JPH08319234A - Percutaneous absorption type antiinflammatory and analgesic plaster - Google Patents

Abstract

PURPOSE: To prepare a transdermal absorption type antiinflammatory analgesic plaster excellent in percutaneous absorption, reduced in physical irritation such as cuticle dissection and hair-tearing, shows systemic effect and no adverse action found in oral preparation. CONSTITUTION: This plaster is obtained by heating and melting each component of a sticky adhesive comprising 20-60wt.% of a softener (liquid paraffin), 1-25wt.% of a tackifier (rosin), 10-50wt.% of a rubber component (styrene- isoprene-styrene block-copolymer), mixing flurbiprofen, casting on a substrate, laminating with a liner and cutting into a desired form. Flurbiprofen is an acidic non-steroidal antiinflammatory agent having a strong antiinflammatory analgesic effect and contained 40mg per sheet (136cm<2> , 12g). The plaster can manifest very effective antiinflammatory analgesic action even in the inflammation to which the topical application is difficult.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a percutaneous absorption type anti-inflammatory analgesic patch containing flurbiprofen as an active ingredient, which is widely used as an anti-inflammatory analgesic in the field of orthopedics. More specifically, it relates to an anti-inflammatory analgesic patch having excellent transdermal absorbability and having a systemic effect.

[0002]

2. Description of the Related Art Recently, non-steroidal anti-inflammatory drugs (NSA)
ID) is used orally or by injection, and has an excellent anti-inflammatory and analgesic effect. Then, transdermal preparations have been developed in which these drugs are brought into contact with the inflamed local area and the drugs are allowed to reach the site directly from the skin, and some of them are already on the market.

Such a transdermal preparation for direct topical application can not only avoid side effects such as gastrointestinal disorders caused by oral preparations, etc., but the transdermally administered drug does not pass through the liver but cuts through the skin. Since it is more absorbed, it is absorbed in the body without being decomposed by the liver, and therefore the drug efficacy is not significantly reduced. In addition, by controlling the transdermal absorbability of a drug, it is possible to maintain a constant blood concentration of the drug over a long period of time, and it is possible to reduce the side effects caused by large-scale absorption of the drug in a short time, such as oral administration. Become. Further, even if a trouble occurs, there are various advantages such as that the drug supply can be immediately stopped by removing the preparation.

As described above, the transdermal preparation for the purpose of topical application has an advantage over the oral preparation, but when the affected area is deep in the tissue or over a wide area, or the skin around the affected area is damaged, the preparation is formulated. When it is difficult to apply the drug, it is difficult to allow the medicinal component to reach the affected area directly from the skin.
Therefore, the transdermal drug preparations currently used and developed have relatively small transdermal drug absorption and are effective for superficial diseases such as myalgia, but in general, such as rheumatoid arthritis, the affected area is deep. Moreover, since the therapeutic effect is not exerted when inflammation is spread over a wide range, it is unavoidable to use the oral agent having the risk of the above-mentioned side effects. And, as the patch of flurbiprofen, which is the active ingredient of the present invention, as a water-based poultice using a lipophilic base, JP-A-4-
Japanese Patent Laid-Open No. 173731 and Japanese Patent Laid-Open No. 6-247847 are disclosed. Further, Japanese Patent Application Laid-Open No. 63-227524 discloses a patch using a rubber-based adhesive base. However, these patches are also intended for local affected areas as described above, and do not exert an anti-inflammatory and analgesic effect systemically when applied locally. Further, it was not satisfactory in terms of skin irritation. Therefore, if a percutaneous absorption type anti-inflammatory analgesic patch with a systemic efficacy of the drug is developed, its value will be extremely large, and it is currently most demanded.

[0005]

In order to solve the above-mentioned problems, in order to make the drug act systemically by skin absorption, it is first necessary to pass through the stratum corneum of the skin, which is a major obstacle to absorption of the drug. It is a condition. In order to overcome this condition, especially when the drug itself has low skin permeability, a technique using a transdermal absorption enhancer is necessary. However, these percutaneous absorption enhancers may cause skin irritation, and their use requires extreme caution. Further, in order to supply the drug for a certain period of time after administration, it is necessary to prevent the preparation from falling off the skin during that time, and it is indispensable to select an adhesive in which skin irritation is sufficiently considered.

[0006]

Means for Solving the Problems Accordingly, the present inventors have:
As a result of earnest research on a transdermal anti-inflammatory analgesic, by specifying flurbiprofen as a drug in the adhesive of this constitution by specifying the composition of the softener and the tackifying resin in the rubber component of the adhesive. In the patch of NSAID, which has little physical irritation such as exfoliation of keratin and hair shaving, and which could only be expected to have a local drug effect until now, it was found that the transdermal absorption is excellent and a systemic effect is exhibited. Based on this finding, it has been possible to obtain an excellent percutaneous absorption type anti-inflammatory analgesic patch which has no systemic side effects despite having a systemic effect.

According to the present invention, an adhesive containing 20 to 60% by weight of a softening agent, 1 to 25% by weight of a tackifying resin, and 10 to 50% by weight of a rubber component is added to a support containing a drug-containing layer containing flurbiprofen. A percutaneous absorption type anti-inflammatory analgesic patch characterized by being laminated on.

The flurbiprofen used in the present invention is
2- (2-Fluoro-4-biphenylyl) propionic acid, an acidic non-steroidal anti-inflammatory drug having strong anti-inflammatory and analgesic effects, which is a substance that has already been widely used as an oral administration agent and a poultice. . And the content is 40 mg per tablet as an oral preparation, and as a poultice,
40 mg is used in one sheet (136 cm ² , 12 g). Also in the present invention, the content is about 40 mg per sheet.

The rubber component used in the present invention acts as an adhesive base of the patch of the present invention, and is composed of natural rubber, styrene-isoprene-styrene block copolymer (SI).
S), ABA type teleblock copolymers such as styrene-butadiene-styrene block copolymer (SBS),
A synthetic rubber such as isoprene rubber is used alone or in a mixture. The blending amount is 10 to 50% by weight. If the amount is less than 10% by weight, the cohesive force will be lost, and adhesive residue will occur during application,
If it exceeds 5% by weight, it becomes too hard and causes poor adhesion.

The tackifying resin is a resin that produces tackiness only when it is combined with an adhesive base, and includes rosin, petroleum resin, coumarone indene resin, polyterpene resin,
Alicyclic saturated hydrocarbon resins and ester gums are preferred.
The blending amount is 1 to 25% by weight. If the amount is less than 1% by weight, the adhesive force is lost and the film is easily peeled off. If the amount exceeds 25% by weight, the adhesive force is too strong to cause pain at the time of exfoliation, causing exfoliation of the corneal layer and causing irritation.

The emollient dissolves and softens the adhesive base material, and by blending the emollient base material, it exhibits soft physical properties having conformability to the skin. As the softening agent, paraffinic oil, higher fatty acid, polybutene, liquid polyisobutylene, vegetable oil and the like are preferable. The blending amount is 20 to 60% by weight. If it is less than 20% by weight, the ability to follow the skin will be lost, and if it exceeds 60% by weight, it will become too soft and the adhesive strength will be lost, and adhesive residue will occur at the time of application. Further, liquid paraffin is the most preferable of the emollients, and when 40 to 50% by weight is used, particularly excellent results can be obtained in terms of the percutaneous absorption of flurbiprofen and the skin irritation of the preparation. .

The support used in the present invention is not particularly limited as long as it is flexible and does not give a feeling of strangeness when attached to the skin. For example, polyolefin, polyester,
Film or sheet of polyurethane, polyvinyl alcohol, polyvinylidene chloride, polyamide, etc., rubber and / or
Or synthetic resin foam sheet, film, non-woven fabric, cotton cloth,
Examples include paper. Nonwoven fabric is preferable from the viewpoint of breathability.

If necessary, the patch of the present invention may be added with a filler used in general patches, an antioxidant such as butylhydroxytoluene, an antioxidant, and a flavoring agent such as peppermint oil. it can.

A method for producing the percutaneous absorption type anti-inflammatory analgesic patch of the present invention will be described. After melting each component of the pressure-sensitive adhesive consisting of rubber component, softening agent and tackifier, add flurbiprofen, spread on a support, cover with a liner, cut into a desired shape to make a product Alternatively, the pressure-sensitive adhesive containing the above-mentioned flurbiprofen is spread on a film that has been subjected to a peeling treatment, and then transferred and pressure-bonded to an appropriate support to obtain a product. Further, the pressure-sensitive adhesive component and flurbiprofen are dissolved and dispersed in a solvent such as hexane, heptane, ethyl acetate, toluene, etc., spread on the above support and dried, covered with a liner, and cut into a desired shape to obtain a product. Alternatively, the pressure-sensitive adhesive containing flurbiprofen is spread on a film that has been subjected to a peeling process, dried, and then transfer-pressed onto an appropriate support to obtain a product.

[0015]

[Function] The percutaneous absorption type anti-inflammatory analgesic patch of the present invention has little skin irritation, and the systemic anti-inflammatory analgesic effect is obtained not only in the topical application but also in oral administration. Side effects can be avoided. Therefore,
It can be used safely and accurately even in diseases where local administration is difficult.

The present invention will be described in more detail below with reference to examples.

[0017]

Example 1 Natural rubber was dissolved in toluene according to the compounding amount shown in Table 1, and polybutene, liquid paraffin, flurbiprofen and peppermint oil, Alcon P80 (alicyclic saturated hydrocarbon resin, Arakawa Chemical Industry ( KK) and butylhydroxytoluene were added and mixed and dissolved. Then, it was spread on a release paper and then dried, and a support was pressure-bonded and transferred onto the surface of the plaster thus obtained to prepare the patch of the invention.

[0018]

Example 2 According to the compounding amounts shown in Table 1, natural rubber and SI
Using S, liquid paraffin, Alcon P80, flurbiprofen, peppermint oil and butylhydroxytoluene, the patch of the present invention was prepared in the same manner as in Example 1.

[0019]

Example 3 According to the compounding amounts shown in Table 1, natural rubber and SI
Using S, butyl rubber, liquid paraffin, Alcon P80, flurbiprofen and butyl hydroxytoluene,
The patch of the present invention was prepared in the same manner as in Example 1.

[0020]

Example 4 According to the compounding amounts shown in Table 1, natural rubber and SI
S, liquid paraffin, ester gum H, flurbiprofen, peppermint oil and butyl hydroxytoluene,
The patch of the present invention was prepared in the same manner as in Example 1.

[0021]

Example 5 According to the compounding amounts shown in Table 1, SIS, liquid paraffin, polyisobutylene, ester gum H, flurbiprofen and butylhydroxytoluene were used, and the patch of the present invention was prepared in the same manner as in Example 1. Prepared.

[0022]

[Table 1]

[0023]

Comparative Example 1 According to the compounding amounts shown in Table 2, natural rubber and SI
A patch was prepared in the same manner as in Example 1, using S, liquid paraffin, polybutene, ester gum H, flurbiprofen, peppermint oil and butylhydroxytoluene.

[0024]

[Comparative Example 2] Acrylic adhesive, flurbiprofen and peppermint oil were used according to the blending amounts shown in Table 2, and Example 1 was used.
A patch was prepared in the same manner as in.

[0025]

[Table 2]

Next, the skin permeation test, skin irritation test and drug efficacy test of the patch of the present invention will be shown to clarify the remarkable effect of the patch of the present invention.

[0027]

[Test Example 1] This test is a skin permeation test. Example 1,
The patch of 4 and Comparative Examples 1 and 2 was subjected to a permeation test using the skin of the back of the hairless mouse, and the permeability of flurbiprofen of each test patch was compared.

Each test patch was applied to the excised skin, mounted on an in vitro membrane permeation tester, and a phosphate buffer solution having a pH of 7.4 was used as the receptor solution to permeate the skin and migrate into the receptor solution. The amount of flurbiprofen coming was measured. The result is shown in FIG. As is clear from FIG. 1, the softening agent composed of liquid paraffin and polybutene each contained 10% by weight,
Comparative Example 1 containing 5% by weight and 31.2% by weight of ester gum H, which is a tackifier, had a lower permeation amount than the patch of the present invention. It is also considered that this is because the amount of liquid paraffin is small and the ability to follow the skin is poor. In Comparative Example 2 in which the adhesive was an acrylic adhesive, the permeability of flurbiprofen was lower than the others.

[0029]

[Test Example 2] This test is a skin irritation test by repeated application. The patches of Examples 2 and 4 and Comparative Example 1 were repeatedly applied to guinea pigs to compare skin irritation.

Using Hertley-type guinea pigs, each test patch was applied to the shaved flank for 23 hours a day, and 1 hour after the removal, the skin at the application site was observed to determine irritation. It was repeated for 5 days. The judgment was scored according to the judgment criteria in Table 3 and the irritation was evaluated. The result is shown in FIG.
As is clear from FIG. 2, the patch of the present invention has lower irritation than Comparative Example 1 containing many tackifying resins as the pressure-sensitive adhesive.

[0031]

[Table 3]

[0032]

[Test Example 3] This test is a drug efficacy test of flurbiprofen of the patch of the present invention. For adjuvant arthritis rats, one patch (140 cm ² ) of Example 1 containing 5 mg of the patch and flurbiprofen powder containing 30 mg of flurbiprofen
% The anti-inflammatory effect of flurbiprofen in oral administration of an oral drug suspended in arabic gum aqueous solution was measured.

Six-week-old male Lewis rats were subjected to adjuvant inflammation, and 20 days later, the patch of Example 1 (3.5 cm × 4 c
Adhesion of m) and oral administration were carried out for 8 days. The patch of Example 1 was applied to the right hind leg for 6 hours a day, and the oral administration was 0.75 mg / kg a day. At the time of inflammation, at the start of administration (20 days after inflammation), 3 days after administration (23 days after inflammation) and 1 week (27 days after inflammation), the paw edema volume of both hind limbs was measured. The edema rate was obtained by measuring the volume of the rat paw before inflammation, measuring the volume V ₀ (ml) at that time, and the volume V ₁ (ml) after inflammation, and using these values, the edema rate (%) As S = (V ₁ −V ₀ ) /
“Mean ± SE” of FIGS. 3 and 4 calculated by V ₀ × 100 is an average value (mean), and the range of up and down of * indicates the degree of variation (SE: standard error) of the value. ing.
* P <0.05, ** p <0.01 VS control has a "significant" difference by statistically testing whether the value of interest is objectively different from the value of "control". When estimated to be *
(P <0.05), and when it is estimated that there is a “highly significant” difference, ** (p <0.01) is marked. In addition, blood was collected 1, 3, 6 and 8 hours after the administration 1 week later, and the blood concentration was measured.

The results of the above test are shown in FIGS. 3, 4 and 5. As is clear from this figure, the patch of the present invention showed a strong anti-inflammatory effect not only on the inflamed site on the applied right hind limb but also on the inflamed site on the left hind limb to which it was not applied. Further, as shown in FIG. 5, the blood concentration of flurbiprofen after oral administration is lower than that of transdermal administration of the patch of the present invention, but shows a high concentration even after 8 hours, It showed the excellent durability of this patch.

[0035]

TEST EXAMPLE 4 This test is a test of the action of the patch of the present invention on gastric mucosa. The damaging effect of the patch of Example 1 applied to the rat gastric mucosa and oral administration was observed.

In Test Example 3, the number of rats in which an ulcer had occurred and the size of the ulcer was measured by slaughtering the stomach 8 hours after administration and 6 hours after administration. The results are shown in Table 4. Damage to the stomach of the patch of the present invention was significantly less than that of oral administration.

[0037]

[Table 4]

[0038]

As described above, the present invention is a patch containing flurbiprofen, which is an NSAID, has less skin irritation, and exerts the same general anti-inflammatory and analgesic effect as when orally administered, Avoid side effects peculiar to oral administration,
Further, the present invention provides a useful patch which exhibits an effective anti-inflammatory and analgesic action even in inflammation where local administration is difficult.

[Brief description of drawings]

FIG. 1 is a graph showing the results of a permeation test on hairless mouse skin.

FIG. 2 is a graph showing the results of skin irritation test on guinea pigs.

FIG. 3 is a graph showing an anti-inflammatory effect on paw edema of the right hind limb to which the patch of the present invention is applied in rats with adjuvant arthritis.

FIG. 4 is a graph showing an anti-inflammatory effect on paw edema of the left hind limb to which the patch of the present invention is not applied in adjuvant arthritis rats.

FIG. 5 is a graph comparing the blood concentration of flurbiprofen after oral administration with the blood concentration after the patch of the present invention was applied.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Office reference number FI Technical display location A61K 9/70 363 A61K 9/70 363 369 369 47/06 47/06 E Z 47/12 47 / 12 E Z 47/30 47/30 E Z 47/44 47/44 E Z

Claims (4)

[Claims] 1. A softening agent 20 to 60% by weight, a tackifying resin 1 to
An adhesive consisting of 25% by weight and 10 to 50% by weight of rubber component,
A percutaneous absorption type anti-inflammatory analgesic patch comprising a support and a drug-containing layer containing flurbiprofen laminated thereon. 2. The softening agent is paraffinic oil, higher fatty acid,
The percutaneous absorption type anti-inflammatory analgesic patch according to claim 1, comprising at least one selected from polybutene, liquid polyisobutylene, and vegetable oil. 3. The transdermal anti-inflammatory analgesic patch according to claim 1, wherein the tackifying resin comprises at least one selected from rosin, petroleum resin, coumarone indene resin, polyterpene resin and polystyrene resin. 4. The transdermal anti-inflammatory analgesic patch according to claim 1, wherein the rubber component is at least one selected from ABA type teleblock copolymers, natural rubber and isoprene rubber.