KR100382373B1 - The polyurethane backing materials having a good property of preventing from back-diffusion of medicine for patch, and the manufacturing method of the same - Google Patents

Abstract

The present invention relates to a polyurethane support for producing a patch having excellent anti-diffusion inhibiting ability of a drug and a method for producing the same, and more particularly, by adding an absorption promoter in preparing a polyurethane film constituting the polyurethane support, Unlike the conventional method to contain the drug has a physical property to suppress the propensity to de-diffuse into a polyurethane film, and relates to a polyurethane support for producing a patch agent excellent in elasticity and a method for producing the same.

Description

The polyurethane backing materials having a good property of preventing from back-diffusion of medicine for patch, and the manufacturing method of the same}

The present invention relates to a polyurethane support for producing a patch having excellent anti-diffusion inhibiting ability of a drug and a method for producing the same, and more particularly, by adding an absorption promoter in preparing a polyurethane film constituting the polyurethane support, Unlike the conventional method to contain the drug has a physical property to suppress the propensity to de-diffuse into a polyurethane film, and relates to a polyurethane support for producing a patch agent excellent in elasticity and a method for producing the same.

The drug is processed into a formulation that is convenient for application and optimally expresses pharmacological effects and then administered to the living body through several routes, and the administered drug is released into the formulation, absorbed and distributed to each organ along the bloodstream and then metabolized. And urinary excretion. In this case, the pharmacological effect of the drug is exerted by the drug that reaches the site of action (receptor) in vivo, and the drug going to another site mainly causes the side effects. Since the efficacy of general drugs is shown in proportion to blood drug concentration, it is necessary to adjust the shape of blood concentration curve by various pharmaceutical techniques. Of course, drugs that have severe side effects when transitioned to anticancer drugs, genetic material or normal tissues need to maximize drug delivery to target sites using special techniques rather than blood concentration control.

Therefore, there is a need to control the in vivo behavior of the drug by various techniques to realize stable and effective drug treatment and to selectively deliver the drug to the site of action. To this end, the drug delivery system (Drug Delivery System, DDS) is used to mean a formulation designed to efficiently deliver the required amount of drugs by reducing side effects of drugs and maximizing efficacy and effectiveness. The structure of such a DDS preparation is largely classified into a drug layer and a support. The drug layer is composed of drugs and other materials such as pressure-sensitive adhesives, absorption accelerators, and the support serves to support the drug layer.

Representative support used in the prior art is that the non-woven fabric is used, which lacks elongation, there is a problem that often falls when attached to the curved part of the human body.

In order to solve this problem, attempts have been made to replace the support with an elastic material such as polyurethane, and in Korea, DDS formulations using a polyurethane support such as Trast (SK Pharma) or Rheumatose (Keun Dang Dang) are commercialized. It came to be. However, when a general polyurethane film is used as a support, there is a problem in that the drug contained in the drug layer is not diffused into the skin but despread toward the film. In order to improve this, domestic DDS formulation-related manufacturers control the deformation of drugs by adjusting the formulation of the drug layer, but there is still a problem of despreading, which requires more fundamental solutions.

Accordingly, the present inventors have made efforts to develop an improved support for DDS preparations while solving the problems as described above more fundamentally. As a result, by introducing absorption promoters such as fatty acid esters, fatty alcohols and solvents contained in the pharmaceutical layer of the patch into the synthesis or compounding of the polyurethane film, it is possible to suppress the back-diffusion of the chemicals, and furthermore, polyethylene and The present invention was completed by coating the silicone in order to realize excellent peelability with respect to the polyurethane film.

Accordingly, the present invention provides a polyurethane support and a method of manufacturing the same that can be easily adhered to the human body with excellent elasticity and excellent in wearing comfort, but also excellent in despreading ability of the drug to maximize the drug effect of the patch applied to the skin. There is this.

Figure 1 shows the configuration of the polyurethane support according to the invention.

FIG. 2 is a graph showing comparison of cumulative skin absorption amount of testosterone according to a support when sorbitan monolaurate and diethylene glycol monoethyl ether are used as an absorption accelerator. FIG.

Figure 3 is a graph showing the comparison of the cumulative skin absorption amount of testosterone according to the support when propylene glycol is used as the absorption accelerator.

Figure 4 is a graph showing the comparison of the cumulative skin absorption amount of testosterone according to the support when dodecanol is used as the absorption accelerator.

[Description of Symbols for Main Parts of Drawing]

1: polyurethane film 2: release paper

The present invention relates to a patch applied to the skin comprising a pharmaceutical layer containing a drug, an adhesive, an absorption accelerator, and a polyurethane support composed of a polyurethane film and a release paper,

The polyurethane film contains 6 to 10% by weight of an absorption accelerator, and is characterized in that the polyurethane support is useful for producing a patch to the skin excellent in anti-diffusion ability of the drug.

In addition, the present invention is a method for producing a polyurethane support for preparing a patch to the skin,

Adding a polyol, glycol, and an absorption accelerator, and then adding 60% of the dimethylformamide to be added, and then raising the temperature to 45 to 55 ° C. while stirring at 30 to 40 rpm,

When the temperature increase is completed, adding 80% of the isocyanate to be added and adding a tin-based catalyst while stirring at 40 ~ 60 rpm, reacting at 65 ~ 85 ℃,

When the isocyanate group is extinguished, at a stirring speed of 40 to 60 rpm and a temperature of 65 to 85 ° C., 5% of the isocyanate to be added is added, and then the remainder of dimethylformamide is added, and 3% of the isocyanate to be added is added, followed by methyl ethyl ketone To obtain a polyurethane prepolymer by adding the other, while reducing the amount of isocyanate, and

It is characterized by a method for producing a polyurethane support for DDS formulations excellent in anti-diffusion inhibiting ability of the drug consisting of a step of coating the prepolymer on a release paper and dried to produce a drug.

The present invention will be described in more detail as follows.

The present invention relates to a polyurethane support and a method for producing the patch having a physical property of suppressing the propensity to de-diffusion into a polyurethane film, excellent elasticity and useful for the preparation of a patch applied to the skin.

When explaining the polyurethane support and the preparation method thereof useful for the preparation of a patch applied to the skin according to the present invention in more detail as follows.

The support of the patch of the present invention consists of a polyurethane film layer and a release paper layer.

First, the polyurethane film layer can be obtained by coating a liquid polyurethane prepolymer on a release paper and drying it. The polyurethane prepolymer is an absorbent, additive, and solvent contained in a pharmaceutical layer of aromatic isocyanate, polyol, glycol, and patch agent. It is prepared using.

As the aromatic isocyanate, 4,4'-diphenylmethane diisocyanate (MDI) is used, and MDI-MT commercially available from Nippon is used.

In addition, the polyol may be a polyester polyol. At this time, in order to increase the durability and chemical resistance of the polyurethane prepolymer, it is preferable to use a polyester polyol and a carbonate polyol in parallel. In other words, K-340 produced by the same chemical and PCD N-980R commercially available from Nippon can be used as an example.

The glycol is used to enhance the strength of the polyurethane prepolymer, and glycols suitable for the present invention are preferably 1,4-butanediol commercially available from BASF and ethylene glycol commercially available from Hyundai Petrochemical.

The absorption accelerator is a component that is characteristically used in the present invention in order to suppress the dispersibility of the drug, the same material as the absorption accelerator contained in the drug layer of the patch. Such absorption accelerators include fatty acid esters, fatty alcohols, and solvents, and fatty acid esters include lauric acid, myristic acid, palmitic acid, linolenic acid, and stearic acid. One or two or more selected from esters such as acid) may be used in combination. Preferably, sorbitan monolaurate (SPAN-20) commercially available from Sigma-Aldrich is used. Fatty alcohols include decanol, dodecanol, linolenyl alcohol, nerolidol, and oleyl alcohol. Preferably, dodecanol is used. Used. Examples of the solvent include ethanol, lauryl chloride, propylene glycol, and the like, and propylene glycol is preferably used. The content of the absorption accelerator used in the reaction is suitably 2 to 3% by weight based on the weight of the polyurethane prepolymer, 6 to 10% by weight based on the weight of the polyurethane film. At this time, when the 3 wt% or more of the polyurethane prepolymer is introduced based on the weight, the reaction stability is lowered and the adhesiveness is excessively imparted to the polyurethane prepolymer.

The additive is used to reduce the viscosity of the polyurethane prepolymer, and in the present invention, a copolymer of acetate and styrene, and a modified substance of silica are added. In this case, the co-conjugate of acetate and styrene is preferably AS-Resin which is commercially available in a die cell, and the modified material of silica is preferably TS-100 which is commercially available from Daegu.

In synthesizing the polyurethane prepolymer, a solvent is used for the dilution of the polymer in addition to the materials listed above, and the solvent used in the present invention is commercially available from dimethylformamide (DMF) and tonen commercially available from DuPont. Methyl ethyl ketone (MEK) is used.

When the polyurethane prepolymer as described above is a liquid phase and is coated on a release paper and subjected to a drying step, the solvent is volatilized in its entirety and is not contained in the final product, thereby obtaining a solid polyurethane film layer.

On the other hand, the release paper used in the present invention is produced by coating polyethylene on both sides of the main material as paper, and then coating silicon on both sides thereof. In this case, the additional coating of silicone is a feature of the present invention. The reason for this is to provide a smooth peelability when peeling the film and the release paper in the manufacturing process of the DDS formulation, thereby preventing the film from sticking to the release paper. to be. It is preferable to use 150-160 g of products per 1 m 2 of such release paper.

As a result of comparative testing of the polyurethane support prepared in the above composition, it was confirmed that the skin transmittance of the drug is always about 1.5 times higher than the conventional one.

Therefore, the polyurethane support and the preparation method thereof useful for the preparation of a patch applied to the skin to suppress the reverse diffusion of the drug according to the present invention as described above can be mainly applied to medicines and the like.

Hereinafter, the present invention will be described in more detail with reference to Examples, but the present invention is not limited to Examples.

Example 1 Preparation of Polyurethane Prepolymer

Polyols (K-340, PCD N-980R), glycols (1,4-butanediol, ethylene glycol) and fatty acid esters were added to the reaction batch in the total order. After the whole amount was added, 60% of DMF which is a solvent was added, and it stirred with the stirrer speed of 30-40 rpm. While stirring, the temperature in the batch is raised to 45-55 ° C. When the temperature is raised to the target temperature, 80% of isocyanate (diphenyl-4,4'-diisocyanate) is added and the stirring speed is increased to 40-60 rpm. After 10 minutes, 0.0003% by weight of the tin-based catalyst was added to the entire prepolymer. At this time, the reaction temperature is maintained at 65 to 85 ℃, the stirring speed is 40 to 60 rpm. Then, if 30% or more of the isocyanate group disappears after 5% of isocyanate is added, the remaining 40% of the solvent DMF is added, but if the isocyanate group is present, the reaction is continued. At this time, the presence of isocyanate group is checked by IR chart machine. Next, if 3% isocyanate is added and after 30 minutes or more, the isocyanate group disappears, and then the total amount of MEK is added to the solvent, but if the isocyanate group is present, the reaction is continued. Then, the isocyanate is added in 0.5% increments to increase the viscosity. At this time, each time isocyanate is added, the isocyanate group is checked each time, and the isocyanate group is extinguished and then added again. Check the viscosity from time to time during the reaction, the viscosity is in the range of 1,000 ~ 1,500 cps at 50 ℃, if the isocyanate group disappeared, add all the additives AS-Resin and TS-100 in order and then stirred for 90 minutes and then packed. The polyurethane prepolymer thus prepared showed a viscosity of 1000 to 2000 cps at 30 ° C. and a solid content of 30%. Table 1 shows components and composition ratios of the polyurethane prepolymer.

Example 2 Method of Casting Film with Polyurethane Prepolymer

Release paper was connected to the coating facility. After the release paper was connected to the coating equipment, the tension was adjusted so that the release paper was tensioned using a tension (tension) controller. In this case, if the tension is too tight, the release paper may overlap, so care should be taken. Then, the temperature in the coating equipment is raised to 90 to 100 ° C., and the method of raising the temperature generally uses steam or oil. In this case, as a coating method, it is generally preferable to use a comma coater, and to adjust the coating clearance to 0.18 to 0.20 mm in order to adjust the thickness of the final cast polyurethane film to 30 to 40 μm. It was. Then, the liquid prepolymer prepared in Example 1 was passed through a coating equipment to obtain a solid film. At this time, the line speed is appropriately adjusted according to the thickness of the cast film. If the film is to be obtained with a thickness of 30 to 40 μm with the prepolymer, the line speed may be adjusted so that the retention time in the coating equipment is 2 minutes. .

Test Example 1 Comparison of Skin Permeability of Pharmaceutical Agents Using Sorbitano Monolaurate and Diethylene Glycol Monoethyl Ether as Absorption Promoter

3% by weight of testosterone and 10% by weight of sorbitan monolaurate and 10% by weight of diethylene glycol monoethyl ether, the absorption accelerators having the composition shown in Table 2, were added to the polyacrylate-based pressure-sensitive adhesive material, and the drug Stir well until dissolved in the solution or evenly mixed. Then, the mixed solution was poured into an impermeable protective layer, and then the substrate layer was coated, and then continuously dried while raising the temperature step by step to prepare a pharmaceutical layer. On the pharmaceutical layer was laminated a polyurethane support prepared according to the composition of Table 2 and stored at room temperature. For the skin absorption experiment of the formulation thus prepared, the skin extracted from humans was attached to the Valia-chein diffusion cell so that the stratum corneum was directed out of the cell, and the dry patch was attached on the skin. The screws of the cell holder were fixed. Then, the cell was filled with a certain amount of receptor solution (PEG 400 / Seline solution = 40/60) and stirred. A certain amount of sample was taken at a predetermined time, quantified by high-performance liquid chromatography, and the results of skin absorption promotion between the supports were compared. The results are shown in Table 2 and FIG. 2.

Referring to Table 2 and Figure 2, it can be seen that the 2.5% by weight of sorbitan mono laurate (sorbitan mono laurate), the polyurethane support introduced into the polyurethane film synthesis has a greater skin absorption effect of the drug than the non-polyurethane support.

Test Example 2 Comparison of Skin Permeability of Pharmaceutical Agents Using Propylene Glycol as Absorption Promoter

In the same manner as in Test Example 1, but propylene glycol (PG) was used as the absorption accelerator of the drug layer, and the polyurethane support was synthesized or blended with propylene glycol and no addition at all. It is shown in Table 3 and FIG. At this time, the mixture was mixed by stirring for 60 minutes at 40 to 60 rpm which is the same stirring speed as in the synthesis.

As shown in Table 3 and Figure 3, when 2.0 wt% of propylene glycol was synthesized or blended into the polyurethane support, the effect of promoting skin absorption was much greater than that of the polyurethane support containing no propylene glycol at all. It was found to be similar.

Test Example 3 Comparison of Skin Permeability of Drugs Using Dodecanol as Absorption Promoter

Dodecanol (Lauryl alcohol) was used as the absorption accelerator of the drug layer, and the polyurethane support was used as a combination of dodecanol (Lauryl alcohol) and no addition at all. The results are compared and shown in Table 4 and FIG. 3.

Looking at Table 4 and Figure 4, it can be seen that when the dodecanol is combined with the polyurethane support, the skin absorption promoting effect is greater than that of the non-polyurethane support. In addition, it can be seen that a formulation containing 2 wt% of dodecanol is more effective than a formulation containing 1 wt% of dodecanol.

As described above, the polyurethane support for producing a patch having excellent anti-diffusion inhibiting ability of the drug of the present invention, and a method for producing the same, in general, by adding a skin absorption promoter to the polyurethane film, which is contained in the drug layer of the patch, It prevents the phenomenon of powder from being diffused back toward the polyurethane film, which is a support, and helps the drug to be smoothly absorbed into the skin, and can be effectively applied to medicines by utilizing the excellent elasticity of the polyurethane film.

Claims (8)

In a patch applied to the skin formed by combining a pharmaceutical layer containing a drug, an adhesive, an absorption accelerator, and a polyurethane support composed of a polyurethane film and a release paper, The polyurethane film contains 6 to 10% by weight of one or two or more absorption accelerators selected from fatty acid esters, fatty alcohols, and solvents (one or two or more selected from ethanol, lauryl chloride, and propylene glycol). Polyurethane support for producing a patch excellent in anti-diffusion inhibitory ability of the drug, characterized in that. delete The method of claim 1, wherein the fatty acid ester is a poly for producing a patch excellent anti-diffusion inhibitor, characterized in that using at least one selected from lauric acid ester, myristic acid ester, palmitic acid ester, linolenic acid ester and stearic acid ester Urethane support. The polyurethane support for preparing a patch according to claim 1, wherein the fatty acid alcohol is at least one selected from decanol, dodecanol, linorenyl alcohol, nerolidol, and oleyl alcohol. . The polyurethane support for preparing a patch according to claim 1, wherein the solvent is propylene glycol. In the production method of the paechwije for preparing polyurethane support, Adding a polyol, glycol, and an absorption accelerator, and then adding 60% of the dimethylformamide to be added, and then raising the temperature to 45 to 55 ° C. while stirring at 30 to 40 rpm, When the temperature increase is completed, adding 80% of the isocyanate to be added and adding a tin-based catalyst while stirring at 40 ~ 60 rpm, reacting at 65 ~ 85 ℃, When the isocyanate group is extinguished, at a stirring speed of 40 to 60 rpm and a temperature of 65 to 85 ° C., 5% of the isocyanate to be added is added, and then the remainder of dimethylformamide is added, and 3% of the isocyanate to be added is added, followed by methyl ethyl ketone Adding, adding and reacting while reducing the amount of isocyanate to obtain a polyurethane prepolymer, and The method of producing a polyurethane support excellent in the anti-diffusion ability of the drug, characterized in that consisting of a step of coating the prepolymer on a release paper and dried. 7. The method of claim 6, wherein the release paper is coated with polyethylene on both sides of the paper, and then coated on both sides with silicone again to produce a polyurethane support having excellent anti-diffusion ability. 7. The method of claim 6, wherein the polyol is a polyester polyol and a carbonate polyol, which are mixed and used.