduction of drug due to detoxification) or gastrointestinal absorption disorder by the hepatic first-pass through the portal vein.

2. The blood profile can be predicted to optimize the treatment effect

3. It is possible to maintain effective blood concentration for a long time by one dose.

4. Easy to administer and remove, excellent patient adaptability.

Percutaneous absorption system has the advantages as described above, has been attracting attention as a new administration method so far, active research is still in progress. In particular, it is known to be useful for drugs with severe metabolism by the first pass, drugs with short half-lives, and drugs having problems with gastrointestinal absorption.

However, although the transdermal administration system is in the limelight as an alternative method of oral administration, there are many drugs that have problems in transdermal absorption. In particular, when looking at the structure of the skin, 20% fat component and 40% keratin protein make skin permeability lower than hydrophilic and ionic drugs compared to lipophilic drugs (Physiological Reviews, 51 (4), October 1972, 702-741).

The prior art relating to such transdermal administration systems of hydrophilic, ionic drugs, describes a storage tank applying an aqueous solution of the drug in US Pat. Nos. 4,645,502, 4,904,475. However, this method is very complicated and economical problem by applying an aqueous solution.

The present inventors have completed the present invention by studying a transdermal administration system of a laminate type including a hydrophilic polymer gel as a matrix and an absorption accelerator.

The structure of the transdermal administration system provided by the present invention comprises a matrix layer in which an ionic drug is dispersed in a hydrogel on a rear layer to prevent drug diffusion, and an adhesive layer for attaching a patch to the skin, and a release layer thereon. It is. The matrix layer contains the active ingredient in the polymer hydrogel to control the release of the drug through the diffusion process.

Therefore, the selection of polymer is very important condition according to the type of drug. Hydrophilic and ionic drugs are very soluble in water, while they are insoluble in organic solvents. Therefore, the polymer for matrix may be a polymer that forms a hydrophilic hydrogel, in particular, polyvinylpyrrolidone, polyvinyl alcohol, or polyacrylate-based polymers. It is desirable to increase the compatibility.

In this way, it is possible to control the release of the drug in the matrix, but as already mentioned, the ionic drug in the skin structure of 20% fat and 40% keratin protein is required to use absorption accelerator to penetrate the skin.

The adhesive layer for attaching the skin of the patch is a path through which the drug released from the matrix passes to reach the skin, and thus, the adhesive layer is excellent in compatibility with the drug and has no phenomenon such as reduced adhesion.

The transdermal administration system, ie, the time it takes to absorb the drug and reach the blood, can be longer than oral or intravenous administration, so including the drug in the adhesive layer can reduce this time.

Thus, the patch manufactured to the adhesion layer is protected by a peeling layer.

Once again explaining the transdermal administration system of the ionic drug provided by the present invention, in order to increase the compatibility with the drug 10-50% (w / w) in the aqueous solution or aqueous dispersion of the polymer forming a hydrophilic hydrogel To dissolve and to add a plasticizer, a thickener and other additives so that the physical properties of the polymer can be coated to prepare a coating solution and coating on the back layer to prepare a drug matrix.

Thereafter, a pressure-sensitive adhesive layer is used to form a pressure-sensitive adhesive layer. At this time, a drug and an absorption accelerator are added to increase initial drug release and permeation amount, and the amount is determined within a range that does not lower the release rate of the desired drug and the adhesion of the polymer.

The final patch is completed by laminating the release layer on the thus prepared.

The back layer can be selected without limitation from polyethylene films, metallic laminates, foam tapes, etc., through which the drug cannot penetrate.

As a polymer used in the matrix layer, which is a characteristic component of the present invention, a water-soluble polymer capable of forming a hydrogel or a polymer dispersion dispersed in water is used to maximize the compatibility with an ionic drug to increase the release rate of the drug. A matrix layer is prepared. Among them, a mixed solution of polyvinylpyrrolidone and polyvinyl alcohol and an aqueous polyacrylate dispersion are particularly preferred in view of the advantages of the coating solution manufacturing process and the physical properties of the prepared matrix.

At this time, the addition of plasticizers such as propylene glycol, glycerin, polyethylene glycol, etc. increases the flexibility of the prepared matrix and also helps the diffusion of the drug into the matrix. The amount used varies depending on the type of polymer, but 20-40% of the amount is appropriate.

As a polymer used for adhesion layer coating, 1 type of polymers, such as a polyisobutylene, an acrylic copolymer, a vinyl acetate acrylate copolymer, and a polymethacrylate, can be selected. Considering the properties of water-soluble and ionic drugs, it is advantageous to use a polyacrylate, polymethacrylate-based pressure-sensitive adhesive.

Absorption accelerators for improving skin permeation of drugs include sulfoxides such as dimethyl sulfoxide, hexylmethyl sulfoxide and decylmethyl sulfoxide, octadecanoic acid, capric acid, lauric acid, linoleic acid, stearic acid and oleic acid. Fatty acids such as aric acid, fatty acid alcohols such as lauryl alcohol, oleyl alcohol, sorbitan monooleate, sorbitan monolaurate, sorbitan monopalmitate, sorbitan monostearate, isopropyl myristate, iso Non-ionic surfactants such as propyl palmitate, PEG monolaurate, N-methyl pyrrolidone, 2-pyrrolidone, propylene glycol, glycerin, polyethylene glycol can be selected and used at least one, It is particularly preferable to use alcohols, fatty acids, ester derivatives of fatty acids, and nonionic surfactants.

When the absorption accelerator and base materials such as propylene glycol, glycerin and polyethylene glycol are used together, the effect may be better depending on the drug.

In such a pressure-sensitive adhesive layer, the absorption accelerator is preferably 5-30% by weight relative to the adhesive polymer, and base materials such as propylene glycol, glycerin, polyethylene glycol and the like used with the absorption accelerator are preferably 5-20% relative to the polymer. On the other hand, the drug of the adhesive layer is preferably 5-30% compared to the polymer.

Once again, the transdermal administration system of the hydrophilic and ionic drug provided by the present invention will be described. A structure consisting of a drug matrix layer prepared using a hydrophilic hydrogel, an adhesive layer including an absorption accelerator and a drug, and a back layer and a release paper The matrix layer is composed of a hydrogel structure having excellent compatibility between the drug and the polymer, and the adhesive layer is composed of fatty acids, nonionic surfactants, fatty acid ester derivatives, alcohols, or a suitable base having an excellent effect on promoting the permeation of the ionic drug. It will include the absorption accelerator used in combination.

The advantage of the present invention is to prepare a transdermal administration system capable of continuously administering a hydrophilic and ionic drug which is difficult to penetrate the skin at a constant rate, and is compatible with the drug by applying a hydrogel matrix type using a water-soluble and hydrophilic polymer. To increase the rate of diffusion of the drug.

In addition, the problem of low skin permeability due to the ionic and hydrophilic properties of the drug was solved by using an absorption accelerator or an absorption accelerator mixed with a base.

Therefore, compared to the prior art storage tank transdermal administration system, it is possible to manufacture a patch that is simple and economical and excellent in patient adaptability.

Examples of hydrophilic and ionic drugs applicable to the transdermal administration system according to the present invention include metal salts such as indomethacin, dichlorophenac, acetazole amide, and metazol amide, naltrexone hydrochloride, naloxone hydrochloride, nalbuphine hydrochloride and phenyl hydrochloride. Prin, chlorpheniramine maleate, phenylpropanolamine hydrochloride, ondansetron hydrochloride, and calcium granitrone.

Although the present invention will be described in detail with reference to the following examples, the present invention is not limited to the examples.

Example 1.

Polyvinylpyrrolidone / polyvinyl alcohol matrix layer coating.

Polyvinylpyrrolidone / polyvinyl alcohol = 2/1, 3/2, 1/1, 2/3, 1/2 (w / w) in distilled water and 10-40% by weight of the total polymer in the solution Dissolve as much as possible. The chlorpheniramine maleate is dissolved in 10-40% of the polymer and propylene glycol is added in 20-50% of the polymer as a plasticizer and mixed well for about 10 minutes. The coating solution for the matrix thus formed was cast to a thickness of 1000 μm on the rear layer and dried at 50 ° C. for about 2 hours (sample numbers 1-1, 1-2, 1-3, 1-4, 1-5).

Thus prepared samples 1-1, 1-2, 1-3, 1-4, 1-5 was analyzed by HPLC for the amount of chlorpheniramine maleate diffused from the matrix using a transdermal dissolution tester. The results are shown in Table 1 below.

Table 1.

Evaluation of Release Rate of Drugs from Polyvinylpyrrolidone / Polyvinyl Alcohol Matrix

As a result, the larger the polyvinylpyrrolidone ratio, the greater the release rate of the drug. Therefore, the desired release rate can be adjusted by adjusting the ratio of the polymer according to the type of drug.

Example 2.

Check the effectiveness of absorption accelerators.

7 weeks old hairless mouse skin on Diffusion cell and lauryl alcohol, oleyl alcohol, oleic acid, capric acid, linoleic acid, lauric acid, N-methyl as absorption accelerator 5% solution was prepared by dissolving pyrrolidone, polyethylglycol monolaurate, isopropyl myristate, isopropyl palmitate, sorbitan monooleate, sorbitan monolaurate, sorbitan monostearate in ethyl alcohol Pour 0.5ml of each cell onto the skin of diffuse cells, leave for 14 hours at 32 ℃, remove the remaining solution on the skin and hydrate with saline solution in the receptor compartment for 30 minutes. .

Next, 4 ml of saturated aqueous solution of chlorpheniramine maleate was filled into the donor compartment to start a diffusion test, and the solution of the receiving membrane was 1, 2, 3, 4, 5, 6, 8, 10, 12 0.5ml each at 16, 20, 24 hours (hr) and analyzed by HPLC for the amount of chlorpheniramine maleate that penetrated the skin.

For comparison, experiments were performed with ethyl alcohol alone without using an absorption accelerator.

The experimental results are shown in Table 2 below.

Table 2.

Check the effectiveness of absorption accelerators

As shown in Table 2, the absorption promoting effect was particularly high in fatty acids, fatty acid ester derivatives, and nonionic surfactants.

Example 3.

Adhesive layer manufacture.

5-30% chlorpheniramine maleate is added to the polyacrylate-based adhesive solution, and the absorption accelerator is oleic acid, capric acid, linoleic acid, lauric acid, isopropyl myristate, isopropyl palmitate, sorbbi Tanmonolate, sorbitan monolaurate, sorbitan monostearate, and oleic acid + proylene glycol are added to each of 5-30% of the polymer and stirred for about 30 minutes. The pressure-sensitive adhesive coating liquid thus prepared was cast on a matrix layer (sample 1-3) prepared in Example 1 with a doctor blade of 250 μm and then dried in a hot air oven at 40 ° C.

For comparison, a sample was prepared in which no absorption accelerator was added to the adhesive layer.

Example 4.

Measurement of Percutaneous Absorption of Drugs from Final Patch.

The patch consisting of the back layer, the matrix, and the adhesive layer prepared in Example 3 was analyzed by HPLC for the amount of chlorpheniramine maleate penetrating the hairless mouse skin using a transdermal dissolution tester.

The results are shown in Table 3 below.

Table 3.

Evaluation of Drug Permeability in Patches with Different Adhesion Layer Compositions

As shown in Table 3, when prepared in the form of a patch, the effect is less than the value confirmed in the solution state, but showed a significant effect compared to the case without addition. And when the absorption accelerator and base are used together, the effect is even greater.

Example 5.

Preparation of transdermal administration system of naloxone hydrochloride and phenylpropanolamine hydrochloride.

Polyvinylpyrrolidone / polyvinyl alcohol = 1/1 in distilled water is dissolved so that the total polymer in the solution is 10-40% by weight. Naloxone hydrochloride and phenylpropanolamine hydrochloride are dissolved in 10-40% of the polymer, and propylene glycol is added in an amount of 20-50% of the polymer as a plasticizer and mixed well for about 10 minutes.

The coating solution for the matrix thus formed was cast to a thickness of 1000 μm on the back layer and dried at 50 ° C. for 2 hours.

5-30% of the drug is added to the acrylate-based adhesive solution, and the absorption accelerator is oleic acid, linoleic acid, sorbitan monooleate, sorbitan monolaurate, and oleic acid + propylene glycol. The pressure-sensitive adhesive coating solution prepared by adding -30% was cast on a matrix layer with a doctor's blade of 250 μm, dried in a hot air oven at 40 ° C. to prepare a patch, and the same procedure as in Example 4 Transdermal penetration rate is measured.

For comparison, a sample was prepared in which no absorption accelerator was added to the adhesive layer.

The results are shown in Tables 4 and 5, respectively.

Table 4.

Evaluation of Permeability Permeability of Naloxone Hydrochloride Patch.

Table 5.

Drug Permeability Evaluation of Phenylpropanolamine Hydrochloride Patch.

As described above, the new transdermal administration system of the hydrophilic and ionic drug according to the present invention has excellent drug release rate, is simple and economical to manufacture, and thus can be usefully used as a new transdermal administration system.

Claims (5)

Hydrogel matrices of hydrophilic and ionic drugs; Sulfoxides such as dimethyl sulfoxide, hexylmethyl sulfoxide, decylmethyl sulfoxide, octadecanoic acid, capric acid, lauric acid, linoleic acid, stearic acid, oleic acid, fatty acids such as lauryl alcohol, Fatty acids alcohols such as oleyl alcohol, sorbitan monooleate, sorbitan monolaurate, sorbitan monopalmitate, sorbitan monostearate, isopropyl myristate, isopropyl palmitate, PEG monolaurate An adhesive layer comprising at least one absorption promoter and a drug selected from a warm surfactant, N-methylpyrrolidone and 2-pyrrolidone; Transdermal administration system consisting of back layer and exfoliation layer The transdermal administration system according to claim 1, wherein the matrix polymer is one or a mixture thereof selected from polyvinylpyrrolidone, polyvinyl alcohol, and polyacrylate polymers. The transdermal administration system of claim 1, wherein the adhesive layer further comprises at least one base selected from propylene glycol, glycerin, and polyethylene glycol. The transdermal administration system according to claim 1 or 3, wherein the absorption accelerator is 5-30% by weight, 5-20% base, and 5-30% drug is added to the adhesive layer. In claim 1, the drug is a metal salt such as indomethacin, diclofenac, acetazole amide, metazol amide, naltrexone hydrochloride, naloxone hydrochloride, nalbutin hydrochloride, phenylephrine hydrochloride, chlorpheniramine maleate, phenylpropanolamine hydrochloride Transdermal administration system which is an ionic drug selected from the onset of the hydrochloric acid dansetrone, granis hydrochloride.