EA032632B1 - Topical pharmaceutical composition having an analgesic and anti-inflammatory effect - Google Patents

Abstract

The invention is related to the field of medicine, in particular, to topical non-steroid anti-inflammatory drugs for the treatment of inflammatory diseases of the locomotive system and soft tissues. The objective of the present invention is provision of an efficient topical non-steroid anti-inflammatory drug of a new generation. Said objective is attained by provision of a topical pharmaceutical composition having an analgesic and anti-inflammatory effect, comprising ketoprofen, dimethyl sulphoxide, camphor, tincture of hot pepper, peppermint oil and pharmaceutically acceptable excipients.

Description

The invention relates to medicine, namely to non-steroidal anti-inflammatory drugs of local application for the treatment of inflammatory diseases of the musculoskeletal system and soft tissues. The present invention is the creation of an effective local non-steroidal anti-inflammatory drugs of the new generation. The problem is solved by creating a pharmaceutical composition for topical use with analgesic and anti-inflammatory effects, containing ketoprofen, dimethyl sulfoxide, camphor, tincture of capsicum, peppermint oil and pharmaceutically acceptable excipients.

032 632 Β1

The invention relates to the pharmaceutical industry and can be used to treat inflammatory diseases of the musculoskeletal system and soft tissues.

At present, in Russia, the range of painkillers and anti-inflammatory drugs intended for topical (skin) application of gels and creams in the dosage form is represented by preparations containing non-steroidal anti-inflammatory drugs (NSAIDs) as active substance: ketoprofen, diclofenac, nimesulide, ibuprofen, piroxicam, indomethacin, phenylbutazone. The peculiarities of the use of these drugs is the difficulty of achieving a balance between providing a quick and pronounced therapeutic effect and minimizing the risk of side effects both from the skin and systemic effects due to the penetration of drugs into the systemic circulation. Due to the fact that both the effectiveness and safety of local NSAIDs are directly dependent on the dose of the drug, as the severity of the therapeutic effect increases, the risk of side effects also increases. In this regard, it seems particularly relevant to create combinations of NSAIDs with other components that can enhance the analgesic and anti-inflammatory effects both by enhancing the penetration of the drug to the lesion, and due to its own analgesic / anti-inflammatory effect, the mechanism of which is different from the action of NSAIDs (to avoid an increase risk of side effects).

The prior art (patent application of the Russian Federation No. 2015137659, publ. 03/10/2017, IPC A61K47 / 10) known pharmaceutical composition containing:

a) from about 10 to 30% non-steroidal anti-inflammatory drugs by weight of the pharmaceutical composition;

b) from about 20 to about 50% solid fat by weight of the pharmaceutical composition;

c) from about 10 to about 30% of a polyester fatty acid ester by weight of the pharmaceutical composition, and

b) from about 5 to about 15% polyethylene glycol polymer by weight of the pharmaceutical composition.

The non-steroidal anti-inflammatory agent is preferably ketoprofen.

The prior art (patent application of the Russian Federation No. 2015115723, publ. 11/20/2016, IPC A61K31 / 192) also known composition for topical use, which is an oil-in-water emulsion and contains from about 0.5 to about 15 wt.% ketoprofen, from about 0.01 to 1 wt.% chelating agent, from about 0.15 to about 1.5 wt.% crosslinked polyacrylic acid copolymer, from about 0.15 to about 1.5 wt.% crosslinked polyacrylic acid homopolymer from about 2.5 to about 6 wt.% oxybenzone, from about 0.25 to about 2.5 wt.% emulsifying agent, from about 5 to about Roughly 15 wt.% water-soluble alkylene glycol, from about 10 to about 30 wt.% C2C3 alkanol, from about 0.5 to about 2.5 wt.% preservative cosmetics, from about 0.02 to about 2 wt.% antioxidant, from about 0.001 to about 0.1 wt.% emollient, a pH modifier in an amount sufficient to maintain the pH of the composition in the range of from about 4.5 to about 6 and the rest is water. Preferably, said topical composition has a cream-like consistency. The composition is used to treat pain.

The prior art (RF patent No. 2259204, publ. 27.08.2005, IPC A61K31 / 7008, A61K31 / 10, A61K31 / 196) also known for the treatment of joint diseases containing saccharide, a compound selected from the group of non-steroidal anti-inflammatory drugs, dimethyl sulfoxide and ointment base, characterized in that it contains a glucosamine salt as a saccharide, and it contains ibuprofen, or nimesulide, or piroxicam, or meloxicam, or diclofenac salt, or indomethacin, or ketoprofen as the non-steroidal anti-inflammatory drug NII, wt.%:

Glucosamine salt 0.5-10.0 Ibuprofen 0.1-10.0 or nimesulide 0.1-1.0 or piroxicam 0.1-1.0 or meloxicam 0.1-1.0 or diclofenac salt 0.1-5.0 or indomethacin 0.1-10.0 or ketoprofen 0.1-5.0 Dimethyl sulfoxide 1,0-20,0 Ointment base Rest.

Closest to the proposed invention are ketoprofen gel 5% (registration number: LS-001968 from 08.09.2006, manufactured by AO VERTEX), containing ketoprofen (5.0 wt.%) And excipients - propylene glycol (10.0 wt.% ), ethyl alcohol 95% (15.0 wt.%), carbomer 940 (1.3 wt.%), triethanolamine (5.2 wt.%), benzalkonium chloride (0.1 wt.%), purified water ( up to 100 wt.%) (according to information about the drug from the official instructions for use). This drug was selected as a prototype.

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The disadvantages of this prototype include:

insufficient severity of analgesic / anti-inflammatory effect when used in therapeutic doses;

insufficiently rapid development of the analgesic effect.

The present invention is the creation of an effective local non-steroidal anti-inflammatory drugs of the new generation.

Technical Results:

increased therapeutic efficacy;

increasing the rate of penetration of the drug through the skin;

acceleration of analgesic action;

expansion of the arsenal of local dosage forms of non-steroidal anti-inflammatory drugs.

The problem is solved, and the technical result is achieved by creating a pharmaceutical composition for local use with analgesic and anti-inflammatory effects, containing ketoprofen and pharmaceutically acceptable excipients, characterized in that the composition further comprises dimethyl sulfoxide, camphor, tincture of capsicum and peppermint oil with the following contents components, wt.%:

ketoprofen 0.4-20.0;

dimethyl sulfoxide 1.0-46.0;

camphor 1.0-23.0;

tincture of capsicum 1.0-15.0, peppermint oil 0.1-10.0;

pharmaceutically acceptable excipients up to 100

According to preferred embodiments, said technical result is also achieved in that said composition has the following content of components, wt.%:

ketoprofen 2.5-10.0; dimethyl sulfoxide 2.5-15; camphor 2.5-10.0; capsicum tincture 3.0-10.0; peppermint oil 0.5-2.0 pharmaceutically acceptable excipients up to 100,

said composition has the following content of components, wt.%:

ketoprofen 5.0; dimethyl sulfoxide 3.0, camphor 3.0; capsicum tincture 4.0; peppermint oil 0.9; pharmaceutically acceptable excipients up to 100;

ketoprofen is present in the form of a free acid or a mixture of two isomers, or their pharmaceutically acceptable salts, or a mixture thereof;

pharmaceutically acceptable salts of ketoprofen are selected from the group consisting of salts of sodium, potassium, calcium, magnesium, tromethamine, hydroxyethylamine, di (hydroxyethyl) amine, tri (hydroxyethyl) amine, lysine, arginine;

pharmaceutically acceptable excipients are selected from the group consisting of perfumes, emulsifiers, stabilizers, ethanol, purified water;

pharmaceutically acceptable excipients are selected from the group consisting of purified water, alginates, vitamins, thickeners, protective colloids, humectants, polyols, panthenol gelling agents, emulsifiers, emulsion stabilizers, ethanol, electrolytes, preservatives, liposomes, diethylene glycol monoethyl ether, carbamides, triglycerides , isoparaffin-laureth-7, xanthan gum, carrageenin, locust bean gum, agar gel, methyl hydroxy cellulose, carboxyme cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, idroksietiltsellyulozu, ethylcellulose, polyacrylates, polyvinyl alcohol, polyvinylpyrrolidone, colloidal silicon dioxide;

said composition is in the form of a cream, ointment or gel.

An advantage of the claimed composition is a more pronounced and rapid therapeutic effect; more pronounced and faster analgesic effect, more pronounced anti-inflammatory effect. The combined use of the mentioned active components causes the effect of potentiating synergism in anti-inflammatory and analgesic effects.

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The multicomponent nature of the drug, the variety of active substances, and the particular mechanisms of the pharmacological effect ensure its high activity.

The invention allows to expand the range of pharmacological effects due to the selection of components that have analgesic, anti-inflammatory, decongestant, locally irritating, warming, distracting and antiseptic properties.

Thus, the claimed composition is a pharmaceutical composition consisting of ketoprofen (a racemic mixture of two enantiomers of 2- (3-benzoylphenyl) propanoic acid), camphor (a racemic mixture of two enantiomers of 1,7,7-trimethylbicyclo [2.2.1] heptane-2 -one), tinctures of fruits of chilli pepper (Sarysit ailiit), peppermint leaf oil (MSShNa p1retya) and dimethyl sulfoxide (dimexide). All components that make up the complex composition are approved for use in medical practice:

Ketoprofen is a non-steroidal anti-inflammatory drug, with local application it has analgesic, anti-inflammatory and anti-edematous effect. When applied topically (in the form of an ointment, cream or gel) it provides a local therapeutic effect in relation to affected joints, tendons, ligaments, muscles;

camphor - when applied topically, it has a local irritating, analgesic, anti-inflammatory and antiseptic effect; exciting the sensitive nerve endings of the skin and subcutaneous tissues, it dilates blood vessels and improves blood circulation in organs and tissues. This leads to a decrease in inflammation, swelling of tissues and pain;

capsicum fruit tincture - when applied topically, it has local irritating, distracting, analgesic, anti-inflammatory and warming effects, it causes increased local blood circulation in the skin, affecting painful processes that are also localized in the depths of tissues;

peppermint leaf oil - when applied topically, it has a moderate antiseptic, anti-inflammatory, anesthetic and distracting effect.

The listed components (ketoprofen, camphor, capsicum pepper tincture, peppermint leaf oil) have different mechanisms of action aimed at stopping pain and inflammation, which provides a complex (synergistic) effect on the affected tissue, due to which a faster and more pronounced therapeutic effect is achieved.

Dimethyl sulfoxide enhances the penetration of ketoprofen through the skin, contributes to a deeper penetration into the tissues of other components of the drug. This leads to an increase in the analgesic and anti-inflammatory effect of ketoprofen in the affected tissues, and can also accelerate the onset of the analgesic effect. Thus, dimethyl sulfoxide potentiates the action of ketoprofen and other components that make up the composition.

All medicinal components that make up the claimed composition have analgesic and anti-inflammatory effects. In the treatment of inflammatory (including post-traumatic) diseases of the musculoskeletal system and soft tissues, the combined use of these components with a unidirectional effect leads to a synergy effect and, therefore, to achieve a more pronounced therapeutic effect compared to using monotherapy. In addition, the presence of dimethyl sulfoxide in the composition provides a more rapid onset of the analgesic effect by accelerating the penetration of active substances through the skin to the lesion.

The composition is theoretically justified; High pharmacological efficacy is practically shown.

The composition of the claimed composition has an analgesic, anti-inflammatory and decongestant effect.

The claimed composition is recommended for use in acute and chronic inflammatory diseases of the musculoskeletal system (joint syndrome with exacerbation of gout, rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, osteoarthritis, osteochondrosis with radicular syndrome, sciatica, inflammatory lesions of the ligaments and tendons, lumbar sinusitis, );

muscle pain of rheumatic and non-rheumatic origin;

post-traumatic inflammation of the soft tissues and musculoskeletal system (injuries and ruptures of ligaments, bruises).

The selected ranges of content in the inventive composition of ketoprofen are due to the minimum effective dose for topical application, which can cause a slight but noticeable decrease in the severity of pain (0.5%), and the maximum tolerated used in clinical practice (20%) - when using a higher the dose is very high the risk of developing systemic side effects due to the drug entering the systemic circulation, as well as increasing sensitivity and the appearance of skin irritation symptoms at the site of eniya, development of contact dermatitis and photosensitivity reactions. Selected ranges for the content of dimethyl sulfoxide (1.0-46.0), camphor (1.0-23.0), tincture of capsicum (1.0-15.0) and peppermint oil

- 3 032632 (0.1-10.0) are selected, on the one hand (minimum value), based on the dose, which, when applied topically, can have a synergistic effect with ketoprofen, and on the other hand (maximum value), based on doses, the excess of which is associated with a high risk of developing systemic side effects due to the ingress of components into the systemic circulation, as well as local skin irritation reactions, contact dermatitis.

In a preferred embodiment of the invention, in the framework of optimizing the effect of the amount of each active component of the claimed composition on the synergistic effect, the optimal ranges of the content of active substances are revealed: ketoprofen - 2.5-10.0; dimethyl sulfoxide - 2.5-15; camphor - 2.5-10.0; tincture of capsicum - 3.0-10.0; peppermint oil - 0.5-2.0; pharmaceutically acceptable excipients - the rest.

In a preferred embodiment of the invention, the following pharmaceutically acceptable excipients are used in the claimed composition:

as a gelling polymer, hypromellose is used predominantly in an amount of from 0.5 to 5 wt.% of the total weight of the composition;

sodium hydroxide is preferably used as a neutralizing agent in an amount of from 0.1 to 2 wt.%;

as a solvent, 96% ethanol is used predominantly in an amount of from 10 to 50 wt.%.

In the particular case of the invention per 1 kg of the claimed composition in gel form is: ketoprofen - 50.0 g; tinctures of fruits of capsicum - 40.0 mg; dimethyl sulfoxide (dimexide) 30.0 mg; camphor - 30.0 g; peppermint leaves oil - 9.0 g, hydroxypropyl methylcellulose (hypromellose) - 20.0 g; sodium hydroxide - 7.5 g; ethanol 96% - 350.0 g; purified water - up to 1000.0 g.

In preparing the pharmaceutical composition according to the present invention, the following prepared substances were used:

peppermint leaf oil substance, manufacturer Bhagat Aromatics Ltd. (India), tincture of chilli fruit, manufacturer of Tver Pharmaceutical Factory OJSC (RF).

The following are examples of the invention, which, however, do not cover all possible embodiments of the invention and do not limit the claimed invention.

Examples of the invention and the implementation of the purpose.

Example 1. Preparation of the drug (in the form of a gel) with a content of ketoprofen of 5 wt.%. Preparation of the alcohol phase.

50 g of ketoprofen and 30 g of camphor are loaded into a reactor with 350 g of 96% ethanol, stirred for 15-30 minutes until completely dissolved, 9 g of peppermint oil and 40 g of tincture of capsicum are added and mixed again for 15-30 minutes.

Preparation of the aqueous phase.

7.5 g of a concentrated sodium hydroxide solution are loaded into the reactor with 463.5 g of purified water, stirred for 15-30 minutes and 20 g of hypromellose are added, again stirred for 4-6 hours to obtain a uniform gel, 30 g of dimethyl sulfoxide are added, mix again 1520 minutes

479 g of the prepared alcohol phase are added to the prepared aqueous phase, stirred for 60-120 minutes to uniformly distribute the active substances with the formation of a gel. Measure the pH of the resulting gel (acceptable pH ranges from 6.0 to 8.0) and filter.

Example 2. Preparation of the drug (in the form of a gel) with a content of ketoprofen of 1 wt.%. Preparation of the alcohol phase.

10 g of ketoprofen and 30 g of camphor are loaded into a reactor with 350 g of 96% ethanol, stirred for 15-30 minutes until completely dissolved, 9 g of peppermint oil and 40 g of tincture of capsicum are added and mixed again for 15-30 minutes.

Preparation of the aqueous phase.

7.5 g of a concentrated sodium hydroxide solution are charged into the reactor with 503.5 g of purified water, stirred for 15-30 minutes and 20 g of hypromellose are added, again stirred for 4-6 hours to obtain a uniform gel, 30 g of dimethyl sulfoxide are added, mix again 1520 minutes

To the prepared aqueous phase add 439 g of the prepared alcohol phase, mix for 60-120 minutes to uniformly distribute the active substances with the formation of a gel. Measure the pH of the resulting gel (acceptable pH ranges from 6.0 to 8.0) and filter.

Example 3. Preparation of the drug (in the form of a gel) with a content of ketoprofen of 2.5 wt.%. Preparation of the alcohol phase.

25 g of ketoprofen and 30 g of camphor are loaded into a reactor with 350 g of 96% ethanol, stirred for 15-30 minutes until completely dissolved, 9 g of peppermint oil and 40 g of tincture of capsicum are added and mixed again for 15-30 minutes.

Preparation of the aqueous phase.

7.5 g of concentrated sodium hydroxide solution are charged into the reactor with 483.5 g of purified

- 4,032,632 water, stirred for 15-30 minutes and added 25 g of hypromellose, stirred again for 4-6 hours to obtain a uniform gel, added 30 g of dimethyl sulfoxide, again mixed for 1520 minutes.

To the prepared aqueous phase add 439 g of the prepared alcohol phase, mix for 60-120 minutes to uniformly distribute the active substances with the formation of a gel. Measure the pH of the resulting gel (acceptable pH ranges from 6.0 to 8.0) and filter.

Example 4. The study of the analgesic activity of the drug (in the form of a gel) with a content of ketoprofen of 5 wt. %

When studying the analgesic activity in the test, a hot plate (see. Guidelines for preclinical studies of drugs. Part One / Edited by AN Mironov [et al.] - M .: Grif and K, 2012. - 944 p .; Guidelines for the experimental (preclinical) study of new pharmacological substances / Edited by R.U. Khabriev. - M .: Medicine, 2005. - 832 p.) On white mice at a dose of 1.4 g / kg (i.e. 1.4 g of ketoprofen per 1 kg of animal weight) a gel preparation with a ketoprofen content of 5 wt.%, obtained according to example 1, showed activity, statistically and significantly superior to that of the comparison drug gel ketoprofen for external use of 5% (according to the prototype). The paw withdrawal time from the source of pain irritation (hot plate) was significantly longer when using the gel according to example 1 - 16.2 s compared to 12.5 s in the group of animals treated with ketoprofen gel (in the placebo group, the withdrawal time was 7.2 s ) The latent period of licking of the hind legs was also longer in the group of animals in which the gel according to example 1 was 38.2 s, compared with the ketoprofen group - 31.7 s, the differences were statistically significant (in the placebo group - 23.2 s). The time to getting up on the hind legs was also statistically longer when using the gel according to example 1 - 49.9 s in comparison with the ketoprofen group - 39.1 s (in the placebo group - 34.4 s).

Example 5. The study of the anti-inflammatory activity of the drug (in the form of a gel) with a content of ketoprofen of 5 wt.%.

A comparative study of the anti-inflammatory activity of the drugs was carried out on a model of chronic immune inflammation (adjuvant arthritis) in rats - it is modeled by subplanar injection of Freund's complete adjuvant into the right hind paw, the effectiveness is assessed by the degree of decrease in the growth of the foot foot of rats (see Guidelines for preclinical studies of drugs. Part One / Under the editorship of AN Mironov [et al.] - M .: Grif and K, 2012. 944 p .; Manual for experimental (preclinical) study of new pharmaceuticals ologicheskih substances / RW, Ed Habrieva -.. M .: Medicine, 2005. - 832 s).. According to the results of a study of drugs at a dose of 1.4 g / kg, a gel preparation for external use with a ketoprofen content of 5 wt%, obtained according to Example 1, showed an activity superior to that of the comparison drug ketoprofen gel for external use of 5%.

When using the gel preparation according to Example 1 at a dose of 1.4 g / kg, a significant decrease in both the primary inflammatory reaction (edema of the right hind paw) and the secondary immunological reaction (edema of the left hind paw) on the 17th, 21st and 26th was found day of the experiment. The use of the drug ketoprofen gel for external use of 5% (according to the prototype) at a dose of 1.4 g / kg led to a statistically significant decrease in only the primary inflammatory reaction (see table).

The influence of the studied drugs on the increase in the volume of the left foot of rats (secondary immunological reaction)

Group 17th day 21st day 26th day absolute values, ml % absolute values, ml % absolute values, ml % The preparation obtained according to Example 1 0.61 79.2 0.58 70.7 0.52 65.8 Ketoprofen gel according to the prototype 0.72 93.5 0.7 85,4 0.63 79.8

A study of the anti-inflammatory activity of drugs was also carried out on a model of acute exudative inflammation (ultraviolet erythema in guinea pigs), the effectiveness was assessed by the severity of erythema and tissue edema (see Guidelines for preclinical studies of drugs. Part One / Edited by A. N. Mironov [ et al.] - M.: Grif and K, 2012. - 944 p .; Manual on the experimental (preclinical) study of new pharmacological substances / Edited by R.U. Khabriev. - M .: Medicine, 2005. - 832 p. .). When using both the gel according to example 1 and ketoprofen according to the prototype at a dose of 1.4 g / kg, a statistically significant decrease in tissue edema was noted. However, a statistically significant decrease in the severity of cutaneous erythema (up to 1 point) was observed only when using the gel according to example 1, the use of ketoprofen according to the prototype did not significantly affect the severity of erythema (severity of erythema - 1.5 points, in the placebo group - 1.6 points) .

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Thus, the present experimental data demonstrated that the test composition has a more pronounced and faster analgesic effect, as well as a more pronounced anti-inflammatory effect compared to the prototype.

The inclusion of additional components that enhance the penetration of ketoprofen, as well as improve blood circulation in soft tissues and have an additional anti-inflammatory, locally irritating and analgesic effect, can increase the effectiveness of therapy compared to the standard local form of ketoprofen.

The preclinical and clinical trials of the gel according to example 1 showed that the drug has a favorable safety profile corresponding to that of the comparison drug, and also surpasses it in terms of pharmacological activity.

Claims (8)

CLAIM 1. A pharmaceutical composition for topical administration with analgesic and anti-inflammatory action, containing ketoprofen and pharmaceutically acceptable excipients, characterized in that said composition additionally contains dimethyl sulfoxide, camphor, tincture of capsicum and peppermint oil with the following components, wt.%: Ketoprofen 0 4-20.0; dimethyl sulfoxide 1.0-46.0; camphor 1.0-23.0; tincture of capsicum 1.015.0; peppermint oil 0.1-10.0; pharmaceutically acceptable excipients up to 100. 2. The pharmaceutical composition according to claim 1, characterized in that said composition has the following content of components, wt.%: Ketoprofen 2.5-10.0; dimethyl sulfoxide 2.5-15; camphor 2.5-10.0; tincture of capsicum 3.0-10.0; peppermint oil 0.5-2.0; pharmaceutically acceptable excipients up to 100. 3. The pharmaceutical composition according to claim 1, characterized in that said composition has the following content of components, wt.%: Ketoprofen 5.0; dimethyl sulfoxide 3.0; camphor 3.0; tincture of capsicum 4.0; peppermint oil 0.9; pharmaceutically acceptable excipients up to 100. 4. The pharmaceutical composition according to claim 1, characterized in that ketoprofen is present in the form of a free acid, or a mixture of two isomers, or their pharmaceutically acceptable salts, or a mixture thereof. 5. The pharmaceutical composition according to claim 4, characterized in that the pharmaceutically acceptable salts of ketoprofen are selected from the group consisting of salts of sodium, potassium, calcium, magnesium, trometamine, hydroxyethylamine, di (hydroxyethyl) amine, three (hydroxyethyl) amine, lysine, arginine. 6. The pharmaceutical composition according to claim 1, characterized in that the pharmaceutically acceptable excipients are selected from the group consisting of perfumes, emulsifiers, stabilizers, ethanol, purified water. 7. The pharmaceutical composition according to claim 1, characterized in that the pharmaceutically acceptable excipients are selected from the group consisting of purified water, alginates, vitamins, thickeners, protective colloids, moisturizers, polyols, panthenol gelling agents, emulsifiers, emulsion stabilizers, ethanol, electrolytes , preservatives, liposomes, diethylene glycol monoethyl ether, triglycerides, urea, carbomers, isoparaffin-laureth-7, xanthan gum, carrageenin, locust bean gum, agar gel, methylhydroxycellulose, carb ksimetiltsellyulozy, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, ethylcellulose, polyacrylates, polyvinyl alcohol, polyvinylpyrrolidone, colloidal silicon dioxide. 8. The pharmaceutical composition according to claim 1, characterized in that the said composition is in the form of an ointment, cream or gel.