JP2014210759A - Emulsion patch of hydrophilic medicine - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide an emulsion patch with high efficiency for disease prevention or treatment.SOLUTION: An emulsion patch comprises a hydrophilic medicine and an emulsion adhesive as essential components, and preferably, further comprises a polyhydric alcohol. A typical hydrophilic medicine is sumatriptan that is a medicine for treating migraine.

Description

  The present invention relates to a transdermally absorbable preparation for preventing or treating a disease, especially an emulsion patch.

Sumatriptan is a molecule similar in structure to serotonin and has a medicinal effect for preventing or treating migraine. Sumatriptan is usually administered by tablet or subcutaneous injection. However, the oral administration method and the subcutaneous injection method using tablets are not desirable administration methods since the duration of the effect is short (Patent Document 1). In order to maintain the effect of sumatriptan for a long time, administration by a patch type patch is desirable (Patent Documents 1 and 2).

Japanese National Patent Publication No. 8-5099749 Special table 2009-520830

  Currently known sumatriptan patches have a problem that the ratio of the amount of hydrophilic drugs absorbed into the skin is small and the efficiency is low. There is a need for a sumatriptan patch that overcomes these weaknesses.

  The patch according to the present invention made to solve the above-mentioned problems is characterized by comprising a hydrophilic drug and an emulsion adhesive as essential components. The emulsion patch in the present invention refers to a transdermally absorbable preparation comprising a substrate mainly composed of an emulsion adhesive and a hydrophilic drug.

  In this specification, a hydrophilic drug is defined as a drug having the highest solubility in water among three solvents of water (including water adjusted to pH by adding an acid or a base), ethyl acetate, and toluene. Specifically, in addition to sumatriptan, bisphosphonates such as alendronate can be mentioned.

  The emulsion adhesive is an adhesive in which latex particles are suspended using water as a solvent. When a hydrophilic drug is mixed in an emulsion adhesive and dried, the hydrophilic drug is present in the latex particles more than in the adhesive because of its low solubility in the adhesive. Emulsion adhesives often contain emulsifiers, so that they are more stabilized between particles. Since the difference in polarity between the drug and the adhesive is large, the rate at which the drug dissolves in the adhesive is extremely small. The latex interparticle layer is considered to form a continuous phase in the emulsion adhesive, and when a patch (emulsion patch) using such an emulsion adhesive is applied to the skin, the drug in the adhesive layer close to the skin surface As it is absorbed by the skin, the internal drug diffuses from the inside to the skin surface and is absorbed by the skin. This diffusion of the drug is performed very smoothly when the phase containing the drug is a continuous phase, so that the drug held in the patch using the emulsion adhesive exhibits high skin permeability. When the concentration of the drug in the emulsion adhesive is high, the drug is dispersed and crystallized. Even so, if the drug has water solubility in the drug crystals, high skin permeability is exhibited.

  On the other hand, in the case of a patch in which a hydrophilic drug is held in a solution-type acrylic adhesive, the hydrophilic drug is crystallized inside the acrylic adhesive. Moreover, since ordinary acrylic pressure-sensitive adhesives have low hydrophilicity (rubber-based pressure-sensitive adhesives are even lower), the speed at which the internal drug moves by diffusion is low. This is because the drug does not form one continuous phase in the acrylic adhesive. It is clear that the same effect as the emulsion adhesive can be expected if the solution-type acrylic adhesive is emulsified and dispersed in water by an appropriate method and mixed with the drug.

  When a polyhydric alcohol such as glycerin coexists in the emulsion adhesive, it is present in the emulsifier phase more than in the adhesive and coexists with the drug, further expanding the drug diffusion route and increasing the drug diffusion rate. To improve the transdermal absorbability of drugs.

  The use of emulsion adhesive increased the transdermal absorption rate of the drug and increased its absorption efficiency.

Sectional view of the patch of the present invention Diagram of blood analysis results using rats Table of biopharmaceutical parameters calculated from FIG.

Examples of the present invention are shown below, but the present invention is not limited to the examples.
Table 1 shows the compositions of the patches of Examples 1 to 8 and Comparative Examples 1 to 3 of the present invention.

(Create patch)
Sumatriptan succinate was dissolved in an appropriate amount of water, and each composition shown in Table 1 was added and dissolved uniformly. While stirring the emulsion adhesive solution containing a predetermined solid content well with a stirrer, the above aqueous solution was added little by little to obtain a uniform mixed solution. The adhesive used was (1) Kazole TS-600 (Methyl acrylate and 2-ethylhexyl acrylate, containing polyoxyethylene nonylphenyl ether as an emulsifier, manufactured by Nippon Carbide), (2) HiPAS10 (methoxy acrylate) There were three types of solution-type pressure-sensitive adhesives having ethyl as the main monomer (Cosmedy Pharmaceutical), (3) HGA64 (solution-type pressure-sensitive adhesives having acrylic acid as the main monomer, manufactured by Cosmedy Pharmaceutical).
The mixed solution was spread on a PET release liner so that the thickness after drying was 60 to 80 μm. After drying, the pressure-sensitive adhesive layer was attached to a PET support (thickness 25 μm), and patches for each of Examples and Comparative Examples were prepared. Two days after the preparation of the patch, the formation of crystals was observed in all of the Examples and Comparative Examples.

(Skin permeability test)
The patches obtained in the above examples and comparative examples were cut into a circle having a diameter of 10 mm. Affixed to the center of the extracted skin obtained by cutting human skin (purchased from Caucasian, IIAM, USA) or pig skin (purchased from Nippon Charles River) or hairless rat (purchased from Shimizu Experimental Materials) to a diameter of 20 mm. It was set in a vertical cell (10 mL volume, 15 mm diameter). Subsequently, the receptor solution (phosphate buffer solution pH 7.4) was sampled over time, and the drug permeability was analyzed by high performance liquid chromatography. The unit is μg / cm ² .
The results are shown in Table 2.

豚皮膚及びラット皮膚の人皮膚換算透過量は以下のように求めた。実施例１，３，６においては同一の製剤を用いての測定である。但し皮膚は人皮膚、ラット皮膚、豚皮膚、をそれぞれ用いた。それゆえ、実施例３，６においては人皮膚換算値を４９．８となるよう換算係数を定め実施例５，７，８、比較例２における人皮膚換算透過量を算定した。
比較例１においては多価アルコールを含まない例、比較例２，３はアクリル溶液型粘着剤を基剤とした例である。いずれもスマトリプタンの経皮吸収量は極めて低いことがわかる。

The human skin equivalent permeation amount of pig skin and rat skin was determined as follows. In Examples 1, 3 and 6, the measurement was performed using the same preparation. However, human skin, rat skin, and pig skin were used for the skin. Therefore, in Examples 3 and 6, the conversion coefficient was set so that the human skin equivalent value was 49.8, and the human skin equivalent permeation amount in Examples 5, 7, and 8 and Comparative Example 2 was calculated.
In Comparative Example 1, an example containing no polyhydric alcohol, and Comparative Examples 2 and 3 are examples based on an acrylic solution type pressure-sensitive adhesive. It can be seen that the percutaneous absorption amount of sumatriptan is extremely low.

(Blood analysis in rats)
The patches of Example 1 and Comparative Example 2 were cut to an appropriate size and applied to the back of Wistar rats (Japan SLC, 12 weeks old, male) that had undergone hair removal. They are called SS emulsion patch and SS HGA Patch, respectively. The drug amount in SS emulsion patch was 30.8 mg / kg, and the drug amount in SS HGA Patch was 43.3 mg / kg. Separately, 38 mg / kg was administered for oral administration (SS oral) and 10 mg / kg was administered for injection (SS iv). Blood was collected over time, centrifuged to obtain plasma, and drug concentration was analyzed by LC / MS / MS. The result is shown in FIG. The vertical axis represents blood concentration of sumatriptan and the horizontal axis represents time.

The biopharmaceutical parameters calculated from the figure are shown in FIG. In FIG. 3, Cmax is the maximum blood concentration (unit: μg / mL), Tmax is the time to give the maximum blood concentration (unit: min), AUC is the area under the blood concentration (unit: μg · min / ml), BA represents the bioavailability (unit:%).
When SS emulsion patch and SS HGA Patch are compared, large differences in AUC and BA are clear, and the superiority of emulsion patches is clear.

11 PET Release Liner 12 Emulsion Adhesive Layer 13 PET Support

Claims (8)

  Emulsion patch with hydrophilic drug and emulsion adhesive as essential components.   The emulsion patch according to claim 1, wherein the hydrophilic drug is sumatriptan or a salt thereof.   Furthermore, it has a polyhydric alcohol, The emulsion patch of Claim 1 or Claim 2 characterized by the above-mentioned.   The emulsion patch according to claim 2 or 3, wherein the concentration of sumatriptan in the emulsion adhesive is 1 to 60%.   The emulsion patch according to claim 2, 3 or 4, wherein sumatriptan is crystallized in the emulsion adhesive.   The emulsion patch according to any one of claims 1 to 5, wherein the emulsion adhesive is an acrylic emulsion adhesive.   The emulsion patch according to claim 3, wherein the polyhydric alcohol is glycerin or 1,3 butanediol.   The emulsion patch according to any one of claims 1 to 5, further comprising a transdermal absorption enhancer.

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