KR910003107B1 - Preparation for trans dermal permeation having ethylene-vinyl acetate matrix - Google Patents

Abstract

The trans dermal permeating of laminating structure is manufactured. by binding the ethylene-vinyl acetate copolymer matrix layer (a) (containg large amt. of vinyl acetate) contg. medicines of fixed concentration as medicines reserving layer, and the ethylene-vinyl acetate copolymer metrix layer (b) (containg small amt. of vinyl acetate) as release controlling layer; forming the adhesive layer (d) and the protecting layer (a) thereon.

Description

Controlled Release Transdermal Absorption Formulation of Ethylene-Vinyl Acetate Substrate Laminated Structure

1 is a polymer drug model of a laminated structure according to the present invention [a: protective film, b: drug storage layer, c: release control film, d: adhesive layer].

2 is a graph showing the release pattern of scopolamine in an ethylene-vinyl acetate laminate structure formulation [(1): Example 1, (2): Example 2].

Figure 3 is a graph showing the scopolamine release pattern in the ethylene-vinyl acetate drug storage layer-release control membrane two-layer structure formulation, wherein the drug storage layer is Elbox 40 [(1): the release control membrane is Elbox 410, (2): the release control film is Elbox 750, (3): the release control film is EVA L123].

4 shows graphs of the release of chloridine in an ethylene-vinyl acetate laminate structure formulation.

5 shows graphs showing the release of Chloride in ethylene-vinyl acetate two-layer or three-pack structural formulations [(1): Elbox 40 / Elbox 410, (2) Elbox 40 / Elbox 550, (3) Elbox 40 / Elbox 410 / adhesive layer, (4) Elbox 40 / Elbox 550 / adhesive layer].

The present invention relates to the development of new transdermal absorption formulations that allow the drug or bioactive substance to be absorbed through the skin at prolonged zero-order or pseudo zero-order rates.

The release rate of the drug from the formulation is controlled to have a constant release rate in the release control membrane in the polymer laminate structure, and the drug storage layer controls the release period of the drug. In addition, the first layer of such formulations is designed to quickly reach therapeutically effective concentrations of drugs in the blood with an initial excess release effect by introducing a pressure-sensitive adhesive mixed with an appropriate amount of drug. The release rate is determined by the degree of distribution and diffusion of the drug into the polymer and various release rates can be obtained by varying these factors.

In recent pharmaceutical fields, oral or parenteral administration of controlled release formulations for minimizing the body's toxicity, increasing the drug's availability, and improving patient compliance by maintaining the effective blood concentration of the drug for a long time. It has been developed a lot through the path.

As part of this effort, transdermal absorption formulations have recently been developed or are being developed for several drugs to allow systemic effects of drugs penetrated through the skin. The administration of the drug through the skin prevents the large amount of metabolism from inactivating in the liver by bypassing the first pass of the drug, and is a drug with a low therapeutic coefficient or metabolized by enzymes in the gastrointestinal tract, resulting in loss of activity. Drugs, drugs that cause gastrointestinal disorders, and drugs requiring long-term administration are very useful route of drug administration. In addition, due to the nature of the formulation, other parenteral preparations, such as injection (muscle injection, intravenous injection, subcutaneous injection), transplantation, and implantation, require surgical sagging or cumbersome and difficult administration, while transdermal absorption formulations require the patient to The formulations can be easily applied or removed, which has advantages over other formulations in terms of patient compliance. Such transdermal absorption formulations can be broadly classified into two types: a reservoir type in which a drug is encapsulated in a polymer membrane, and a monolithic type in which a drug is dispersed in a polymer simple matrix layer. The diffusion and distribution mechanism causes the system to be released into the system at zero or pseudo zero speed for a period of time.

In the former case using a polymer membrane, the drug or physiologically active substance is enclosed in a thin film made of a polymer so that the permeability of the polymer membrane can control the release rate. The formulation can be encapsulated inside the membrane by dissolving or dispersing the drug in a solid or liquid carrier, if necessary, but in any case the permeability of the drug in the carrier must be greater than the permeability of the drug in the polymer membrane and the application of the system to the human body. During the period the drug must maintain a saturated concentration in the carrier. This formulation has the advantage of showing a constant release rate, which is very important in terms of drug efficacy and safety in the body, but as a disadvantage, the burden of manufacturing cost increase due to manufacturing troubles than a simple matrix (monolit) formulation Is holding. The latter simple matrix type is a form in which a drug is dispersed in a polymer exhibiting an appropriate permeability to the drug, and the rate of release from this formulation is inversely proportional to the square root of time.

That is, it can be seen that the release rate of the drug from the dosage form initially shows a high release rate, and the release rate decreases with time. Nevertheless, the reason why simple matrix formulations are of greater commercial value is their ease of manufacture and low production costs.

The present invention has both the advantages of the two types of formulations while the disadvantages are minimized formulations.

That is, according to the present invention, by laminating the four layers of the protective layer, the drug storage layer, the release control layer, and the adhesive layer each having a polymer simple matrix form, the preparation method of the preparation is easy and at the same time for a predetermined time. A novel controlled release transdermal absorption formulation is provided which allows for drug release of the drug.

The polymer laminate structure according to the present invention is composed of a polymer simple substrate layer having four different roles. The polyisobutene adhesive layer, the first layer attached to the skin (FIG. 1 (d)), has a continuous penetration of the drug into the skin through intimate contact of the formulation with the skin. The time to reach saturation concentration in the skin of the drug was shortened to an effective blood concentration in a short time.

Also, if necessary, skin absorption accelerators such as fatty acids, alcohols, urea, sorbitol, pyrrolidone, dimethyl sulfoxide, decylmethyl sulfoxide, sodium laurate, isofurophyll myristate, pyroglutamic acid, azone and surfactant may be used. It is possible to add.

The second layer (FIG. 1 (c)), the release control membrane, is a polymer thin film that allows the system to exhibit a constant release rate at steady state. The release rate control ability of the release control membrane and the size of the system attached to the skin allow a wide range of desired release rates to be obtained so that, of course, in skin-controlled formulations such as nitroglycerin, leropranolol, and estrogen-containing transdermal absorption preparations, It is also suitable if the system needs to control its release rate, such as clonidine and scopolamine. As the emission control membrane used in the present invention, as the ethylene-vinyl acetate copolymer, various permeability can be obtained according to the change of crystallinity according to the amount of vinyl acetate in the polymer.

The third polymer layer [Fig. 1 (b)] is a drug-containing layer in which one or two or more drugs are dispersed or dissolved, and are mostly dispersed above a saturated concentration to keep the chemical activity of the drug constant for a certain period of time. . The polymer used in the drug storage layer may be the same or different types of polymer material as the release control membrane, and in any case should be an inert material that is not reactive to the drug to be used with the external environment, and does not cause toxicity in human application. It must be a biocompatible material. In addition, it should be a material that has adequate flexibility and elasticity and is free from inconvenience in handling and use. Commonly used materials include ethylene-vinyl acetate copolymer, polyethylene, polypropylene, polyacrylonitrile, polybutyl methacrylate, polyvinylidene chloride, polybutadiene, styrene-butadiene copolymer, polyurethane, polyacrylamide, Polydimethylsiloxane, polycarbonate, vinyl chloride, vinyl acetate, styrene, vinylidene chloride, copolymers of dialkyl fumarate and acrylonitrile, and the like. The polymer used in the present invention is an ethylene-vinyl acetate copolymer. Vinyl acetate content was 5% -40% and Melt Index was 1-500. In this drug storage layer, various additives such as dissolution aids, gelling agents, and surfactants can be mixed and dispersed together with the drug to increase the diffusion and distribution of the drug to the polymer, and a plasticizer or ultraviolet ray to change the polymer properties. Additives such as stabilizers, antioxidants, preservatives, tackifiers and skin absorption accelerators can be used.

The fourth layer (Fig. 1 (a)), which is the outermost layer of the formulation, is a polymer layer with little drug permeation, which protects the drug in the drug storage layer from the external environment. It inhibits volatilization and serves as a support for the formulation. The protective layer is prepared by laminating a metal thin film such as an aluminum thin film and a polymer. The polymers used are mainly polyethylene terephthalate, polyvinyl chloride, polyethylene, and polypropylene.

Hereinafter, the present invention will be described in detail by way of examples.

Example 1

Ethylene-vinyl acetate copolymer high weight (Elbox 40, Dupont) 18% by weight of scoformin (Sigma) 3% by weight of chloroform solution was cast on an aluminum-coated polyethylene terephthalate film auxiliary layer of about 50㎛ The drug storage layer of was prepared. Here, a 35 μm thick ethylene vinyl acetate copolymer polymer (Elbox 650, DuPont) film prepared by an inflation method as a release control film was laminated at 80 ° C., and then an adhesive layer having a thickness of about 50 μm again on the release control film. Was prepared and laminated at 25 ° C. The adhesive layer comprises 13% by weight of high molecular weight polyisobutene (Vistanex MML 140, Exxon), 12% by weight of low molecular weight polyisobutene (Tetrax 6T, Japan Petrochemical Co., Ltd.), 30% by weight of mineral oil (Sigma), A chloroform solution containing 4.5% by weight of polyamine was prepared and then cast on a polyethylene terephthalate film surface treated with silicone.

The laminated structure was cut into a circular disk shape so as to have an area of 2.5 cm 2, mounted on a continuous flow eluting device at a temperature of 32 ° C., and then phosphate buffer solution (pH 7.4) was discharged at a flow rate of 5 ml per hour to be released. Scopolamine was quantified by liquid chromatography. The release test for 72 hours resulted in a constant release rate of 15 μg per hour after 200-300 μg excess release in the first few hours [FIG. 2 (1)].

Example 2

A drug storage layer, a release control membrane, and an adhesive layer were prepared and laminated as in Example 1, but as the adhesive layer, 15 wt% of high molecular weight polyisobutene, 13 wt% of low molecular weight polyisobutene, 25 wt% of mineral oil, and scopolamine The drug release test was carried out in the same manner with a composition of 4.5% by weight and showed a constant release rate of 10 μg per hour after the initial 200-300 μg excess release [FIG. 2 (2)].

Example 3

As a result of using the ethylene-vinyl acetate copolymer polymer (Elbox 150, DuPont) as the drug storage layers in Examples 1 and 2, the same results as in Examples 1 and 2 were obtained, respectively.

Example 4

As a result of using the ethylene-vinyl acetate copolymer polymer (Elbox 210, DuPont) as the drug storage layers in Examples 1 and 2, the same results as in Examples 1 and 2 were obtained, respectively.

Example 5

In Examples 1 and 2, ethylene-vinyl acetate copolymer polymer (Elbox 410, DuPont) was used as the drug storage layer, and the same results as in Examples 1 and 2 were obtained, respectively.

Example 6

A double layer in which a 35 μm thick ethylene-vinyl acetate polymer (Elbox 410, DuPont) film was laminated on the drug storage layer prepared in the same manner as in Example 1 was used for 40 hours under the same conditions as in Example 1. The release test resulted in a release rate of 30-40 μg per hour after the initial excess release (FIG. 3 (1)).

Example 7

Using the ethylene-vinyl acetate copolymer polymer (Elbox 750, DuPont) as the release control membrane in Example 6, the release rate of 15-25㎛ per hour was shown (Fig. 3 (2)).

Example 8

As a result of using the ethylene-vinyl acetate copolymer polymer (YV L123, Hanyang Chemical Co., Ltd.) as the release control membrane in Example 6, the release rate was 10-20 µg per hour [Fig. 3 (3)].

Example 9

In Example 1, the release test was performed in the same manner with the thickness of the release control film being 70 μm, and a steady release rate of 13 μg per hour was shown at steady state.

Example 10

In Example 1, the release test was conducted in the same manner with the release control film having a thickness of 100 μm. As a result, a constant release rate of 9 μg per hour was shown at steady state.

Example 11

In Example 1, a laminated structure was prepared by using clonidine (Sigma) instead of scopolamine as a drug, cut into a circular disk having an area of 3.5 cm 2, and then subjected to a release test for 7 days in the same manner. Release rate was shown (Figure 4).

Example 12

The laminated structure of clonidine was prepared using the polymer composition of Example 2, and tested in the same manner as in Example 11, and showed a steady state release rate of 4 µg per hour.

Example 13

In Example 1, a drug storage layer was prepared using clonidine instead of scopolamine, and then a 35 μm-thick ethylene-vinyl acetate copolymer polymer (Elbox 410, DuPont) film was laminated as an emission control film, and the area was 3.5 cm 2. The release test was carried out by cutting into a circular disk of. As a result of the test for 48 hours, the release rate was increased up to 9 hours and then decreased to the first rate (Fig. 5 (1)).

Example 14

In Example 13, when the ethylene-vinyl acetate copolymer polymer (Elbox 550, DuPont) was used as the release control membrane, the release rate tended to decrease with time in the range of 15-50 μg. 5 degrees (2)].

Example 15

After the adhesion layer of Example 1 was laminated on the laminated structure of Example 13, the same test as in Example 13 was carried out, and the steady state release rate of 8 µg / hour was obtained (Fig. 5 (3)).

Example 16

After the adhesive layer of Example 1 was laminated on the laminated structure of Example 14, the release test was conducted in the same manner as in Example 13. As a result, a steady state release rate of 3 µg / hour was shown (Fig. 5 (4)).

Claims (14)

A drug storage layer containing a certain concentration of drug is combined with an ethylene-vinyl acetate copolymer substrate layer having a high vinyl acetate content, and an ethylene-vinyl acetate copolymer substrate layer having a low vinyl acetate content as a release control film, and the adhesive layer and the protective layer. A transdermal absorbent formulation of a laminated structure in which a layer is added to form a single piece. The method of claim 1, wherein an ethylene-vinyl acetate copolymer having a vinyl acetate content of 18-40% by weight is used as the drug storage layer. The method of claim 1, wherein the drug storage layer is uniformly dispersed in the ethylene-vinyl acetate copolymer by weight of drug in an ethylene-vinyl acetate copolymer using solvent casting. The method of claim 1, wherein the drug is released at a zero order rate for a long time using an ethylene-vinyl acetate copolymer having a vinyl acetate content of 5-18% by weight as a release controlling membrane. The method of claim 4, wherein the release rate of the drug is controlled by varying the thickness of the release controlling membrane or the vinyl acetate content. The method according to claim 1, wherein the adhesive layer is composed of high molecular weight polyisobutylene and low molecular weight polyisobutylene as main components, and mineral oil is added to increase the adhesiveness and increase the initial release rate of the drug. The method of claim 1, wherein the initial excess release rate is increased by incorporating an appropriate amount of drug in the adhesive layer to rapidly reach a therapeutically effective blood concentration. The method of claim 1, wherein a polyethylene terephthalate film coated with a silicone or other release agent is attached to the outside of the adhesive layer to protect the formulation, and to peel off during application. The method of claim 1, wherein an aluminum coated polyethylene terephthalate film or polypropylene film is used as the protective layer. The method of claim 1, wherein the drug storage layer, release control layer, adhesive layer, and protective layer are laminated at 25-150 ° C. using a laminator. The method according to claim 1 or 10, wherein the laminated structure is cut into circular or rectangular disks having an area of 1-20 cm 2 to be formulated into formulations of various sizes having different release amounts. The method according to claim 1, wherein the drug is a transdermal absorption formulation of clonidine, which is used to treat hypertension, and scopolamine, which is used to treat anemia. The method of claim 1, wherein the clonidine is formulated into a transdermal absorption formulation that exhibits a release area of 1.3-2.5 μg per unit area and unit time. The method of claim 1 or 12, wherein the scopolamine is formulated into a transdermal absorption formulation that exhibits a release area of 3-5 μg per unit area and unit time.

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