JP3420456B2 - Transdermal drug-coated membrane - Google Patents

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a method in which a transdermal drug is applied to the skin via a semipermeable membrane, and the drug is gradually absorbed into the body by adjusting the arrival speed of the drug to the skin. The present invention relates to a skin absorbable drug coating film.

[0002]

2. Description of the Related Art Conventionally, in the case of locally applying an analgesic or an anti-inflammatory agent, a method of directly applying to the affected area has been adopted. In this case, the drug was rubbed against clothes or the like and could not be applied in a large amount, and the effect was transient. A method of applying a drug to a sheet material such as woven cloth, non-woven cloth, and paper and directly applying it to the affected area in order to maintain the action is also performed, but a poultice drug in which the physical effect takes precedence over the pharmacological effect. And so on. The method of directly contacting the skin with a high concentration of the drug often not only strongly irritates the skin, but also the high concentration of the drug may be absorbed into the body to cause a negative effect.

On the other hand, the present applicant has developed a special natural polysaccharide / polyhydric alcohol composition by kneading a natural polysaccharide in a system of polyhydric alcohol in a broad sense. The film formed by this composition has high strength and semi-permeability, and has particularly good affinity with human skin, and not only does it cause symptoms such as allergies when directly applied to the skin, but also positively. It effectively has the effect of healing skin damage such as bilans and burns.

[0004]

There is a drug capable of relieving itching, pain, inflammation and the like of the skin by applying it to the skin. However, there has been no means for continuously supplying these drugs to the skin surface in small amounts for a long period of time without burdening the skin. Therefore, there has been a demand for a treatment method in which the skin is covered with a breathable film and the drug is continuously supplied to the skin little by little without any burden on the skin.

[0005]

The present invention is intended to solve the above-mentioned problems, and its constitution is at least one stock solution selected from polyhydric alcohols, sugar alcohols, monosaccharides, disaccharides and oligosaccharides. Alternatively, it is obtained by uniformly kneading at least one natural polysaccharide selected from carrageenan, alginic acid, alginate, alginic acid derivative, agar, locust bean gum, guar gum, glucomannan, chitin and pullulan in a concentrated solution. Characterized in that a transdermal drug is interposed between the semipermeable membrane formed by film-forming the natural polysaccharide / polyhydric alcohol composition and the breathable base material layer, or It is characterized in that a percutaneously absorbable drug is contained in the air-permeable base material layer, or a surfactant is mixed in the semipermeable membrane.

According to the present invention, the film composed of the above-mentioned natural polysaccharide / polyhydric alcohol composition has a function of directly covering the skin surface and healing bilane and defects of the skin, and at the same time, a substance having a relatively low molecular weight is used. Focusing on the existence of the function of allowing the drug to pass, the drug is slowly supplied to the skin through this film. As a result, the drug is gradually supplied to the skin surface in small amounts over a long period of time to exert an effective therapeutic effect. There is no adverse effect on the skin because it is covered with a film that has the effect of healing skin defects without impeding skin breathing.

[0007]

BEST MODE FOR CARRYING OUT THE INVENTION The drug used in the present invention may be any compound capable of penetrating a film composed of a natural polysaccharide / polyhydric alcohol composition. Specifically, it is water-soluble and has a too large molecular weight. Not a compound. Although it is not possible to determine suitability based on the molecular weight alone, the molecular weight is generally 500.
0 or less, preferably 3000 or less, more preferably 10
It is 00 or less.

The type of drug is not particularly limited, and a drug desired to act locally is preferable. For example, antihistamines are used for insect bites and rashes, analgesics and anti-inflammatory agents are bruised,
It can be used for redness, pain, rheumatoid arthritis, low back pain, gout attacks, fever, etc. The anticancer agent also acts on skin cancer at a high concentration only locally, and therefore can be effectively used without aggravating systemic symptoms. In addition, if a drug that is difficult to use can be transdermally administered by oral administration because it passes through the digestive tract and the liver, the drug can be effectively acted by a simple means. In the case of transdermal administration, capillaries are attached to the dermis, so that it is effective if the drug can reach the dermis.

The natural polysaccharide / polyhydric alcohol composition used in the present invention is a powder having a little dampness obtained by kneading a natural polysaccharide in a system of polyhydric alcohol in a broad sense. It is believed that by kneading in a system of a polyhydric alcohol, a natural polysaccharide and a polyhydric alcohol react with each other to change into a complicated three-dimensional structure. When this natural polysaccharide / polyhydric alcohol composition is dissolved in water, it becomes a viscous aqueous solution, and the film obtained by forming a film from this aqueous solution has a high level that cannot be compared with a film formed by dissolving the raw materials as it is. Strength.

Examples of polyhydric alcohols are polyhydric alcohols in a narrow sense such as propylene glycol and glycerin; sorbitol, mannitol, maltitol, xylitol,
Sugar alcohols such as reduced starch saccharified products; monosaccharides such as glucose, fructose, galactose, xylose; disaccharides such as saccharose, maltose, lactose; products of decomposition of starch such as sweet potato, juga potato and corn by enzymes and acids. Examples thereof include oligosaccharides containing certain trisaccharides, tetrasaccharides, pentasaccharides, hexasaccharides and the like. In the system of polyhydric alcohol, when the polyhydric alcohol is a liquid such as glycerin, it is a stock solution or a concentrated solution, and when the polyhydric alcohol is a powder such as sorbitol, it is used as a concentrated solution. A concentrated solution is a solution of 50% by weight or more, preferably 70% by weight or more.

The natural polysaccharide is kneaded in this concentrated solution of polyhydric alcohol. Examples of natural polysaccharides include carrageenan, alginic acid, alginates, alginic acid derivatives, agar, locust bean gum, guar gum, glucomannan, chitin and pullulan. The natural polysaccharides are not one type, and a combination of these can be used to produce a film having desirable characteristics. In kneading, addition of alkali, protein, polypeptide, amino acid or the like may be used in combination. When kneading, the reaction progresses quickly if kneading is performed while heating a little. When kneading at room temperature, the reaction proceeds sufficiently by storing the kneaded product for a long time.

A natural polysaccharide / polyhydric alcohol composition is dissolved in water to form a viscous aqueous solution of 2 to 4% by weight, and this aqueous solution is spread by a conventional method such as a rotor drawing method or a solvent drawing method to form a film. To do. After spreading, a film can be easily obtained by hot air or warm air. This film contains 5 to 20% of water and has high strength.

The substrate needs to be breathable. When it is air-blocking, the skin covered with the percutaneously absorbable drug coating film of the present invention inhibits skin respiration and impairs the health of the skin. However, since a drug is supplied, a porous film having fine air holes for blocking bacteria is preferable. Although a commercially available porous film can be used, when the film thickness is thin, it can be reinforced with a non-woven fabric or the like before use.

In the coating film 1 of the present invention, the transdermal drug 4 may be present between the semipermeable membrane 2 and the substrate 3 as shown in FIG. The semipermeable membrane 2 is used by applying it so that the semipermeable membrane 2 directly contacts the skin 5. The production method is not particularly limited, and a method of impregnating the base material 3 with an aqueous solution of the percutaneously absorbable drug 4, drying it, and then spreading an aqueous solution of the natural polysaccharide / polyhydric alcohol composition can also be used. In this case, the semipermeable membrane 2 and the transdermal drug 4
And the layers of the substrate 3 are not clearly separated. However, the transdermal drug 4 does not leak to the outside of the base material 3 and tends to move toward the semipermeable membrane 2. Alternatively, the transdermal drug 4 may be sprayed on the base material 3 and a semipermeable membrane may be formed thereon.

Further, in forming the film of the natural polysaccharide / polyhydric alcohol composition, it is possible to previously dissolve the transdermal drug 4 in an aqueous solution of this composition. In this case, a film in which the transdermal drug 4 is contained in the semipermeable membrane is obtained. In order to further promote the absorption of the transdermal drug 4, a surfactant can be mixed in the semipermeable membrane. As the surfactant, any of a cationic type, a nonionic type and an anionic type can be used, and a cationic type and a nonionic type or a nonionic type and an anionic type can be used in combination. Examples thereof include sodium alkylbenzene sulfonate, lauryl dimethylamine oxide, dodecyl sulfate, Tween 80, cetylpyridinium chloride and the like.

[0016]

Example 1 30 parts by weight of glucomannan, 10 parts by weight of locust bean gum, 5 parts by weight of carrageenan and 5 parts by weight of pullulan were kneaded in about 50 parts by weight of glycerin at about 80 ° C. and slightly moist. A powdery natural polysaccharide / polyhydric alcohol composition was obtained.

Indomethacin [Wako Pure Chemical Industries, Ltd.] was neutralized with caustic soda to give 1% of indomethacin sodium salt.
An aqueous solution was prepared and applied on the surface of the base material 3. As the base material, a polypropylene porous film (made by Hoechst Japan) reinforced with a polypropylene non-woven fabric to have a thickness of 0.4 mm was used. After applying indomethacin sodium salt at a rate of 0.0013 g / cm ² to this porous film, it was dried at 35 ° C. for 1 hour. A circular hole having a diameter of about 4 cm is made in a polypropylene film, and the porous film coated with indomethacin is superposed, and the periphery of the hole is fused in a circular shape so that the exposed area of the porous film becomes 1
It was set to 2.5 cm ² . This is also the application area of indomethacin sodium salt.

3 parts by weight of the natural polysaccharide / polyhydric alcohol composition prepared in Example 1 was dissolved in 97 parts by weight of water, and the viscous aqueous solution obtained was spread on the surface of the above substrate by a rotor drawing method. After drying with hot air at 70 ° C. for 1 hour, a transdermal drug-coated film of the present invention coated with a semipermeable membrane composed of a natural polysaccharide / polyhydric alcohol composition was obtained. Semipermeable membrane thickness, 0.15mm
And 0.20 mm were obtained. The water content of this film was 12%.

Example 2 As a natural polysaccharide, glucomannan (10 parts by weight), pullulan (20 parts by weight) and guar gum (20 parts by weight) were used as in Example 1 except that a natural polysaccharide / polyhydric alcohol composition was used. A coating film of the present invention coated with a permeable membrane was obtained. Two types of semipermeable membrane thickness, 0.18 mm and 0.23 mm, were obtained. The water content of this coating film was 11%.

Semipermeable Membrane Permeation Test of Drugs A test was conducted using the apparatus shown in FIG. Reference numeral 6 denotes an inner cylinder, the lower end of which was covered with the semipermeable membrane surface of the coating film 1 prepared in Examples 1 and 2 as the lower surface, and the outer periphery of the inner cylinder 6 was airtightly fixed. 7 is a fixture. This inner cylinder 6 is filled with ultrapure water 400
The semi-permeable membrane was attached to the outer cylinder 8 into which the ml was injected so that the semipermeable membrane was in contact with the water surface, and the water in the outer cylinder 8 was slowly stirred using the magnetic stirrer 9. Reference numeral 10 is a rotor, 11 is a thermometer, and 12 is ultrapure water. The outer cylinder 8 was immersed in a constant temperature water bath at 37 ° C. 20 is a constant temperature water tank. Ultrapure water 12 is 17 mΩ ^-1 ,
It was manufactured by Millipore Co., Ltd., ultrapure water manufacturing apparatus.

The indomethacin sodium salt applied to the base material 3 passes through the semipermeable membrane 2 below and gradually transfers to the ultrapure water in the outer cylinder. Therefore, the concentration of indomethacin in the water in the outer cylinder 8 increases. Outer cylinder 8 every predetermined time
The water inside was collected, the absorption spectrum at 318.5 nm was measured using an absorptiometer, and the total amount of indomethacin sodium salt in the water in the inner cylinder was calculated. Assuming that the total amount of indomethacin sodium salt contained in the entire coating film 1 is eluted, indomethacin Na salt = 0.0013 g / cm ² × 12.5
cm ² = 0.0163 g, in contact time of semipermeable membrane with indomethacin N eluted
The relationship with% of the total amount of salt a is shown in FIGS. 3 and 4.

FIG. 3 shows the measurement results of the coating film 1 obtained in Example 1. The white circles indicate the case where the semipermeable membrane thickness is 0.20 mm, and the black circles indicate the semipermeable membrane thickness 0. This is the case of 15 mm. FIG. 4 shows the measurement results of the coating film 1 obtained in Example 2, where the white triangles are for a semipermeable membrane having a thickness of 0.23 mm, and the black triangles are for a semipermeable membrane having a thickness of 0.18 mm. Is the case.

Oxygen Permeation Test As shown in FIG. 5, a container having a maximum capacity of 1 liter was used symmetrically by loading a diaphragm.
Reference numeral 13 is a diaphragm supporting member composed of two frames, and the coating film 1 of the present invention is sandwiched between the frames and fixed at a predetermined position in the container. The coating film 1 obtained in Examples 1 and 2 was used as the diaphragm. An air-blowing glass ball 15 is loaded into the first chamber 14 separated by the diaphragm, and the glass ball 15 is ventilated from the air pump 16. Air pump 16 is NR
A K air pump up type 2 (manufactured by Nippon Rikagaku Co., Ltd.) was used, and the rotor 10 was inserted at the bottom of the container. The electrode 18 of the dissolved oxygen meter and the thermometer 11 are inserted in the second chamber 17, and the electrode 18
And a dissolved oxygen meter 19 manufactured by IIJIMA ELECTRONICS MFG Co. LTD. The rotor 10 similar to that of the first chamber 14 was placed in the bottom of the container.

0.67 in each of the first chamber 14 and the second chamber 17
5 liters of water at 20 ° C. was charged and the mixture was slowly stirred at a common speed in both chambers. When the experiment was started, a fixed volume of air was blown from the glass bulb 15 in the first chamber 14 to measure the amount of dissolved oxygen in the second chamber 17. The dissolved oxygen permeation amount (Q) is calculated by the following formula. Q = [DO at measurement (ppm) -DO at start of experiment (ppm)
)] / Membrane area (cm ² ) DO = dissolved oxygen amount The experimental results of Example 1 are shown in Table 1, and the experimental results of Example 2 are shown in Table 2. Further, this result is shown in the graph of FIG.

[0025]

[Table 1]

[0026]

[Table 2]

Example 3 An indomethacin ointment was applied to a thigh area which was swollen red to a diameter of about 5 cm by a batter, and then the transdermal drug-coated film obtained in Example 1 having an area of 8 cm was applied. The drug reached the skin little by little over a long period of time, the effect was persistent, and the next day, swelling was observed.

[0028]

INDUSTRIAL APPLICABILITY According to the present invention, a drug can be slowly absorbed through the skin, and when it is desired to act locally at a high concentration, it is effective for relieving skin inflammation and analgesia, and inflammation inside the skin. Can be applied to. Further, since the semipermeable membrane of the present invention is not only breathable but also has an action of healing a wound on the skin, it has a very high affinity with the skin and there is no possibility of causing a harmful effect by long-term use.

[Brief description of drawings]

FIG. 1 is a schematic diagram showing the relationship between a transdermal drug-coated film and the skin.

FIG. 2 is a sectional view of a drug permeability test apparatus.

FIG. 3 is a graph showing the relationship between the time during which the coating film of Example 1 is in contact with water and the elution rate.

FIG. 4 is a graph showing the relationship between the time during which the coating film of Example 2 is in contact with water and the dissolution rate.

FIG. 5 is a cross-sectional view of an oxygen permeability measurement test device.

FIG. 6 is a graph showing the relationship between the amount of permeated dissolved oxygen and time.

[Explanation of symbols]

1 coating film 2 semi-permeable membrane 3 base materials 4 drugs 5 skin 6 inner cylinder 7 Fixture 8 outer cylinder 9 magnetic stirrer 10 rotor 11 thermometer 12 Ultrapure water 13 Diaphragm support 14 Room 1 15 glass spheres 16 air pump 17 Second Room 18 electrodes 19 Dissolved oxygen meter 20 constant temperature water tank

Claims (3)

(57) [Claims] 1. Carrageenan, alginic acid, in a concentrated or concentrated solution of at least one selected from polyhydric alcohols, sugar alcohols, monosaccharides, disaccharides and oligosaccharides.
Natural polysaccharide / polyhydric alcohol composition obtained by uniformly kneading at least one natural polysaccharide selected from alginate, alginic acid derivative, agar, locust bean gum, guar gum, glucomannan, chitin and pullulan. A percutaneously absorbable drug coating film, characterized in that a percutaneously absorbable drug is interposed between a semipermeable membrane formed by film forming and a breathable base material layer. 2. Carrageenan, alginic acid, in a concentrated or concentrated solution of at least one selected from polyhydric alcohols, sugar alcohols, monosaccharides, disaccharides and oligosaccharides.
Natural polysaccharide / polyhydric alcohol composition obtained by uniformly kneading at least one natural polysaccharide selected from alginate, alginic acid derivative, agar, locust bean gum, guar gum, glucomannan, chitin and pullulan. Is formed by laminating a breathable base material layer on a semipermeable membrane formed by film formation, and the transdermal drug is provided on the semipermeable membrane, the breathable base material layer or the semipermeable membrane and the breathable base material layer. A percutaneously absorbable drug coating film characterized by being contained. 3. The transdermal drug-coated membrane according to claim 1 or 2, wherein the semipermeable membrane contains a surfactant.