JP2005213192A - Antiinflammatory analgesic for external use - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide an antiinflammatory analgesic for external use which is a nonsteroidal-antiphlogistic-analgesic-containing external preparation having an improved ability to penetrate and diffuse into tissues situated beneath the skin and besides being lowly irritating to the skin and preventing retarded percutaneous absorption of the external preparation containing the nonsteroidal antiinflammatory in a relatively high concentration permits the nonsteroidal antiinflammatory to be efficiently delivered into e.g., inflamed or painful muscle and joint tissues. <P>SOLUTION: The antiinflammatory analgesic for external use having a heretofore unattainable good effect is developed as the result of the finding that the above problem can be completely solved by selecting an arylacetic acid nonsteroidal antiinflammatory analgesic as the nonsteroidal antiinflammatory analgesic and adding an antihistamine thereto. <P>COPYRIGHT: (C)2005,JPO&NCIPI

Description

  The present invention relates to an anti-inflammatory analgesic external preparation containing an arylacetic acid-based non-steroidal anti-inflammatory agent and an antihistamine and having excellent permeability and diffusibility in a tissue deeper than the skin.

  Conventionally, non-steroidal anti-inflammatory agents are known as anti-inflammatory analgesics with relatively few side effects. Nonsteroidal anti-inflammatory drugs suppress the production of prostaglandins related to inflammation and pain by inhibiting cyclooxygenase, which catalyzes the first reaction in the arachidonic acid cascade, which is a metabolic pathway that enhances pain. .

However, since prostaglandins have unfavorable effects such as inflammation and pain, they exhibit a variety of effects in the body, so the administration of nonsteroidal anti-inflammatory drugs suppresses the production of prostaglandins more than necessary. Then, serious side effects may occur. For example, cyclooxygenase type I, which is an isozyme of cyclooxygenase, is related to gastric mucosal protection and renal function. Therefore, when this is inhibited by a nonsteroidal anti-inflammatory agent, digestive disorders and renal dysfunction may occur.
Accordingly, the development of non-steroidal anti-inflammatory agents as external preparations that hardly cause these side effects has been promoted.

However, some non-steroidal anti-inflammatory agents have a poor transdermal absorption dose, and the effect when administered as an external preparation may be extremely reduced as compared with the case of oral administration.

Therefore, techniques for improving the percutaneous absorption dose of non-steroidal anti-inflammatory agents are being studied, but most of the techniques are techniques for enhancing percutaneous absorption. For example, Patent Document 1 discloses an indomethacin patch, which describes that the patch is excellent in transdermal absorbability and has no problem of skin irritation. In addition to this, there are many techniques whose formulation is designed from the viewpoint that improvement of transdermal absorbability is a problem to be solved and a nonsteroidal anti-inflammatory agent reaches the blood through the skin.

However, a transdermal absorbability evaluation test using blood concentration as an index is never satisfactory for evaluating the value of a non-steroidal anti-inflammatory drug delivery system. Because topical preparations containing non-steroidal anti-inflammatory drugs are intended for local anti-inflammatory analgesia, the point that the analgesics should reach is not the blood but the tissue itself that is causing inflammation and pain Because.

In other words, in order to obtain a high drug blood concentration, it is sufficient that the drug can reach the dermis where the capillaries exist, but the tissue that causes inflammation and pain is usually deeper than that muscle and joint tissue. There are many. Therefore, in order for a nonsteroidal anti-inflammatory agent to exert a sufficient anti-inflammatory analgesic effect, it is essential to reach a portion deeper than the dermis.
Nevertheless, in the conventional formulation design, the actual condition is that the penetrability and diffusibility into deeper sites than the dermis are not considered.

Another method for improving the transdermal absorption dose of a nonsteroidal anti-inflammatory agent is to increase the concentration of the nonsteroidal anti-inflammatory agent in the preparation.
If the concentration in the preparation is increased, the amount of drug per unit skin area to be administered increases, and the percutaneous absorption dose also increases. However, in a topical preparation for a nonsteroidal anti-inflammatory agent, increasing the concentration of the nonsteroidal anti-inflammatory agent in the formulation has important problems in terms of percutaneous absorption and formulation.

First, the problem of percutaneous absorption is the problem of non-steroidal anti-inflammatory drug diffusibility in living tissues. Conventionally, the concentration of a non-steroidal anti-inflammatory drug is 1% or higher, and the absorption level is almost the same and the effect does not change. The phenomenon is attributed to the low diffusion of nonsteroidal anti-inflammatory drugs within the subcutaneous tissue.
When an external preparation containing a non-steroidal anti-inflammatory agent is administered, the non-steroidal anti-inflammatory agent is transferred to the skin. However, when the non-steroidal anti-inflammatory drug has low diffusivity, the non-steroidal anti-inflammatory drug remains in the skin tissue. As a result, the non-steroidal anti-inflammatory agent concentration in the skin tissue increases, and the non-steroidal anti-inflammatory agent in the skin tissue becomes saturated. Therefore, the transition from the external preparation of the nonsteroidal anti-inflammatory agent to the skin tissue is slowed down.

In other words, even if the preparation of non-steroidal anti-inflammatory agent for external use is very good, if the diffusion of non-steroidal anti-inflammatory agent in skin tissue is poor, the transition rate from the preparation to skin It becomes rate-limiting within. Therefore, it is considered that the absorption efficiency of the high-concentration non-steroidal anti-inflammatory agent-containing topical agent is reduced compared to the low concentration, and no matter how much the concentration of the non-steroidal anti-inflammatory agent is increased, it is not reflected in the anti-inflammatory analgesic effect.

In addition, if a high-concentration non-steroidal anti-inflammatory agent preparation is used without solving the problem of diffusion of the non-steroidal anti-inflammatory agent in the subcutaneous tissue, there is a risk that safety may decrease due to problems such as skin irritation. This is because the non-steroidal anti-inflammatory agent itself is considered to cause irritation as the concentration of the non-steroidal anti-inflammatory agent in the skin tissue increases.

On the other hand, in the diclofenac sodium-containing emulsified external preparation described in Patent Document 2, the concentration of diclofenac sodium in the muscle tissue directly under the drug application part is tested together with the concentration of diclofenac sodium in the crystal. However, this drug concentration in muscle is never satisfactory, and no experiment has been conducted from the viewpoint of drug diffusion in muscle tissue.

Regarding the composition of the preparation, the patch of Patent Document 1 includes indomethacin, polyethylene glycol, a water-soluble polymer compound and a crosslinking agent, and the external preparation of Patent Document 2 includes diclofenac sodium, dialkyl ester of carboxylic acid. In addition, oleyl alcohol and polyhydric alcohol are used as components. In other words, in these preparations, the percutaneous absorption of the drug is improved by utilizing absorption of the skin of the solvent, etc., but since the solvent etc. diffuses quickly in the tissue, the drug can be transported deeply. The solvent concentration cannot be maintained as much. Therefore, it is difficult to reach non-steroidal anti-inflammatory agents to deep tissues.

In contrast to these techniques, the topical anti-inflammatory analgesic composition described in Patent Document 3 is characterized by containing an antihistamine rather than a solvent together with a nonsteroidal anti-inflammatory agent. However, only the skin permeability is tested in the patent publication, and the permeability and diffusibility in tissues deeper than the skin are not considered at all.

JP 2001-26540 A Japanese Patent Laid-Open No. 9-12452 JP 2002-128698 A

As described above, various external preparations containing non-steroidal anti-inflammatory agents that have improved skin permeability have been known so far.
However, in the prior art, none of the techniques for utilizing high concentrations of non-steroidal anti-inflammatory drugs has taken into account the diffusion of non-steroidal anti-inflammatory drugs in the subcutaneous tissue.

Therefore, the problem to be solved by the present invention contains a non-steroidal anti-inflammatory agent containing a non-steroidal anti-inflammatory agent-containing external preparation, and has excellent permeability and diffusibility in a tissue deeper than the skin. The object is to provide a topical anti-inflammatory analgesic agent that not only has low skin irritation, but also can efficiently administer a non-steroidal anti-inflammatory agent to muscles or joint tissues with inflammation or pain.

In order to solve the above-mentioned problems, the present inventors made various adjustments for external preparations containing high concentrations of non-steroidal anti-inflammatory agents and conducted extensive research on their tissue diffusibility. As a result, the present inventors completed the present invention by finding that all of the above problems could be solved by selecting an arylacetic acid-based one as a nonsteroidal anti-inflammatory agent and adding an antihistamine to it as an external preparation.
That is, the anti-inflammatory analgesic external preparation of the present invention is characterized by containing an aryl acetate non-steroidal anti-inflammatory agent and an antihistamine.
The antihistamine is preferably diphenhydramine, and the arylacetic acid non-steroidal anti-inflammatory agent is preferably indomethacin or diclofenac sodium.

The anti-inflammatory analgesic external preparation containing an arylacetic acid-based non-steroidal anti-inflammatory agent according to the present invention has good diffusibility in the subcutaneous tissue, and is an external preparation containing 5% or more of an arylacetic acid-based non-steroidal anti-inflammatory drug. The transdermal absorbability is remarkably improved. Furthermore, the skin irritation of high concentrations of arylacetic acid non-steroidal anti-inflammatory agents is reduced. In addition, increasing the solubility of the arylacetic acid-based non-steroidal anti-inflammatory agent in a solubilizer increases convenience in terms of formulation and production.
Therefore, this anti-inflammatory analgesic external preparation is extremely excellent as an anti-inflammatory analgesic.

The greatest feature enjoyed by the external preparation according to the present invention is that it contains an antihistamine, which makes it extremely excellent in permeability and diffusibility below the skin tissue after the arylacetic acid non-steroidal anti-inflammatory agent penetrates the skin. It is in.
In other words, there have been external preparations that used a combination of a nonsteroidal anti-inflammatory agent and an antihistamine in the past, but mainly for the purpose of improving skin permeability, such as diffusibility for the drug to reach the affected area directly. It was not considered.

However, the present inventors have found that if a non-steroidal anti-inflammatory agent is selected from arylacetic acid and combined with an antihistamine, the penetration and diffusion into deep tissues can be remarkably improved. completed.

In addition, the external preparation of the present invention is excellent in transdermal absorbability, has also improved the slowing of absorption efficiency with increasing drug concentration, and also has skin irritation possessed by arylacetic acid non-steroidal anti-inflammatory agents. Suppressed and stable.
Hereinafter, embodiments of the present invention that exhibit such characteristics and effects thereof will be described.

The “aryl acetic acid-based non-steroidal anti-inflammatory agent” used in the present invention is a non-steroidal anti-inflammatory agent having a structure of acetic acid substituted with an aryl group containing a heteroaryl group such as an aromatic hydrocarbon group indole group. And the α-position of the acetic acid is a methylene group (that is, the acetic acid group in the structure is substituted only by the aryl group and is not substituted by another group such as a lower alkyl group) (See “Medical Drugs Japan Pharmaceutical Collection”, edited by Japan Pharmaceutical Information Center, Jiho Co., Ltd., “Today's therapeutic drug explanation and manual”. Therefore, the arylpropionic acid series such as ibuprofen, ketoprofen, zaltoprofen, naproxen, pranoprofen, loxoprofen, flurbiprofen, thiaprofenic acid, etc., in which the acetic acid residue in the structure is substituted with methyl group as well as aryl group Those classified as “non-steroidal anti-inflammatory agents” are not included in the “aryl acetate non-steroidal anti-inflammatory agents” of the present invention.

Examples of the “aryl acetic acid non-steroidal anti-inflammatory agent” of the present invention include indole acetic acid such as indomethacin; phenyl acetic acid such as diclofenac, ibufenac, arcfenac, methiazine acid and ampenac; indenyl acetic acid such as sulindac; Non-steroidal anti-inflammatory agents such as pyrrole acetic acid type; naphthyl acetic acid type such as nabumetone and salts thereof can be mentioned, and it is preferable to use one or more selected from these. Among these arylacetic acid non-steroidal anti-inflammatory agents, indomethacin or diclofenac is particularly preferable. This is because it has been demonstrated by the examples described later that good results are shown. Indomethacin is known to have poor percutaneous absorbability in a state where it is not dissolved in the base, but is inferior in stability in a dissolved state. However, if the constitution of the present invention is adopted, these problems also occur. Can be solved.

“Antihistamines” are roughly classified into two groups for each histamine receptor subtype. Histamine receptor H1 inhibitor effective in treating allergic diseases such as urticaria, eczema, dermatitis, allergic rhinitis and histamine receptor H2 inhibitor effective in treating gastric ulcer by suppressing gastric acid secretion It is.

The “antihistamine” used in the present invention is not particularly limited as long as it is conventionally used as a medical antihistamine, but is particularly preferably a histamine receptor H1 inhibitor, such as diphenylpyralin, diphenhydramine, cyproheptadine, triprolidine. Histamine receptor H1 inhibitors such as promethazine, homochlorcyclidine, alimemazine, clemastine, chlorpheniramine, and mequitazine, and salts thereof, and one or more of these may be selected and used Is preferred.
Of these antihistamines, diphenhydramine is particularly preferred. This is because it has been demonstrated that good results are shown in Examples described later.

The “antihistamine” used preferably has a cation such as an amino group. The cationic group and the carboxyl group in the acetic acid structure of arylacetic acid-based non-steroidal anti-inflammatory agents are ion-associated to improve the pharmacokinetics by covering each ionic group part with a hydrophobic part. This is because it is considered that the transdermal absorbability, diffusibility and skin irritation of the anti-inflammatory agent high concentration external preparation are improved.

For example, when these antihistamines are dissolved together with indomethacin and diclofenac sodium, they become soluble in solvents that were difficult to dissolve in the case of indomethacin and diclofenac sodium alone, such as esters, and the range for selection of the solubilizing agent is expanded. A good formulation can be adjusted. In addition, the solubility of indomethacin and diclofenac sodium, which are necessary in large amounts, is improved in compatibility, and can be dissolved with a small amount of solubilizing agent. In addition, an oily component can be formed just by warm-mixing diclofenac or indomethacin with these antihistamines, and can be formulated without a solubilizer. That is, the present invention not only uses antihistamines for improving transdermal absorbability and reducing skin irritation of external preparations containing high-concentration non-steroidal anti-inflammatory agents, but also solubilizing agents or dissolving agents for aryl acetate non-steroidal anti-inflammatory agents. It can also be used as an agent. Furthermore, although the reason is not clear, the transdermal absorbability of arylacetic acid non-steroidal anti-inflammatory agents can be improved by incorporating these antihistamines.

The above effect is particularly high when the content of the antihistamine is 0.2 to 5 parts by mass with respect to 1 part by mass of the arylacetic acid non-steroidal anti-inflammatory agent.

Although the compounding quantity of the aryl acetic acid type non-steroidal anti-inflammatory agent mix | blended with the external preparation of this invention is not restrict | limited, 0.5-50 mass% is preferable with respect to the whole external preparation. More preferably, it is 3 to 30% by mass, and particularly preferably 5 to 20%. If the blending amount is less than 0.5% by mass, the anti-inflammatory effect can not be expected so much. This is because the effect is further improved at 5% or more. Moreover, when it exceeds 50 mass%, a side effect will become strong, and when it exceeds 20 mass%, it will increase a problem in formulation. Moreover, 0.1-30 mass% is preferable with respect to the whole external preparation, and, as for the compounding quantity of the antihistamine mix | blended with the external preparation of this invention, 1-20 mass% is more preferable. This is because if the blending amount is less than 1% by mass, the effect of improving transdermal absorbability of the arylacetic acid-based nonsteroidal anti-inflammatory agent becomes insufficient, and if it exceeds 50% by mass, side effects may become strong.

Examples of the salt of the antihistamine that can be used as the active ingredient of the present invention include hydrohalides such as hydrofluoride, hydrochloride, hydrobromide, hydroiodide; nitrate, perchlorate, sulfuric acid Inorganic acid salts such as salts and phosphates; lower alkane sulfonates such as methane sulfonate, trifluoromethane sulfonate and ethane sulfonate; aryl sulfonic acids such as benzene sulfonate and p-toluene sulfonate Salts; amino acid salts such as ornithate and glutamate; and carboxylates such as fumarate, succinate, citrate, tartrate, maleate and tannate.

Examples of the dosage form of the external preparation according to the present invention include ointments, lotions, aerosols, plasters, aqueous cataplasms, etc., but if the dosage form is used as an external preparation, There is no particular limitation.

The external preparation of the present invention includes a base (for example, natural rubber, isoprene rubber, polyisobutylene, styrene-isoprene-styrene block copolymer, styrene-butadiene-styrene block copolymer, styrene-ethylene, if necessary. Rubbers such as butylene-styrene block copolymer, (meth) acrylic acid alkyl ester (co) polymer, polyacrylic acid ester, methacrylic acid ester, polyisobutylene, polybutene, liquid polyisoprene; petrolatum, cetanol, beeswax, Oils such as lanolin and liquid paraffin; water-soluble polymers such as carboxyvinyl polymer, starch acrylate, sodium polyacrylate, and carmellose sodium; glycerin; macrogol; silicic anhydride, etc.), excipients (for example, sucrose Sugars such as dextrin Starch derivatives; cellulose derivatives such as carmellose sodium; water-soluble polymers such as xanthan gum], colorants, lubricants (for example, metal stearates such as calcium stearate and magnesium stearate; sodium lauryl sulfate, lauryl sulfate) Lauryl sulfates such as magnesium; starch derivatives in the above excipients, etc.], binders (for example, the above excipients and magrogor), emulsifiers, thickeners, wetting agents (for example, glycerin, etc.), Stabilizers (for example, parahydroxybenzoates such as methyl paraben and propyl paraben; alcohols such as chlorobutanol, benzyl alcohol and phenylethyl alcohol; benzalkonium chloride; phenols such as phenol and cresol; thimerosal; Nothing Acetic acid; sorbic acid, etc.), preservative, solvent (eg, water, propylene glycol, butylene glycol, isopropanol, ethanol, glycerin, diethyl sebacate, isopropyl myristate, diisopropyl adipate, myristyl palmitate, stearyl stearate, myristic acid Myristyl, ceryl lignocerate, lactyl serolate, lactelyl lactate, etc.), solubilizer, suspending agent (eg, carmellose sodium), antioxidant (eg, sodium bisulfite, L-ascorbic acid, sodium ascorbate) , Butylhydroxyanisole, butylhydroxytoluene, propyl gallate, tocopherol acetate, d1-α-tocopherol, etc.), supplements (for example, peppermint oil, L-menthol, camphor, zimo) , Tocopherol acetate, glycyrrhetinic acid, nonylic acid vanillylamide, red pepper extract, etc.), buffering agents, can be incorporated in conventional amounts such as pH adjusting agent.

Although the usage-amount of the external preparation which concerns on this invention changes with the kind of containing active ingredient, a patient's symptom, age, etc., generally it is preferable to apply to an adult once to several times a day. More preferably, it is applied once or twice a day, but the number of administration may be increased depending on the symptoms.

  EXAMPLES Next, although an Example and a test example are shown and this invention is demonstrated in more detail, these do not limit this invention at all.

  First, according to the mixing ratio of Table 1, test solution No. 1 containing indomethacin, an arylacetic acid non-steroidal anti-inflammatory agent, was used. 1-2 were prepared.

Separately, gelatin 5%, isopropyl myristate 3%, carmellose sodium 1%, polyvinyl alcohol 3%, polysorbate 80 1%, glycerin 12%, and purified water 75% were heated to a uniform solution. After mixing, this was added into a predetermined container at a depth of 4 cm, and then cooled to prepare a gel.

Each test solution No. 500 mg / cm ² on this gel. 1-2 were layered. After standing at room temperature for 7 days, a gel was cut out from the upper layer every 1 cm, and the concentration of indomethacin in each of the four fractions from the upper layer was measured. The concentration was measured by grinding the gel, extracting with methanol, and analyzing this by high performance liquid chromatography. The results are shown in FIG. 1 as an average value of values obtained with N = 4 per sample.

FIG. 1 shows a test solution No. 1 containing polyethylene glycol as a base and containing indomethacin. It is the graph which showed the osmosis | permeation diffusivity of 1 and 2 (concentration 10%), and is the multilayer bar graph which overlaid the indomethacin density | concentration of fraction 2,3,4. In addition, since fraction 1 is a part which touches a test liquid directly, it has not measured.

From the results, comparing the degree of osmotic diffusivity of indomethacin with the sum of the concentrations in fractions 2, 3, and 4, the test solution containing diphenhydramine has improved osmotic diffusivity. That is, it was demonstrated that the infiltration of indomethacin was greatly improved by adding diphenhydramine.

The test solution N0.1-2 containing indomethacin, which is an arylacetic acid non-steroidal anti-inflammatory agent, prepared according to the formulation of Table 1 was used to test the osmotic diffusivity for meat pieces.

First, gauze was drawn on a petri dish having a diameter of 9 cm, and the test solution No. 10 g of 1, 2 was added and moistened. Red beef was cut into a 2 × 2 × 4 cm rectangular parallelepiped, and a piece of meat was placed on the gauze so that 2 × 2 cm was the bottom, wrapped and left at 4 ° C. for 48 hours. Thereafter, meat pieces were cut from the lower layer every 1 cm, and the concentration of indomethacin was measured in the three fractions of fractions 0 to 1 cm, 1 to 2 cm, and 2 to 3 cm from the bottom. Concentration measurement was performed by high performance liquid chromatography after grinding pieces of meat and extracting with methanol. The test was performed at N = 6 for each test solution, and the average value is shown in FIG.

FIG. 2 is a graph showing indomethacin concentrations of fractions 1 to 2 cm and 2 to 3 cm of test solutions 1 and 2 from the left. The fractions 0 to 1 cm were excluded because they were in direct contact with the test solution.

From the results, it was found that the infiltration diffusivity of indomethacin was remarkably improved when diphenhydramine was added, and extended to a fraction having a depth of 2 to 3 cm. Therefore, it was demonstrated that the effect of improving the osmotic diffusivity by adding the antihistamine of the arylacetic acid non-steroidal anti-inflammatory agent is observed not only in the gel but also in the actual muscle tissue.

  Conventional external preparations containing non-steroidal anti-inflammatory agents cannot be said to have good effects, but by using the present invention that can transfer non-steroidal anti-inflammatory agents deep into the subcutaneous tissue, it has never been better It may be possible to provide a topical preparation containing a non-steroidal anti-inflammatory agent having various effects.

It is explanatory drawing which showed the osmosis | permeation diffusivity of the test liquid containing indomethacin. It is explanatory drawing which showed the osmosis | permeation diffusivity of the test liquid containing indomethacin.

Claims (4)

Anti-inflammatory analgesic topical agent comprising an arylacetic acid non-steroidal anti-inflammatory agent and an antihistamine The anti-inflammatory analgesic external preparation according to claim 1, wherein the antihistamine is diphenhydramine. The anti-inflammatory analgesic external preparation according to claim 1 or 2, wherein the arylacetic acid non-steroidal anti-inflammatory agent is indomethacin or diclofenac sodium. The anti-inflammatory analgesic external preparation according to claim 1, 2 or 3, wherein the ratio of the arylacetic acid non-steroidal anti-inflammatory agent with respect to 100 parts by mass of the anti-inflammatory analgesic external preparation is 5 parts by mass or more.

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