The preparation for external use containing loxoprofen

 

(57) Abstract:

Anti-inflammatory analgesic external use drug contains loxoprofen or its pharmaceutically acceptable salt in an amount of 0.1 - 5 wt.% the total weight of the drug and crotamiton in the amount of 0.5 - 5 wt.% the total weight of the preparation. the product provides when applied to the skin metabolism loxoprofen in the TRANS-Oh form using a present in the skin ketone-reduction enzyme. Through the use of crotamiton the drug has a uniform distribution of loxoprofen, high stability and does not cause skin irritation. 2 C. and 16 h.p. f-crystals, 5 PL.

The scope of the invention

The invention concerns an anti-inflammatory analgesic for external use containing as an active ingredient loxoprofen (Loxoprofen or its pharmaceutically suitable salt.

Art

Sodium salt of loxoprofen (correct name: 2-[para-(2-oxacyclopentane)phenyl] propionic acid), otherwise known as loxoprofen sodium (Loxoprofen sodium), has excellent efficacy of non-steroidal anti-inflammatory agent type phenylpropionic acid and is widely COI is/P> By the way, loxoprofen sodium is a prodrug. When oral administration it is converted in the body in the TRANS-Oh form (correct name: 2-[para-(TRANS-2-hydroxycarbonylmethyl)phenyl]propionic acid), which, as is well known in practice, demonstrate excellent anti-inflammatory activity [Matsuda and others , Japanese Journal of Inflammation, so 2, N 3, Summer. pages 263-266 (1983)]. The enzyme (ketone-reduction enzyme), which is associated with this metabolism, is present mainly in the liver and kidney [Tanaka and others , Japanese Journal of Inflammation, so 3, N 2, Spring, pp. 151-155 (1983)], and it is known that TRANS-HE has inhibitory activity against cyclooxygenase, prostaglandin-producing enzyme, approximately 80 times greater than loxoprofen sodium [Matsuda and others, Japanese Journal of Inflammation, so 2, N 3, Summer, pp. 263 - 266 (1983)]. In accordance with the foregoing, it is clear that before loxoprofen sodium will be able to show their excellent anti-inflammatory analgesic activity, he must pass through the liver or kidneys, where it is activated.

Thus, if loxoprofen sodium is used as the external use drug, it should be handled not as with anti-inflammatory pain reliever such as LASS="ptx2">

However, still many patent applications devoted to preparations for external use containing as an active ingredient an anti-inflammatory painkillers, in particular, for the basics of preparations for external use, and some of the applications indicate anti-inflammatory analgesic agent as an example of the active ingredient contained in the product, or which can be added to the basis, and some of them indicate loxoprofen sodium as a specific example of an anti-inflammatory analgesic agent. However, most of these applications simply indicate loxoprofen in the description as an example of anti-inflammatory analgesic agent. Although some of these patent applications are referenced crotamiton (crotamiton) as an example of the solvent for the active ingredients, which is one of the components, and the hallmark of this application, none of the applications actually does not disclose a preparation containing loxoprofen and crotamiton.

On the other hand, with regard to loxoprofen and its sodium salt, the external use drug disclosed in (1) is Laid open Patent Application Japan N Hei 4-99719, (2) Laid-open Patent H is the group of a new framework, contain a certain type of fatty acid ester and polyhydric alcohols, and is designed to improve the speed with which the active ingredient penetrates the skin; as an example there get transdermal patch, which contains loxoprofen sodium.

(2) disclose the specific solvent [2-(2-methoxy-1-methylethyl)-5-methylcyclohexanol] and external use drug containing this solvent, as an example, there get lexaprophentermineiy patch, its adhesion to the skin and preserve it assess in the examples. However, none of patent claim does not apply pharmacological effects loxoprofen sodium when it is used in the form of the external preparation.

In addition, when the applicants of the present invention has been drug loxoprofen sodium for external use containing the ester of fatty acid and polyhydric alcohol in accordance with (1), and observed it in time, it has precipitated crystals loxoprofen. Usually, upon receipt of drugs of some substances for external use add solvent to avoid crystallization and precipitation of the active ingredient. The choice of the optimal solvent awlaelo dissolution of the drug may occur reduced the release of active ingredient from the base and reduced its transfer to the place of impact, not providing sufficient therapeutic effects. In other words, one cannot expect the solvent, the optimum for a particular active ingredient will be optimal for other active ingredients.

On the other hand, examples of research Laid open Patent Application Japan N Sho 57-4919 (the above (3)) described the pharmacological effects of drugs outside of the solution loxoprofen in Croton oil and ointments, obtained by simply adding loxoprofen sodium to Plastibase 50W. However Croton oil is a toxic substance that is used as a stimulus, Katarzyna gene in cancer research [THE MERCK INDEX, twelfth edition, page 2665], so it is not suitable for mixing with the drug. In addition, the effectiveness of the drug, including a combination of loxoprofen sodium and Plastibase 50W, not dependent on dose.

Description of the invention

As described above, loxoprofen is a prodrug, it is the TRANS-HE form, the active metabolite, demonstrates strong anti-inflammatory analgesic activity, and the enzyme that promotes the conversion of loxoprofen active metabolite exists mainly in pecan is through the skin TRANS-HE form of loxoprofen allows you to maintain the application site the greater number of TRANS-HE forms, than absorption through the skin of loxoprofen to achieve excellent anti-inflammatory analgesic actions. However, studies of absorption through the skin, conducted by the applicants of the present invention on the TRANS-HE form, showed that TRANS-HE form may be absorbed with great difficulty.

As a result of intensive studies anti-inflammatory analgesic preparation for external use containing as an active ingredient loxoprofen sodium, the applicants of this invention have found that (i) loxoprofen, has excellent ability to penetrate through the skin to the TRANS-HE form, which is the active metabolite, so this entry through the skin gives the opportunity to accumulate in the skin enough loxoprofen, and that (ii) if in the skin for a long period of time retained a sufficient number of loxoprofen, surprisingly, he is using ketone-reduction enzyme is transformed into TRANS-Oh form even in the skin, and there it is possible to maintain an effective amount of TRANS-shape IT. As for the above tasks get drug loxoprofen, the applicants of this invention have found that the use as aseparate of loxoprofen for external use, which has high stability and does not cause skin irritation. That is, the adulteration of crotamiton as solvent in the preparation of loxoprofen for external use prevents the deposition of loxoprofen in the form of crystals, and the result is a product with excellent uniform distribution of the active ingredient. This drug has the potential to greatly increase the speed and amount of absorption of loxoprofen through the skin, and provide a continuous supply of loxoprofen, which allows to maintain a sufficient concentration of loxoprofen in the skin at the application site. As first confirmed by the applicants of the present invention, further loxoprofen becomes in the skin of TRANS-Oh form, thus allowing to maintain a sufficient amount of TRANS IT is the form of the preparation. The result found that the application of this drug provides excellent local anti-inflammatory analgesic effect, and that this drug does not cause skin irritation. On the basis of these findings, the authors have developed the present invention.

The present invention concerns:

(1) method of producing TRANS-HE forms, including pravr the skin ketone-reduction enzyme; and

(2) anti-inflammatory analgesic preparation for external use containing loxoprofen or its pharmaceutically suitable salt and crotamiton.

Anti-inflammatory analgesic preparation for external use, described in (2), preferably is a drug topical application, characterized in that:

(3) application of external use drug causes the skin metabolism loxoprofen or its pharmaceutically suitable salt in his TRANS-Oh form, the concentration of the TRANS-IT forms higher in the dermal layer of the skin at the application site than in plasma.

Anti-inflammatory analgesic preparation for external use, described in (2) or (3), more preferably is:

(4) drug topical application, in which the content of crotamiton is from 0.5 to 5 weight % of the total weight of the drug;

(5) drug topical application, in which the content of crotamiton is from 1 to 2 percent by weight of the total weight of the drug;

(6) drug topical application, in which the content of loxoprofen or its pharmaceutically suitable salt is from 0.1 to 5 weight % of the total weight of the drug;

(7) preparato is from 0.15 to 2 percent by weight of the total weight of the preparation; or

(8) drug topical application, in which the content of loxoprofen or its pharmaceutically suitable salt is from 0.5 to 2 percent by weight of the total weight of the preparation.

Other preferred anti-inflammatory analgesic external use drug is arbitrary combination of elements, each of which is selected from a group consisting of (2) and (3), (4) and (5) and (6) to(8).

In addition loxoprofen or its pharmaceutically suitable salts and crotamiton the above anti-inflammatory analgesic drug topical application can include additives commonly used in preparations for external use. Preferred examples of such anti-inflammatory pain medications for external use include in addition to loxoprofen or its pharmaceutically suitable salts and crotamiton:

(9) the preparation for external use, containing from 0.5 to 80 weight % (of the total weight of the preparation) of a solvent and/or agent to accelerate the penetration through the skin;

(10) the external use drug containing from 3 to 30 weight % (of the total weight of the preparation) of water-soluble polymer;

(11) the external use drug containing from 5 to 20 weight % (from obseg the o % (of the total weight of the preparation) soluble in oil polymer;

(13) the external use drug containing from 10 to 80 weight % (of the total weight of the preparation) soluble in oil polymer;

(14) the external use drug containing from 5 to 60 weight % (of the total weight of the preparation) of wetting agent; or

(15) the preparation for external application containing from 10 to 45 weight % (of the total weight of the preparation) of wetting agent.

Preferred drugs, which include two or more elements selected from (10)-(15). [However, you cannot select (10) and (11) and (14) and (15)].

In addition, another aspect of this invention is the provision of an anti-inflammatory analgesic preparation for external use, as described in any of paragraphs (2) through (15), in the form of a patch, ointment, cream, lotion, or aerosol.

According to this invention, the expression "pharmaceutically suitable salt" in the definition of "loxoprofen or its pharmaceutically suitable salt" means a salt of a cation with a carboxyl group present in the molecule loxoprofen. Such salts preferably include alkali metal salts such as sodium salt, potassium salt and lithium salt; salts of alkaline earth metals, such as salt and calcium salt m ammonium salts; salts of amines, such as salt tert-octylamine, salt dibenzylamine, salt of the research, salt of glucosamine, salt Olkiluoto phenylglycine ester, salt, Ethylenediamine salt, N-methylglucamine, guanidine salt, salt diethylamine, salt, triethylamine salt of dicyclohexylamine, salt N,N'-dibenziletilendiaminom, salt chloroprocaine, salt of procaine, diethanolamine salt, a salt of N-benzylpenicillin, salt piperazine, salt Tetramethylammonium, salt of Tris(hydroxymethyl)aminomethane, and other such organic salts; and salts of amino acids such as salt of glycine, lysine salt, arginine salt, salt, ornithine salt of glutamic acid and a salt of aspartic acid. Pharmaceutically suitable salts are preferably water-soluble salts and more preferably sodium.

In addition, if loxoprofen or its pharmaceutically suitable salt" to leave on the air or precrystallization, they absorb water or used for the recrystallization solvent, becoming a hydrate or MES, which are also included in this invention.

Whether some external use drug drug for which "drug use external application causes the skin metabolism LWE above in the dermal layer of the skin at the application site, than in plasma", you can check using this drug, for example, in experimental animals, such as rats or mice, and measuring the concentration of TRANS-HE form (µg/ml) in plasma and the dermal layer of the skin at the application site after a certain time (for example, four or eight hours) after application. Specifically, it can easily be checked by conducting experiments according to the method described below in Example Research 3".

With regard to the present invention, the content of loxoprofen sodium in the preparation for external use is not limited to a particular range as long as the drug is feasible, but is preferably from 0.1 weight% (more preferably about 0.15 percent by weight and most preferably 0.5 wt% to 5 weight% (more preferably 2 weight%) of the total weight of the preparation. An excessively small amount of active ingredient gives a poor performance, while an excessively large amount of the active ingredient is no advantage and, thus, inefficient from the point of view of the price.

The content is used as a solvent chromatone not specifically limited as long as the drug is feasible, but is preferably from 0.5 vesaite.

the pH of the drug topical application is preferably from 4.0 (more preferably 5.0, and most preferably to 5.5 to 7.5 (more preferably 7, and most preferably about 6.5).

This drug topical application may include various bases used for conventional drugs external application, such as another solvent that can be used with crotamiton; agent for accelerating penetration through the skin, water-soluble polymer that can be used as an adhesive agent and/or film-forming agent; soluble in oil polymeric compound which can be used as an adhesive agent and/or agent for improving adhesiveness; humidifier; surfactant; propellant and other pharmaceutically suitable additives without restrictions as long as they do not give harmful effects.

Other solvents which dissolve loxoprofen or its pharmaceutically suitable salt, virtually no restrictions as long as they can be used together with crotamiton without getting harmful effects, and choose them, for example, water, alcohols, pharmaceutically suitable fatty acids and their esters and oil components the s content is preferably from 20 weight % (more preferably 40 weight % to 80 weight % (more preferably 60 weight %) of the total weight.

The alcohols may be any of the common alcohols without particular limitations as long as they do not give harmful effects. Such alcohols include, for example, aliphatic alcohols such as methanol, ethanol, propyl alcohol and isopropyl alcohol; aliphatic polyhydric alcohols such as propylene glycol, octanediol, 1,3-butanediol, ethylene glycol, polyethylene glycol, glycerin and D-sorbitol; aliphatic and aromatic alcohols such as benzyl alcohol. The content of the alcohol is preferably from 0.5 weight % (more preferably 3 weight% to 10 weight % (more preferably 5 weight %) of the total weight of the preparation. However, the content of propylene glycol, polyethylene glycol, glycerol or D-sorbitol used as described below humidifiers, are not restricted to these values.

Pharmaceutically suitable fatty acids and their esters can be any of the common fatty acids and esters without particular limitations as long as they do not give harmful effects. Preferred pharmaceutically suitable fatty acids and their esters are fatty acids that have from 3 (more preferably 10 to 30 (more preferably 20) carbon atoms, such as capric acid is terinova acid, laurinlactam, isopropylmyristate, isopropyl, aerolef, diisopropylamide, Diisopropylamine, glycerylmonostearate or ethylenglykolether. Their preferred esters are alkalemia esters having from 5 (more preferably 12) to 50 (more preferably 40) carbon atoms or esters of alkalophiles having from 8 (more preferably 12) to 30 (more preferably 24) carbon atoms. In combination, you can use one or more fatty acids and their esters. Preferred fatty acids are oleic acid and laurolactam. The content of such a fatty acid or its ester is preferably from 0.5 weight% (more preferably 1 weight% to 20 weight% (more preferably 15 weight%) of the total weight of the preparation.

The oil component, such as animal fat, vegetable oil and terpene compound, can be well-known oil component without particular limitations as long does not give harmful effects. Such oil components include, for example, almond oil, olive oil, tsubaki oil, peach oil, peppermint oil, soybean oil, sesame oil, mink oil (mink oil), cottonseed oil, corn oil, tore the oil, soy lecithin, squalane, d1 -, or 1-menthol, 1-menthone, limonene, pinene, piperitone, terpinen, terpinolene (terpinolene), terpinol (terpinol), karber (carbeol), dl-camphor, N-methyl-2-pyrrolidone or liquid paraffin. The preferred oil components are peppermint oil and eucalyptus oil. In combination, you can use one or more types of such oil components. Their content is preferably from 0.5 weight % (more preferably 1 weight% to 10 weight % (more preferably 5 weight %) of the total weight of the preparation.

Excessive amounts of these solvents can cause the selection of an oil component of a preparation obtained by mixing it with a water-soluble base, and the resulting preparation may cause skin irritation. Therefore, preferably, the solvents were mixed in amounts that do not cause the above phenomena.

Agent for accelerating penetration through the skin can be any conventional agent without particular limitations as long as he will not cause difficulties or have any other influence. Preferred agents for accelerating penetration through the skin include, for example, alcohols and polyhydric alcohols, such as ethanol, are impregnated left acid and myristic acid, and their esters; animal fats, vegetable oils and terpene compounds, such as peppermint oil, 1-menthol, d1-camphor, and N-methyl-2-pyrrolidone. Agents to accelerate the penetration through the skin can also be used as solvents or described further moisturizers.

Water-soluble polymer that can be used as an adhesive agent and/or film-forming agent may be a known compound without particular limitation as long as he will not cause difficulties or have any other influence. Such water-soluble polymers include, for example, polyacrylic acid, polyacrylate sodium; acrylic ester copolymers and their emulsions; cellulose derivatives such as methylcellulose, ethylcellulose, carboxymethylcellulose and sodium carboxymethylcellulose; gum Arabic; gelatin; casein; polyvinyl alcohol; polyvinylpyrrolidone; copolymers metilfenidato ether/maleic anhydride and its emulsion and natural polysaccharide such as agar. In combination, you can use one or more types of these compounds, and their content is preferably from 3 weight% (more preferably 5 weight% to 30 weight% (more preferably 20 weight%) of Ob sodium polyacrylate, you can use activated alumina, synthetic aluminum silicate or hydroxide of aluminum as aluminum compounds, which can carry out the crosslinking reaction.

In addition, as the humidifier mostly use acrylic starch; polyhydric alcohols such as glycerin, propylene glycol, polyethylene glycol or D-sorbitol, and combinations you can use one or more of such compounds. Their content is preferably from 5 weight % (more preferably 10 weight% to 60 weight % (more preferably 45 weight %) of the total weight of the preparation.

The polymer soluble in the oil, which can be used as an adhesive agent and/or agent for stickiness, can be any conventional polymer without particular limitations as long as he will not cause difficulties or have any other influence. Such soluble in oil polymers include natural rubber, isoprene rubber, polyisobutylene rubber, styren-butadiene rubber, styren-isoprene-terenowy block copolymer, styren-butadiene-terenowy block copolymer, copolymer of (meth) acrylic ester, silicone resin, rosin, polybutene, lanolin, vaseline, plastibase, bee wasitline is from 5 weight % (more preferably 10 weight% to 95 weight % (more preferably 80 weight %) of the total weight of the preparation.

In addition, you can use the required amount of surface-active substances, such as sorbitan monooleate or polyoxyethylene sorbitan monooleate; agent for pH control, such as tartaric acid or citric acid; or other pharmaceutically suitable additives, such as bentonite, kaolin, talc or titanium oxide. Their content is preferably from 0.1 weight % (more preferably 0.5 wt %) to 15 weight % (more preferably 10 weight %) of the total weight of the preparation.

The preparation for external use according to this invention preferably is a:

(1) anti-inflammatory analgesic preparation for external use containing at least 0.1 to 5 weight % loxoprofen sodium, from 0.5 to 5 weight % of crotamiton, from 0.5 to 80 weight % of the solvent and/or agent to accelerate the penetration through the skin, from 3 to 30 weight % of water-soluble polymer and/or from 5 to 95 weight % of the polymer, soluble in oil, and from 5 to 60 weight % of a humectant, all of the total weight of the preparation.

Preferred:

(2) anti-inflammatory analgesic preparation for external use containing, at least, from 0.15 to 2 varinia penetration through the skin, from 5 to 20 weight % of a water-soluble polymer and/or from 10 to 80 weight % of polymer, soluble in oil, and from 10 to 45 weight % of the humidifier, all of the total weight of the preparation.

Preferred:

(3) anti-inflammatory analgesic preparation for external use containing at least 0.5 to 2 weight % loxoprofen sodium, 1 to 2 weight % of crotamiton, from 0.5 to 80 weight % of the solvent and/or agent to accelerate the penetration through the skin, from 5 to 20 weight % of a water-soluble polymer and/or from 10 to 80 weight % of polymer, soluble in oil, and from 10 to 45 weight % of the humidifier, all of the total weight of the preparation.

This anti-inflammatory analgesic preparation for external use can be obtained by applying the following method of obtaining.

If you get an anti-inflammatory analgesic preparation for external use containing as an active ingredient loxoprofen, this drug can be obtained by dissolving loxoprofen in crotamiton and optional add any of the above "different bases used for conventional drugs external application".

On the other hand, if you get anti-b and suitable salt of loxoprofen, this drug can be obtained by dissolving the pharmaceutically suitable salts loxoprofen in a suitable solvent (e.g. water, methanol, ethanol or the like), mixing the resulting solution with crotamiton and optional add any of the above "different bases used for conventional drugs external use". Any of the above "different bases used for conventional drugs external application" can be added to the above solution of the active ingredient or crotamiton before mixing this solution with crotamiton.

In particular, when you get an anti-inflammatory analgesic preparation for external use containing as an active ingredient loxoprofen sodium, this drug can get concrete specified below.

Get the mixture containing loxoprofen sodium by dissolving 0.1 to 5 weight % loxoprofen sodium 20-60 weight % of solvent (e.g. water) are added to a mixture solution of 5-20 weight% of sodium polyacrylate, 20-35 weight percent of glycerin, 1-5 weight % alcohol and a suitable quantity of the solution prepared in advance, regulating pH, and stirring the mixture. With the new % solvent and/or agent to accelerate the penetration through the skin and an appropriate amount of pharmaceutically suitable additives. Then get the necessary anti-inflammatory analgesic preparation for external use by adding with stirring a mixture containing crotamiton, to the mixture containing loxoprofen sodium, add back the appropriate number of water suspensions of the crosslinking reagent (e.g., gel, aluminum hydroxide or the like), and sufficient stirring of the mixture.

Adding to the above external use drug 10-30 weight % of the polymer compounds soluble in oil, you can obtain the product with less water content.

When you get the drug for external use, containing mainly soluble in oil polymers, oil product can be obtained by using as the adhesive agent isoprene or polyisobutylene (in the case of the method with solvent), or a block copolymer of styrene-isobutylene (in the case of the way with hot melt) and applying the agent to the stickiness along with crotamiton and other above an oil component as the solvent and the agent accelerate penetration through the skin.

According to the present invention obtained in this way external use drug containing loxoprofen sodium, namazyvanii side of the substrate is applied a removable film of polyethylene, polypropylene, polyester or the like. The resulting preparation can be applied as a patch.

In addition, the external use drug can be applied, not smearing him on the substrate, as an ointment or cream that is applied, as is, on the treated place.

It can also be used as a lotion, diluting aqueous solvent (e.g. water, ethanol or the like) and optionally adding there suspendisse agent (for example, gum Arabic, sodium alginate, nutricology or hydroxypropylcellulose) or emulsifier (for example, sorbitan monooleate or polyoxyethylenesorbitan monooleate) for a complete homogenization of the solution.

Differently, it can be applied as an aerosol, diluting solvent to reduce the viscosity, adding there suspendisse agent or emulsifier and filling appropriate containers with a solution together with propellant (for example, dimethyl ether or liquefied natural gas).

The dosage of anti-inflammatory analgesic preparation for external use can depend on the symptoms, the patient's age and the number of active ingredients in the product, but it is desirable that the preparation for external use according to nanesenia 10 g) loxoprofen a day on the treated part of the body of an adult. Expect that the duration of action of this drug topical application provides sufficient anti-inflammatory analgesic effect when applied once a day, but daily dose external application can be applied on the treated place separately several times.

Anti-inflammatory analgesic preparation for external use of the present invention is effective in the prevention or treatment of osteoarthritis, rheumatoid arthritis, lumbago, shoulder, shoulder periarthritis, tendonitis, inflammation of the "tendon peripheries", humeral epicondylitis (tennis elbow), muscle pain or swelling/pain after injury.

The best option of carrying out the invention

Below the invention is described with reference to examples, comparative examples and examples of research. However, this invention is not limited to these examples.

[Example 1] . The external use drug containing 2% loxoprofen sodium.

2,268 g of the dihydrate loxoprofen sodium (equivalent to 2 g loxoprofen sodium) are added to 8 ml of water and dissolve in it. Then dissolve 0.6 g of tartaric acid in 45.5 ml of water; add to this a solution of 11.5 g of sodium polyacrylate and 27 g glicees, obtaining the mixture containing loxoprofen sodium (mixture A). Next, mix 2 g of crotamiton, 1 g peppermint oil and 2.5 g of kaolin, receiving a mixture containing crotamiton (mix In). Mixture B is added under stirring to a mixture of a and add to this mixture 1 ml of water dispersion containing 0.05 g of a gel of aluminum hydroxide, and the resulting mixture is stirred. Determine the weight of the mixture, then add water up to 100 g and the mixture well stirred. The resulting preparation for external use containing 2% loxoprofen sodium, smear on a non-woven material in an amount of 10 g/10 x 14 cm and the drug is put in a polyethylene film, the resulting preparation is cut into pieces of a certain required size and used as samples for the study.

[Example 2] . The drug for external use, containing 1.2% loxoprofen sodium.

1,361 g of the dihydrate loxoprofen sodium (equivalent to 1.2 g loxoprofen sodium) is dissolved in 4 ml of water.

Then the solution is treated in a similar manner as described in example 1, obtaining the sample for the study of drug topical application, containing 1.2% loxoprofen sodium.

[Example 3] . The preparation for external use, containing 1% loxoprofen NAT is.

Then the solution is treated in a similar manner as described in example 1, obtaining the sample for the study drug for external use, containing 1% loxoprofen sodium.

[Example 4] . The external use drug containing 0.6% of loxoprofen sodium.

of 0.68 g of the dihydrate loxoprofen sodium (equivalent to 0.6 g loxoprofen sodium) is dissolved in 4 ml of water.

Then the solution is treated in a similar manner as described in example 1, obtaining a sample of the preparation for external application containing 0.6% of loxoprofen sodium.

[Example 5] . The external use drug containing 0.5% loxoprofen sodium.

0,567 g of the dihydrate loxoprofen sodium (equivalent to 0.5 g loxoprofen sodium) is dissolved in 4 ml of water.

Then the solution is treated in a similar manner as described in example 1, obtaining a sample of the preparation for external application containing 0.5% loxoprofen sodium.

[Example 6] . The preparation for external use containing 0.3% loxoprofen sodium.

0.34 g of the dihydrate loxoprofen sodium (equivalent to 0.3 g of loxoprofen sodium) is dissolved in 4 ml of water.

Then the solution is treated similarly, ka is Raven sodium.

[Example 7]. The preparation for external use, containing 0.25% loxoprofen sodium.

0,284 g of the dihydrate loxoprofen sodium equivalent to 0.25 g of loxoprofen sodium) is dissolved in 4 ml of water.

Then the solution is treated in a similar manner as described in example 1, obtaining the sample for the study drug for external use, containing 0.25% loxoprofen sodium.

[Example 8]. The external use drug containing 0.15% of loxoprofen sodium.

0.17 g of the dihydrate loxoprofen sodium (equivalent to 0.15 g loxoprofen sodium) is dissolved in 4 ml of water.

Then the solution is treated in a similar manner as described in example 1, obtaining a sample of the preparation for external application containing 0.15% of loxoprofen sodium.

[Example 9] . The preparation for external use, containing 1% loxoprofen sodium.

Carrying out the process similar to that described in example 2, using 1 g (instead of 2 g) of crotamiton and receiving the sample of the preparation for external use, containing 1% loxoprofen sodium.

[Example 10]. A lotion containing 1% loxoprofen sodium.

1,134 g of the dihydrate loxoprofen sodium (equivalent to 1 g of oxopropanenitrile in 10 g of glycerol and 20 g of propylene glycol and mix thoroughly. To this mixture is added to the above solution loxoprofen and then to this mixture is added when mixing the surface-active compound, 0.5 g of Tween 80 and 0.25 g of Span 20, receiving a lotion containing 1% loxoprofen sodium.

[Example 11]. The preparation for external use, containing 1% loxoprofen.

To a solution of 0.6 g of tartaric acid in 45.5 ml of water is added to 11.5 g of sodium polyacrylate and 27 g of glycerin, mix everything together, getting a mixture containing glycerol. Then add 2.5 g of kaolin to a solution of 1 g of loxoprofen in a mixture of 2 g of crotamiton and 1 g of oil of peppermint, then the resulting mixture is thoroughly mixed, obtaining a mixture containing loxoprofen. This mixture, containing loxoprofen add with stirring to a mixture containing glycerin, add the water dispersion of 1 ml containing 0.05 g of a gel of aluminum hydroxide, and mix everything together. Determine the weight of the mixture and add water to 100 g of the mixture is Then thoroughly mixed, receiving the drug for external use, containing 1% loxoprofen.

[Example for reference 1] . The preparation for external use, containing 1% TRANS-IT forms.

To a solution of 0.6 g of tartaric acid in 45.5 ml of water is added to 11.5 g of sodium polyacrylate and 27 1 g TRANS-HE forms, which is the active metabolite, in a mixture of 2 g of crotamiton and 1 g of oil of peppermint, then the resulting mixture is thoroughly mixed, obtaining a mixture containing the TRANS-Oh form. This mixture containing the TRANS-Oh form, add with stirring to a mixture containing glycerin, add water dispersion containing 0.05 g of a gel of aluminum hydroxide, and mix everything together. Determine the weight of the mixture and add water to 100 g of the mixture is Then thoroughly mixed. The resulting preparation for external use, containing 1% TRANS-shape IT, smear on a non-woven material in an amount of 10 g/h cm and the drug is put in a polyethylene film, the resulting preparation is cut into pieces of a certain required size and used as samples for the study.

[Comparative example 1]

Carrying out the process similar to that described in example 3, except that no use of crotamiton, with the aim of obtaining the sample for the study drug for external use, containing 1% loxoprofen sodium.

[Comparative example 2]

Carrying out the process similar to that described in example 3, using 2 g of oleic acid instead of 2 g of crotamiton the tx2">

[Comparative example 3]

Carrying out the process similar to that described in example 3, using 2 g of isopropylmyristate instead of 2 g of crotamiton and receiving the sample of the preparation for external use, containing 1% loxoprofen sodium.

[Case Study 1]. The deposition time of the crystals in the external use drug containing loxoprofen sodium.

In the patches (drugs) external use obtained in examples 1 and 9 and Comparative examples 1-3, immediately after preparation, see deposition of crystals loxoprofen sodium, to the naked eye or the microscope. Next, store the samples at room temperature in an aluminum bag and observe the deposition of crystals over time in the same way as described above.

The results are presented in table 1.

As clearly shown in table 1, in the preparations described in examples 1 and 9 and containing as solvent crotamiton, loxoprofen not planted for a long period of time. That is, the addition of crotamiton significantly improves the stability of preparations for external use containing loxoprofen sodium.

[Case Study 2]. Test "ptx2">

Patches (drugs) external use obtained as described in example 3 and Comparative example 1, subjected to in vitro test for penetration, using the skin of rats. To test their penetrating ability through the skin to determine the concentration of loxoprofen and TRANS-HE form, which is the active metabolite after drug application.

For research use each patch external use with a diameter of 1 cm

The male rats Wistar Imamichi (age 7 weeks) injected intraperitoneally pentobarbital sodium in quantities of 1 mg/kg, after which they are under anesthesia. Then shave the hair on the abdomen, using the device for cutting and razor. Then take out a piece of skin in the form of a disk with a diameter of 2.2, see Remove the layer of fat beneath the cloth of the dermis of the skin and the resulting skin is fixed on a vertical diffusion cell for tests on penetration, which was kept at 37oC. the Preparation is applied on the stratum corneum epidermidis on the diffusion cell and added to 4.5 ml of Tyrode (Tyrod''s solution) as the receiving solution from the dermal layer. Within 24 hours of study drug from time to time take samples of 0.5 ml of the receiving solution and investigate it is the means. Then take samples of the host fluid (0.5 ml of a solution of Tyrode without drugs), incubated it at 37oC, add it to the receiving fluid to keep the volume constant. The cumulative amount of drug after penetration through the skin increases linearly with time.

Below is a method of high performance liquid chromatography (HPLC).

An equal amount of ethanol solution [10 mg/ml ethyl-para-hydroxybenzoate (produced by Wako Pure Chemical Industry Co., Ltd.)] as an internal standard is added to collected together and mixed samples.

Conditions of carrying out the measuring method of high performance liquid chromatography (HPLC).

Column: CAPCELLPACK C18 (4.6 x 150 mm; production Shiseido Co., Ltd. ).

Mobile phase: 1% phosphoric acid/acetonitrile = 5/2

The column temperature: 40oC

The flow rate: 1 ml/min

Detected wavelength: 222 nm

Retention time: loxoprofen - 12.7 minutes

TRANS-HE shape - 10.7 minutes

CIS-HE shape - 11.9 minutes

ethyl-para-benzoate - 7.6 minutes

The results are presented in table 2.

The results of the study drugs, described in Prime TRANS-Oh form, which is its active metabolite, without passing through the liver and kidneys. In addition, comparison of the preparations described in example 3 and Comparative example 1 shows that addition of crotamiton increases at twice the speed of penetration of loxoprofen and four times the rate of increase of TRANS-HE forms in the host liquid (you can assume that this corresponds to the TRANS-HE form, which exists under the dermal layer). As a result, at a certain time after application of the drug in the receiving solution, there is a very large number of TRANS-shape IT is.

In addition, the results from the preparation described in example for reference 1, show that TRANS-HE form, which is the active metabolite, shows low penetrating ability through the skin, and that the increase in the content of TRANS-HE form in the receiving solution is small, even when using the TRANS-Oh form. If we compare these results with the results of the preparation described in example 3, then suddenly find that when using loxoprofen sodium, which is a prodrug, the rate of increase of TRANS-HE forms in receiving more fluid, giving a greater amount of TRANS-HE form in which the auger of external use drug, containing loxoprofen sodium.

Patches obtained according to the method described in example 3, labeled14C and containing 1% loxoprofen sodium, place the skin on the back of rats at 4, 8 and 24 hours, determine the concentration of active metabolites in the dermal tissue of the skin and in the blood plasma.

The male rats Wistar Imamichi (age 7-8 weeks; three rats in each group) remove the hair on the back, using the device for a hair clipper and shaver, impose pieces of drug of size 2 x 1,75 cm on the skin of rats. In rats, which used the drug through various time taking samples of blood plasma (0.5 to 2 ml) and kill rats. Using cellophane adhesive tape, removed from the skin layer stratum corneum in the middle where you applied the medication. To remove part of the dermis (corium) of its punch, using a punch (diameter 1.0 cm). After removal of fat and capillaries remote part of the cut. Then the pieces of chopped skin add a five-fold amount of methanol to the mixture and the resulting mixture was centrifuged for 10 minutes at 1800 g and 4oC, obtaining the supernatant in the form of an extract. Similarly, the handle above the blood plasma, receiving the extract. Then each extract is dried and utverjdayut reduced Inoi chromatography (TLC) to determine the concentration of active metabolites.

Determine, based on the method of thin-layer chromatography performed as follows.

The above sample in methanol is applied in-line on the TLC plate (silica gel 60F254; Art N 5714, produced by MERCK Co.) together with authentic sample of loxoprofen and its metabolites and three times solution using benzene : acetone : acetic acid (80:15:5) manifesting as the solvent for the manifestation of samples so that the length of the track showing the solvent has reached 15 see After developing the TLC plate is dried and covered with a protective film (4 μm; production DIAFOIL Co.), and then glued to the plate images (ROUND-VA; production of Fuji Film Co., Ltd.) and kept in a sealed lead box within 24 hours. Then use the analyzer bioisoprene (FOJIX BA100; production of Fuji Film Co., Ltd.) for radioactive reading the image on the plate images to create autoradiogram. The shown position of the authentic sample metabolite confirm, using 254-nm UV lamp. Then autoradiogram fractionary on the background area and the area of radioactive range loxoprofen (unchanged form) or TRANS-HE form (active metabolite) to count each).

Concentration loxoprofen (unchanged form) and TRANS-HE form (active metabolite) is calculated as follows.

The concentration determined using the total concentration, calculated from the radioactive concentration of the sample before the TLC operations, as well as calculated above ratio.

The results are shown in table 3.

As clearly shown in table 3, the concentration of TRANS-HE form, which is the active metabolite, in the dermal layer 40 times higher than the concentration in plasma, and the concentration of loxoprofen, which is unchanged form the dermal layer 300 times higher than in plasma. This shows that loxoprofen sodium is transferred directly to a particular place.

In addition, the number during the application remains constant, this shows that the product provides adequate performance when used once a day.

[Case Study 4]. Suppression of swelling of the feet, caused by Karenina (carrageenin crural edema).

Patches of external actions loxoprofen sodium, described in examples 2, 4, 6 and 8 examined the effect of suppressing swelling of the feet, caused by Karenina.

In this research the og, using an electrical appliance for cutting hair, and injected under the skin of the sole of the left hind legs of 0.1 ml of 0.5% saline Karenina (carrageenin) in order to cause inflammation. Immediately after induction of inflammation is applied to stop the drug of size 2 x 1,75 cm and measure the volume of the sole of the foot through 1, 2, 3, 4 and 5 hours after induction of inflammation, watching the effect of the suppression of this medicine external application and using as the degree of swelling degree of the increase of the sole of the foot after induction of inflammation with respect to the same volume before injection of the agent, inducing inflammation. The effect of suppression reaches the maximum value at 4 hours after induction.

For comparison take a "control group", which induce inflammation as described above and in which rats left untreated.

In addition, take the "core group", in which rats treated with the drug of the same composition as described in example 1, except loxoprofen sodium. The results are presented in table 4.

As clearly shown in table 4, the preparation containing 0.15% or more loxoprofen sodium, demonstrated a significant effect of suppression compared to the control and the base is Trogo inflammation.

[Case Study 5]. Anti-inflammatory effect on adjuvant arthritis (adjuvant arthritis).

Explore the anti-inflammatory effect on adjuvant arthritis patches containing loxoprofen sodium, described in examples 1, 3, 5 and 7.

For this study using male rats Lewis (age 8 weeks), 10 rats in each group. Clean Mycobacterium butyricum killed when heated and treated cells suspended in liquid paraffin as long as the volume of the suspension reaches 6 mg/ml Then the suspension is sterilized at 120oC and used as adjuvant. Measure the volume of both hind limbs and injected into the skin of the base of the tail with 0.1 ml of a suspension of killed cells, which is heated to 50-60oC. Rats, which must be induced inflammation, enter adjuvant and 19 days on the periphery of the sole of the right hind limb of each rat impose a slice preparation of size 2 x 1,75 cm (drug cut). Preparation leave for 9 days. Determine the increase in the soles of both hind legs on the day of imposition of the drug as a 100% degree of swelling, and every day watching the changes in this volume.

"Control group" and "core group" are the same as described in table 5, confirmed that a product containing 0.5% or more loxoprofen sodium, provides a significant inhibitory effect depending on the concentration, compared to control and basic groups. Thus, this drug is effective against chronic inflammation.

Industrial applicability.

Adding crotamiton as a solvent for external use drug containing loxoprofen or its pharmaceutically suitable salt, prevents the deposition of loxoprofen in the form of crystals, thus, it is possible to provide the drug, the active ingredients dispersed in a suitable manner. This drug allows a substantial increase in the rate and amount of absorption of loxoprofen through the skin, and also makes it possible to maintain a continuous supply of loxoprofen, allowing continuous accumulation of sufficient concentration loxoprofen in the skin at the place of its application. Then loxoprofen transformed in the skin in the TRANS-Oh form, giving thus the possibility of providing sufficient amounts of TRANS IT forms at the place of use. As a result, the use of this drug can provide excellent local analgesic the neck irritation of the skin and is effective in the prevention or treatment for example, osteoarthritis, rheumatoid arthritis, lumbago, shoulder, shoulder periarthritis, tendonitis, inflammation of the "tendon peripheries", humeral epicondylitis (tennis elbow), muscle pain or swelling or pain after injury.

1. The method of obtaining TRANS-HE form of loxoprofen, including the application of loxoprofen or its pharmaceutically acceptable salt on the skin and providing the metabolism of TRANS-Oh form of the specified active ingredient using present in the skin ketone-reduction enzyme.

2. Anti-inflammatory analgesic preparation for external use containing loxoprofen or its pharmaceutically acceptable salt in an amount of 0.1 - 5 weight. % of the total weight of the drug and crotamiton in the amount of 0.5 - 5 weight. % of the total weight of the drug and provides when applied to the skin metabolism loxoprofen or its pharmaceutically acceptable salt of TRANS-Oh form using a present in the skin ketone-reduction enzyme.

3. Anti-inflammatory analgesic external use drug under item 2, characterized in that the concentration of TRANS-IT forms higher in the dermal layer of the skin at the site of application of the drug than in plasma.

4. ProTV it crotamiton is 1 - 2 wt.% the total weight of the preparation.

5. Anti-inflammatory analgesic preparation for external use according to any one of paragraphs.2 to 4, characterized in that the content of loxoprofen or its pharmaceutically acceptable salt is 0.15 - 2 wt.% the total weight of the preparation.

6. Anti-inflammatory analgesic preparation for external use according to any one of paragraphs.2 to 4, characterized in that the content of loxoprofen or its pharmaceutically suitable salt is 0.5 - 2 wt.% the total weight of the preparation.

7. Anti-inflammatory analgesic preparation for external use according to any one of paragraphs.2 to 6, characterized in that it additionally contains a solvent and/or agent to accelerate the penetration through the skin in amounts of 0.5 to 80 wt.% the total weight of the preparation.

8. Anti-inflammatory analgesic preparation for external use according to any one of paragraphs.2 to 7, characterized in that it additionally contains a water-soluble polymer in an amount of 3 to 30 wt.% the total weight of the preparation.

9. Anti-inflammatory analgesic preparation for external use according to any one of paragraphs.2 to 7, characterized in that it additionally contains a water-soluble polymer in an amount of 5 to 20 wt.% from Obama of PP.2 - 9, characterized in that it additionally contains soluble in oil polymer in an amount of 5 to 95 wt.% the total weight of the preparation.

11. Anti-inflammatory analgesic preparation for external use according to any one of paragraphs.2 to 9, characterized in that it additionally contains soluble in oil polymer in an amount of 10 to 80 wt.% the total weight of the preparation.

12. Anti-inflammatory analgesic preparation for external use according to any one of paragraphs.2 to 11, characterized in that it additionally contains a wetting agent in kolichestvo 5 to 60 wt.% the total weight of the preparation.

13. Anti-inflammatory analgesic preparation for external use according to any one of paragraphs.2 to 11, characterized in that it additionally contains a wetting agent in an amount of 10 to 45 wt.% the total weight of the preparation.

14. The drug according to any one of paragraphs.2 to 13, characterized in that the anti-inflammatory analgesic external use drug is a patch.

15. The drug according to any one of paragraphs.2 to 13, characterized in that the anti-inflammatory analgesic external use drug is an ointment.

16. The drug according to any one of paragraphs.2 to 13, characterized in that the anti-Christ. p. 2 - 13, characterized in that the anti-inflammatory analgesic external use drug is a lotion.

18. The drug according to any one of paragraphs.2 to 13, characterized in that the anti-inflammatory analgesic external use drug is an aerosol.

 

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