KR19990065619A - Matrix patch composition and preparation method thereof - Google Patents

Abstract

As a transdermal permeation method of hormonal agents such as estradiol, a matrix patch composition prepared by mixing a water-soluble polymer dissolved in a mixed solvent in a solution consisting of a hormonal agent, a skin extender, and an adhesive, and then evaporating the solvent is a cellulose-based water-soluble polymer. By increasing the permeability of the hormonal agent as well as increase the stability does not occur crystallization of the hormonal agent during the stability experiment.

Description

Matrix patch composition and preparation method thereof

[Industrial use]

The present invention relates to a transdermal permeation method of a hormonal agent, and more particularly, includes a hormonal agent such as estradiol, a skin expanding agent, a pressure-sensitive adhesive, and a water-soluble polymer, and a matrix type having improved drug stability and permeability by a water-soluble polymer. A patch composition, a method for producing the same, and a matrix patch including the same.

[Prior art]

Estradiol is a female hormone secreted by the ovaries of normal women and plays an important role in the development and maintenance of secondary sexual characteristics of the reproductive system.

However, after reaching the menopause of women in their 40s, estradiol, which is released from the ovary, is deficient, causing changes in depression, osteoporosis, severe mood changes, and sweating. Therefore, estradiol should be artificially administered to prevent or treat it.

Conventional estradiol administration can be divided into oral and injection methods and transdermal methods.

Percutaneous transfusion is advantageous in many ways over oral and injectable administration to provide drugs locally or systemically.

For example, oral administration has a disadvantage in that a large amount of drugs are degraded due to severe metabolism of the liver, so that an excessive amount of drug must be administered in order to obtain a constant drug, and repeated administrations in order to maintain the drug effect.

In order to solve this problem, there is a need for a method of effectively supplying drugs and minimizing side effects to the human body. Since the transdermal drug delivery system is directly and regulated to the body without the metabolism of the liver, All the disadvantages caused by oral administration are resolved, and the pain and mental burden of the patient caused by the injection method can be reduced, and there is no discomfort.

Transdermal drug delivery systems using estradiol can be classified into two methods.

One of them is the Shivagai Corporation membrane controlled transdermal drug delivery system described in US Pat. Nos. 4,379,454, 4,681,584, and 4,698,062, and the like. It is in the reservoir and has a membrane on the side where the drug is released. It is thick and complicated to manufacture.

The other is a matrix diffusion controlled transdermal drug delivery system, in which the drug is uniformly dispersed on a polymer matrix having a defined surface area and thickness. Research is underway at pharmaceutical companies and is currently marketed by Samyang Corp. and Ilyang Pharm.

However, the matrix type may cause crystallization of hormonal agents in the matrix due to heat and moisture during stability experiments.

The present invention is to solve the problems of the prior art as described above, an object of the present invention is to minimize the crystallization of hormonal agents that may appear in the form of a thin, simple manufacturing process and can maximize the stability and drug release It is to provide a matrix patch composition.

1 is a cross-sectional view of a matrix patch made in accordance with one embodiment of the present invention.

Figure 2 is a graph comparing the estradiol permeation rate with time of the formulations prepared by Examples and Comparative Examples of the present invention.

* Explanation of symbols for main parts of the drawings

A: drug support layer, B: drug reservoir layer, C: pressure-sensitive adhesive layer, D: release paper layer.

[Means for solving the problem]

In order to achieve the above object, the present invention is a hormone, skin extender, pressure-sensitive adhesive and ethyl cellulose, carboxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl methyl celluloid, dextran, poloxomer, polyvinyl It provides a matrix patch composition comprising a water-soluble polymer selected from the group consisting of pyrrolidone, polyethylene glycol, polyethyl glycol and mixtures thereof.

Among the water-soluble polymers, hydroxypropyl methyl cellulose is more preferable, and hydroxypropyl methyl cellulose is a water-soluble polymer, but because it is amphiphilic, it has a surfactant property, and this property is a hydrophobic drug estradiol in a water-soluble adhesive It serves to suppress crystallization.

The hormone is selected from the group consisting of estradiol, estrogen, testosterone, progesterone, and mixtures thereof, and the skin extender is methyl pyrrolidone, fatty alcohol, diethyl toluamide and these It is selected from the group consisting of a mixture of, and preferably comprises 0.1 to 50% by weight based on the total composition.

If the amount of the skin swelling agent is out of the above range, the permeation amount of the drug decreases, and the adhesion of the patch decreases.

The pressure-sensitive adhesive is selected from the group consisting of a rubber pressure sensitive adhesive, an acrylic pressure sensitive adhesive and SBR (Styrene-Butadiene Rubber) latex.

The composition ratio of the mixture of the hormonal agent and the skin expanding agent and the pressure-sensitive adhesive is preferably 0.1-1: 0.1-10 by weight ratio, and the composition ratio of the water-soluble polymer and the skin expanding agent is preferably 1-10: 0.1-1 by weight ratio. Do.

If each composition ratio is out of the above-mentioned range, the mechanical properties of the patch are lowered, the drug is not released constantly, which results in inaccurate efficacy, and the adhesive strength of the patch is lowered.

The present invention also provides a matrix patch including a drug storage layer comprising a drug support layer and the matrix patch composition described above formed on the drug support layer.

Preferably, the matrix patch further includes an adhesive layer formed on the drug storage layer.

A cross-sectional view of the matrix patch of the present invention is shown in FIG.

The matrix patch of the present invention comprises a drug support layer (A), a drug reservoir layer (B) containing a matrix patch composition, an adhesive layer (C) and a release paper layer (D).

In addition, the present invention comprises the steps of preparing a first mixture solution by dissolving a hormone in the skin dilator, adding a pressure-sensitive adhesive to the first mixture solution to prepare a second mixture solution, water-soluble polymer in the second mixture solution It provides a method for producing a matrix patch composition comprising the step of preparing a fourth mixed solution by adding a third mixed solution prepared by dissolving in a mixed solvent, and heating the fourth mixed solution.

The mixed solvent is preferably a mixture of a compound selected from the group consisting of ethanol, methanol and acetone and a compound selected from the group consisting of methylene chloride and chloroform, and the present invention further includes a step of raising one layer further with an adhesive after the heating step. It is desirable to.

EXAMPLE

The following presents preferred examples and comparative examples to aid in understanding the invention.

However, the following examples are merely provided to more easily understand the present invention, and the present invention is not limited to the following examples.

Example 1

1 part by weight of estradiol was completely dissolved in 0.4 part by weight of a mixture of methyl pyrrolidone and diethyl toluamide, which are skin extenders, and 3 parts by weight of AT-85, an acrylic pressure-sensitive adhesive, was mixed and then hydroxypropylmethyl was added to the mixture. 10 parts by weight of a solution prepared by dissolving 0.5 parts by weight of celluloid in 3 parts by weight of ethanol and 7 parts by weight of methylene chloride was added. The solution was mixed completely homogeneously with a homogenizer and placed in a 70 ° C. drying oven to evaporate the solvent to prepare a 60 micron thick patch.

Example 2

The pressure-sensitive adhesive was further applied to the patch prepared in the same manner as in Example 1 to a thickness of 10 microns.

Comparative Example 1

Beta-diol of Ilyang Pharmaceutical, a matrix diffusion control transdermal preparation, was used.

Skin permeation experiments were performed using the estradiol transdermal preparations obtained in Examples 1-2 and Comparative Example 1.

The experiment was performed by euthanizing a 6-week-old hairless mouse to remove the skin, and then carefully removing and washing the subcutaneous fat inside the skin to a Franz-type diffuser having a volume of about 20 ml and a diffusion area of 5 cm 2. After the preparation, the preparation for transdermal penetration was performed.

Phosphate buffered solution (phosphate buffered saline, PBS, pH 7.4) was added to the inside of the diffusion apparatus, and the estradiol permeation rate over time was measured by HPLC while maintaining a constant temperature of 36.5 ° C.

In addition, the stability experiments were carried out at 60 ℃, 75% humidity is shown in Table 1 the results.

Hours One 2 3 4 5 6 7 8 9 Example 1 ▲ Example 2 Comparative Example 1 ▲ ●

▲: Partially Generated Crystal

●: Fully crystallized

From the results of FIG. 2, it can be seen that the patches prepared according to Examples 1 and 2 have a higher permeation rate of the drug compared to the formulation of Comparative Example, and the results of Table 1 are determined in Example 1 and Example 2 It is understood that stability is high from this late generation or no crystal formation.

The present invention can solve the problem of crystallization of hormonal agents during stability experiments as well as increasing the permeability of hormonal agents by using water-soluble polymers in the preparation of matrix patches as compared to conventional methods.

Claims (17)

Hormonal agents; Skin dilators; adhesive; And In the group consisting of ethyl cellulose, carboxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl methyl celluloid, dextran, poloxomer, polyvinylpyrrolidone, polyethylene glycol, polyethyl glycol and mixtures thereof Selected water soluble polymers; Matrix patch composition comprising a. The method according to claim 1, The hormone agent is selected from the group consisting of estradiol, estrogen, testosterone, progesterone and mixtures thereof. The method according to claim 1, The skin extender is selected from the group consisting of methyl pyrrolidone, fatty alcohols, diethyl toluamide and mixtures thereof, the patch composition comprising 0.1 to 50% by weight based on the total composition. The method according to claim 1, The pressure-sensitive adhesive is a patch composition selected from the group consisting of a rubber pressure sensitive adhesive, an acrylic pressure sensitive adhesive and SBR latex. The method according to claim 1, The composition of the mixture of the hormonal agent and the skin extender and the pressure-sensitive adhesive is 0.1-1: 0.1-10 by weight ratio. The method according to claim 1, The composition ratio of the water-soluble polymer and the skin extender is 1-10: 0.1-1 by weight ratio. Drug support layer; And A drug storage layer comprising the matrix patch composition of claim 1 formed on the drug support layer; Matrix patch comprising a. The method according to claim 7, The matrix patch is a matrix patch further comprises a pressure-sensitive adhesive layer formed on the drug storage layer. Preparing a first mixed solution by dissolving a hormone in a skin dilator; Preparing a second mixed solution by adding an adhesive to the first mixed solution; Preparing a fourth mixed solution by adding a third mixed solution prepared by dissolving a water-soluble polymer in a mixed solvent to the second mixed solution; And Heating the fourth mixed solution; Method of producing a matrix-type patch composition comprising a. The method according to claim 9, The hormone is selected from the group consisting of estradiol, estrogen, testosterone, progesterone and mixtures thereof. The method according to claim 9, The skin expanding agent is selected from the group consisting of methyl pyrrolidone, fatty alcohols, diethyltoluamide and mixtures thereof, using 0.1 to 50% by weight based on the total composition. The method according to claim 9, The pressure-sensitive adhesive is selected from the group consisting of a rubber-based adhesive, an acrylic pressure-sensitive adhesive and SBR latex. The method according to claim 9, The composition ratio of the first mixed solution and the pressure-sensitive adhesive is 0.1-1: 0.1-10 by weight ratio. The method according to claim 9, The water-soluble polymer is ethyl cellulose, carboxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl methyl celluloid, dextran, poloxomer, polyvinylpyrrolidone, polyethylene glycol, polyethyl glycol and mixtures thereof Manufacturing method selected from the group consisting of. The method according to claim 9, The composition ratio of the water-soluble polymer and the skin extender is 1-10: 0.1-1 in weight ratio. The method according to claim 9, The mixed solvent is a mixture of a compound selected from the group consisting of ethanol, methanol and acetone and a compound selected from the group consisting of methylene chloride and chloroform. The method according to claim 9, After the heating step further comprising the step of further increasing the pressure-sensitive adhesive.