JP4807721B2 - Anti-inflammatory analgesic topical - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide an anti-inflammatory/analgesic external preparation having little skin stimulation which is the external preparation containing etodolac as NSAID (non-steroidal antiinflammatory drug), excellent not only in dermal permeability, but in permeability and dispersibility in tissues in a part deeper than the skin, directly acting on muscules and joint tissues having inflammation and pains, and having little skin stimulation. <P>SOLUTION: The anti-inflammatory/analgesic external preparation contains etodolac and a local anesthetic. Preferably, the preparation contains 1 pt. mass etodolac and 0.1-1.5 pts.mass local anesthetic. <P>COPYRIGHT: (C)2005,JPO&amp;NCIPI

Description

  The present invention relates to an external preparation having anti-inflammatory analgesic effect.

  Conventionally, non-steroidal anti-inflammatory drugs (hereinafter referred to as “NSAID”) are known as anti-inflammatory analgesics. This NSAID inhibits cyclooxygenase (hereinafter referred to as “COX”), which catalyzes the first reaction in the arachidonic acid cascade, which is a metabolic pathway that enhances pain, thereby producing prostaglandins related to inflammation and pain. It has the effect of suppressing.

  However, prostaglandins exert a variety of effects in addition to the effects of inflammation and pain, and serious side effects may occur if the production of prostaglandins is suppressed more than necessary by administration of NSAIDs. There is. For example, when the action of COX is suppressed, the activity of lipoxygenase is enhanced and leukotriene is increased, thereby decreasing the secretion of gastric juice and at the same time increasing the active oxygen that destroys the gastrointestinal mucosa and causing ulcers. Other side effects, such as renal dysfunction, liver dysfunction, and skin rash, are known, and aspirin asthma may be induced, especially as it is life-threatening.

  Therefore, NSAID has been developed as an external preparation that hardly causes these side effects. That is, by delivering NSAID to the affected area through the skin, systemic side effects can be reduced and the drug concentration can be increased locally at the affected area.

  However, some NSAIDs have extremely poor skin permeability, and the effects when administered as an external preparation are extremely reduced compared to when administered orally. Therefore, various techniques for improving NSAID skin permeability have been studied.

  For example, the invention described in Patent Document 1 is an external anti-inflammatory analgesic composition containing an NSAID and a local anesthetic, and an improvement in skin permeability is the solution. And in the Example of the said literature, the composition containing the loxoprofen sodium which is NSAID, and a local anesthetic is prepared, The evaluation test of the skin permeability is described.

  However, assessment of skin permeability alone is by no means satisfactory for determining the value of NSAID drug delivery systems. This is because the site where pain occurs is a muscular tissue or a joint tissue, and the point that the NSAID should reach is not a skin surface portion where capillaries are present but a deeper portion where muscular tissue exists. That is, even if only the skin permeability and the blood concentration are improved, it has osmotic diffusion in muscle tissue and the like, and the drug does not always act directly on the affected area. In fact, according to the findings by the present inventors, depending on the NSAID, there is a case where the osmotic diffusibility in the tissue is lowered by adding a local anesthetic. Nonetheless, in the conventional formulation design, the penetration and diffusion properties deeper than the dermis were not considered at all.

  Furthermore, even if the preparation exhibits high skin permeability, if the NSAID cannot be penetrated and diffused deeply, the drug must remain on the surface of the skin, resulting in secondary effects such as reduced safety due to skin irritation. Can cause serious disability. Moreover, it is considered that when the concentration of NSAID is increased inside the skin surface, the concentration gradient with the drug existing outside the skin is decreased, and the absorption efficiency is decreased. As a result, even if the content of NSAID in the external preparation is increased, the absorbed amount does not increase and the effect is not improved. Therefore, the NSAID concentration in the external preparation so far is about 1% at most, and added more than that. The effect was supposed to be saturated.

  Similar to the invention of Patent Document 1, other preparations containing an NSAID and a local anesthetic are known. For example, Patent Document 2 describes an external patch containing a local anesthetic and an NSAID from the viewpoint of acting on both the inflamed site and the peripheral nervous system, and examples of NSAID include indomethacin and the like. Yes. However, there is no description about etodolac, and the literature discloses sensory test results as examples, but there is no description about skin permeability and the like.

  Patent Document 3 also describes a salt formed from an NSAID having a carboxyl group and a local anesthetic having an amino group, and etodolac is also described as an example of the NSAID. However, the technique described in the document improves the sustained release of drugs such as injections by reducing the water solubility of NSAID, and is not intended for use as an external preparation. Therefore, there is no description or suggestion about skin permeability or osmotic diffusion in muscle tissue. Moreover, the salt actually manufactured in the Example of the said literature is only what contains difunisal as NSAID.

By the way, COX mainly includes type 1 and type 2 isozymes. COX-1 is constitutively expressed in most tissues in the body and is thought to play a role in maintaining the stability of the living body, such as the protective action of the gastric mucosa. On the other hand, the normal expression level of COX-2 is low, but is induced by inflammatory stimuli or the like. Therefore, if COX-2 can be selectively inhibited, it is considered that inflammation and the like can be reduced while suppressing biological damage. However, NSAIDs such as indomethacin and diclofenac that are specifically disclosed as examples in the above-mentioned patent literatures inhibit COX non-selectively. Therefore, even if the skin permeability of these external preparations is increased, side effects accompanying an increase in the blood concentration of the drug may be a problem, and the meaning of making the external preparation disappears.
Japanese Patent Laid-Open No. 14-128699 (Claims, paragraph [0001], Example 1) International Publication No. 01/047559 Pamphlet (Claims) WO03 / 099293 pamphlet (claims, examples)

  As described above, preparations containing NSAIDs and local anesthetics have been known so far, and some external preparations containing loxoprofen have taken into consideration improvements in skin permeability. However, none of the conventional techniques considers the permeability and diffusibility in the muscles and joint tissues below the skin. Furthermore, according to the findings by the present inventors, the behavior of a preparation containing NSAID and a local anesthetic in muscle tissue is not uniform, and the coexistence of a local anesthetic reduces the osmotic diffusivity of NSAID. There is also.

  Therefore, the problem to be solved by the present invention is an external preparation containing NSAID, which not only has excellent skin permeability, but also has excellent permeability and diffusibility in tissues deeper than the skin, inflammation and pain Another object of the present invention is to provide an anti-inflammatory analgesic external preparation that can directly act on muscular and joint tissues with low skin irritation.

  In order to solve the above-mentioned problems, the inventors of the present invention have made extensive studies on a composition containing an NSAID, particularly a structure excellent in osmotic diffusibility in muscle tissue or the like. As a result, it was found that the preparation using etodolac, which is an NSAID having a specific chemical structure, and a local anesthetic has significantly higher osmotic diffusivity in muscle tissue than other combined preparations, and completed the present invention. .

  That is, the anti-inflammatory analgesic external preparation of the present invention is characterized by containing etodolac and a local anesthetic.

  In the said anti-inflammatory analgesic external solvent, the thing whose ratio of the local anesthetic with respect to 1 mass part of etodolac is 0.1-1.5 mass parts is suitable. Similarly, it is also preferable that the molar ratio of the local anesthetic to etodolac is 0.1 to 1.8. This is because, within such a range, the object of the present invention can be achieved, and a preparation excellent in skin permeability and permeation diffusivity can be obtained.

  As the local anesthetic, lidocaine is preferable. This is because the combination with etodolac is proved to be suitable by the examples described later.

  The anti-inflammatory analgesic external preparation according to the present invention is not only excellent in skin permeability, but also has significantly improved permeability and diffusibility in deep skin such as muscle tissue. As a result, since the slowdown of drug absorption is suppressed, even if a relatively large amount of NSAID (etodolac) is added to the preparation, its effect can be exhibited as it is. In addition, skin irritation, which has been a problem with conventional NSAID-containing external preparations, is also reduced. Therefore, the anti-inflammatory analgesic external preparation of the present invention is used for chronic pain such as rheumatoid arthritis, osteoarthritis, and low back pain; inflammatory diseases such as periarthritis and tendonitis; neck-arm syndrome; pain due to surgery, trauma, etc. It is extremely excellent as a preparation used for the treatment and treatment.

  The anti-inflammatory analgesic external preparation of the present invention has a gist in that it contains etodolac and a local anesthetic.

  Etodolac used in the present invention has a chemical name of 1,8-diethyl-1,3,4,9-tetrahydropyrano [3,4-B] indole-1-acetic acid. It has been used as an agent. In the present invention, those synthesized by a known method or commercially available etodolac may be used.

  NSAIDs have many chemical structures in common, such as indoleacetic acid such as indomethacin, salicylic acid such as difunisal, phenylpropionic acid such as loxoprofen, phenylacetic acid such as diclofenac, oxicam acid such as meloxicam, etc. May be classified. However, etodolac, known as an excellent NSAID, has a unique chemical structure as described below and does not fall into any of these categories.

  Etodolac is also an excellent selective inhibitor of COX-2. Therefore, although the external preparation of the present invention is excellent in skin permeability, there is little concern about side effects even if the blood concentration increases when administered as an external preparation. In addition, since the external preparation of the present invention also has osmotic diffusibility in muscle tissue, etc., etodolac stagnate on the skin surface and is absorbed from the capillaries to increase only the blood concentration, acting locally. Can be made.

  The “local anesthetic” used in the present invention is not particularly limited as long as it is conventionally used as a medical local anesthetic, but for example, lidocaine, tetracaine, procaine, dibucaine, benzocaine, bupivacaine, mepivacaine and These salts can be mentioned, and it is preferable to use one or more selected from these. Of these local anesthetics, lidocaine is particularly preferred. This is because it has been demonstrated that excellent effects can be exhibited by the examples described later.

  The “local anesthetic” used preferably has a cationic group such as an amino group. When the cationic group and the carboxyl group of etodolac are ion-associated, each ionic group part is covered with a hydrophobic part to improve pharmacokinetics, and skin permeability, osmotic diffusion and skin irritation are improved. Because it is considered.

  As for the quantity of etodolac mix | blended with the external preparation of this invention, 1-50 mass% is preferable with respect to the whole external preparation. If the blending amount is less than 1% by mass, the analgesic effect may be insufficient, and if it exceeds 50% by mass, side effects may tend to be strong. The external preparation of the present invention has improved osmotic diffusivity in muscle tissue and the like as well as the skin permeability of etodolac, so that the effect is not saturated and the effect according to the blending amount can be exhibited. Is more preferably 3% by mass or more, particularly preferably 5% or more. For the same reason, the amount of the local anesthetic added to the external preparation of the present invention is also preferably 1 to 50% by mass with respect to the entire external preparation.

  The mixing ratio of etodolac and local anesthetic in the external preparation of the present invention is not particularly limited, but the ratio of local anesthetic to 1 mass part of etodolac is preferably 0.1 to 1.5 parts by mass. Similarly, the molar ratio of the two is not particularly limited, but it is preferable that the molar ratio of the local anesthetic to Etodolac 1 is 0.1 to 1.8. This is because, within such a range, the etodolac skin permeability and osmotic diffusivity can be improved. Furthermore, the blending ratio is more preferably about 0.2 parts by mass or more and about 1.1 parts by mass or less, and the molar ratio is more preferably about 0.2 or more and about 1.3 or less. This is because a preparation excellent in skin permeability and osmotic diffusibility can be obtained by making the molar number of etodolac and local anesthetics approximately equal in consideration of use as a pharmaceutical. However, the above range is given a width because the object of the present invention can be achieved even if either one of the drugs is somewhat excessive. For example, as in the examples described later, the present invention can be applied even if the amount of etodolac (molecular weight: 287.35) and lidocaine (molecular weight: 234.34) in the preparation is made equal and the number of moles of lidocaine is slightly larger than the number of moles of etodolac. The effect which concerns on can fully be exhibited.

  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 Rubbers such as butylene-styrene block copolymer, (meth) acrylic acid alkyl ester (co) polymer, poly (meth) acrylic ester, polyisobutylene, polybutene, liquid polyisoprene; petrolatum, cetanol, beeswax, lanolin, Oils such as liquid paraffin, carboxyvinyl polymer, starch acrylate, sodium polyacrylate, carmellose sodium, polyethylene glycol and other water-soluble polymers; crotamiton; diethyl sebacate; silicic anhydride, etc.], excipients (eg Sugars such as sucrose; Dextst Such as carmellose sodium; water-soluble polymers such as xanthan gum; colorants, emulsifiers, thickeners, wetting agents (eg glycerin, etc.), stabilizers (eg methyl paraben, propyl) Parahydroxybenzoates such as paraben; alcohols such as chlorobutanol, benzyl alcohol, and phenylethyl alcohol; benzalkonium chloride; phenols such as phenol and cresol; thimerosal; acetic anhydride; sorbic acid, etc.), Preservative, solvent (eg water, propylene glycol, butylene glycol, isopropanol, ethanol, glycerin, diethyl sebacate, isopropyl myristate, diisopropyl adipate, myristyl palmitate, stearic acid Allyl, myristyl myristate, lignocerate, ceryl celloselate, lactelyl cerate, etc.), solubilizer, suspending agent (eg, carmellose sodium), antioxidant (eg, sodium bisulfite, L-ascorbine) Acid, sodium ascorbate, butylhydroxyanisole, butylhydroxytoluene, propyl gallate, tocopherol acetate, dl-α-tocopherol, etc.), supplements (eg mint oil, L-menthol, camphor, thymol, tocopherol acetate, glycyrrhetinic acid) , Nonylic acid vanillyl amide, pepper extract, etc.), buffer, pH adjuster, etc. can be blended in the usual blending amount.

  When producing the external preparation of the present invention, it is preferable to first mix etodolac or a salt thereof and a local anesthetic or a salt thereof. Specifically, both are added to a solvent and mixed with stirring, or both are directly heated and mixed.

  The salt used here is not particularly limited as long as it is pharmacologically acceptable. Even when a salt is used as a raw material, it is considered that the object of the present invention is achieved by a strong interaction between etodolac and a local anesthetic.

  Examples of the salt of the local anesthetic that can be used as the active ingredient of the present invention include hydrohalides such as hydrofluorate, hydrochloride, hydrobromide and hydroiodide; nitrate and perchloric acid. Inorganic acid salts such as salts, sulfates and phosphates; salts of lower alkane sulfonic acids such as methane sulfonate, trifluoromethane sulfonate and ethane sulfonate; benzene sulfonate and p-toluene sulfonate And carboxylic acid salts such as fumaric acid, succinic acid, citric acid, tartaric acid, oxalic acid and maleic acid. Of these, hydrochloride can be most preferably used.

  As the solvent in the case of mixing etodolac and a local anesthetic using a solvent, those generally used in producing a pharmaceutical composition are preferable. Moreover, an oily component is formed only by heating and mixing etodolac and a local anesthetic, and a formulation can be made without a solvent. For example, by putting both in a mortar and grinding while mixing, an oily component can be formed with frictional heat.

  In the present invention, the local anesthetic is not only used for reducing skin irritation, but can also be used as a solubilizing agent or solubilizing agent for etodolac. Furthermore, although the reason is not necessarily clear, the inclusion of these local anesthetics improves the skin permeability and osmotic diffusion of etodolac.

  What is necessary is just to add and mix the mixing | blending component according to each dosage form mentioned above to the mixture of the obtained etodolac and the local anesthetic. The manufacturing method should just employ | adopt the well-known method according to each dosage form.

  The anti-inflammatory analgesic external preparation of the present invention thus obtained can sufficiently exhibit its effect even when more etodolac is added than the conventional etodolac-containing external preparation. In addition, since the permeability to the skin and the osmotic diffusivity in the deep part of the skin are improved, the drug does not accumulate in the skin surface layer and has little skin irritation, and the drug is delivered to the affected area (muscle, joint tissue, etc.). be able to. Therefore, the external preparation of the present invention is an etodolac preparation that can be directly applied to affected areas such as chronic pain and has an excellent effect.

  Although the usage-amount of the external preparation of 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 Hereinafter, the present invention will be described more specifically with reference to examples. However, the present invention is not limited by the following examples, but may be appropriately modified within a range that can meet the purpose described above and below. It is also possible to implement, and they are all included in the technical scope of the present invention.

Production Example 1
According to the mixing ratio of Table 1, etodolac and the like were dissolved in macrogol 400 to prepare test solution 1 containing etodolac and lidocaine and test solution 2 containing only etodolac. In addition, the numerical value in Table 1 is a mass part.

Test Example 1 Osmotic diffusivity test in muscle tissue The etodolac-containing test solutions 1 and 2 prepared in Production Example 1 were tested for osmotic diffusivity on meat pieces. First, gauze was drawn on a petri dish having a diameter of 9 cm, and 10 g of the test solution 1 or 2 was added. Separately, red beef was cut into 2 × 2 × 4 cm cuboids, placed on gauze so that 2 × 2 cm was the bottom, covered with polyvinylidene chloride film, and allowed to stand at 4 ° C. for 48 hours. Then cut the meat pieces from the lower layer every 1 cm, and measure the concentration of etodolac as the amount contained in 1 g of meat pieces in the three fractions of 0-1 cm, 1-2 cm, 2-3 cm from the bottom. did. Concentration measurement was performed by grinding each piece of meat, adding 5 mL of methanol to extract etodolac, and then analyzing by high performance liquid chromatography. The test was performed at N = 6 for each test solution. The results are shown in Table 2 as the average value. The fraction 0 to 1 cm was excluded from the results because it was a portion that was in direct contact with the test solution.

  From these results, it was found that the osmotic diffusivity of etodolac in muscle tissue was remarkably improved when lidocaine was blended, extending to a fraction having a depth of 2 to 3 cm. Moreover, according to the knowledge by the present inventors, an external preparation containing etodolac and a local anesthetic is excellent in skin permeability. Therefore, in the external preparation of the present invention, it is considered that etodolac absorbed percutaneously permeates and diffuses into the deep skin layer without remaining on the skin surface and can directly act on the affected area.

Production Example 2 Preparation of Tape Formulation According to the Present Invention Etodolac-lidocaine blended tape preparation was prepared by the solvent method with toluene at the blending ratio (parts by mass) shown in Table 3. Specifically, etodolac, lidocaine and macrogol were first heated and mixed at 40 ° C. until clear. Separately, styrene-isoprene-styrene block copolymer, liquid paraffin, alicyclic saturated hydrocarbon resin and dibutylhydroxytoluene are dissolved in toluene, and a mixture of etodolac and lidocaine is added and mixed to obtain a uniform melt. Got. This melt was coated on a release film (polyester) using a coating machine so that the weight of the paste after drying was 100 g / m ^2, and then dried by heating to evaporate toluene. A support (nonwoven fabric) was bonded to the obtained coated surface, and this was cut into a desired size to obtain a tape agent.

Claims (4)

An anti-inflammatory analgesic external preparation containing etodolac and lidocaine , wherein the molar ratio of lidocaine to etodolac is 0.1 to 1.8 . The anti-inflammatory analgesic external preparation according to claim 1, wherein a molar ratio of the lidocaine to the etodolac is 0.2 to 1.3 . The anti-inflammatory analgesic external preparation according to claim 1 , wherein the molar ratio of lidocaine to etodolac is 1 . The anti-inflammatory analgesic external preparation according to any one of claims 1 to 3, wherein the external preparation is a tape preparation.