EA028759B1 - Pharmaceutical composition for external application containing dexketoprofen salt and method of production thereof - Google Patents

Abstract

The invention relates to the field of medicine and the chemical-pharmaceutical industry, specifically to a medicament containing a non-steroidal anti-inflammatory agent for external use which has an analgesic and anti-inflammatory effect, as well as a method for preparation thereof. A pharmaceutical composition is proposed, containing dexketoprofen trometamol and the target additives dimethylsulfoxide, ethanol (96%), carbomer, neutralizer, flavorant and purified water. The composition preferably contains as a carbomer a hydrophobically modified cross-linked polyacrylate carbomer Carbopol® Ultrez 21 Polymer, as a neutralizer tetrahydroxypropylethylenediamine (Neutrol® TE), and as a flavorant lavender oil. A method of preparing a pharmaceutical composition is also proposed. The claimed medicament has a high analgesic activity and prolonged efficient anti-inflammatory action. Dexketoprofen in the formulation of the preparation is very stable and does not precipitate in case of contact of the drug with air, which eliminates risks for the quality of the drug during its production and the efficiency of the action when used by patients. When rubbing the drug into the skin there is no rolling into clots and excessive stickiness. The proposed method for preparation of the composition eliminates risks of obtaining an inhomogeneous preparation and simplifies the technological process.

Description

The invention relates to the field of medicine and the pharmaceutical industry, specifically to a medicinal product for external use, containing a salt of dexketoprofen and an organic base, which has an analgesic and anti-inflammatory effect, as well as a method for its preparation.

Known drugs containing the active substance (2K5) -2- (3benzoylphenyl) propionic acid (ketoprofen), which is a mixture of 5 (+) and K (-) enantiomers, in external dosage forms (Russian Drug Register: Encyclopedia of Medicines . - t! sgps! -usg8yup. - \ y \ y \ u.g15ps1.gi). These drugs are prescribed for adults as an analgesic and anti-inflammatory agent in rheumatoid arthritis (in the initial stages of the inflammatory process without abrupt changes in the joints), ankylosing spondylitis, acute gout, traumatic and infectious arthritis, osteoarthritis, bursitis, tenosynovitis, radiculitis, neuralgia, myalgia, phlebitis, periflebita , lymphangitis, injuries of soft tissues and musculoskeletal system (bruises, sprains, dislocations, injuries of the meniscus, etc.). They are prescribed for painful, inflammatory or traumatic lesions of the joints, tendons, ligaments and muscles (arthritis, periarthritis, arthrosinovitis, tendonitis, tendosynovitis, bursitis, bruises, sprains, dislocations, damage to the meniscus of the knee, torticollis, lumbago); phlebitis, peripheralitis, lymphangitis, superficial lymphadenitis; inflammatory processes of the skin (erythema, etc.).

RF patent No. 2238722 describes a pharmaceutical composition with analgesic and anti-inflammatory effects (in particular, in the form of a gel for external use), which contains a therapeutically effective amount of ketoprofen 1.5-5.5% and target additives: ethyl alcohol - 36.048.0% , nipagin - 0.05-0.25%, carbomer - 0.93-2.48%, trometamol - 0.95-1.70%, flavor - 0.03-0.20% and water up to 100%. As a flavoring agent, it contains lavender and / or neroli oil, as a carbomer SatBoro1® 940 ΝΕ or Satboro1® 980 ΝΕ.

The specified composition and other preparations of ketoprofen for external use have certain disadvantages. Firstly, they contain a mixture of 5 (+) and K (-) enantiomers of ketoprofen. However, according to the literature (РГССНшса1 apf οΐίηίοαΐ Фсус1ортсп1 о! ФсхксУргоГсп 1готс1ата1 / Мai1соп Ό., Ltidak K., Oataa M. s. AG / Yugidk. 1996, 52, 5рр1. 5. P. 24-46; FG 1Is sGPsasu apf! o1sgaY1yu oG FsxksYurgoGsp apf kSyurgoGsp ίη 1Is 1gsa1tsp1 oG rptagu FuktspoggIsa / E / sigFa M., Sops ^ ko R.k., Bap / op K. s. a1. (12 5рр1.). 655-735), it is more rational to use the ketoprofen enantiomer dexketoprofen in the form of trometamol salt in preparations 5 (+), which, for example, allows to increase the effectiveness of the specific action of systemic drugs tions in the form of injections and tablets. Secondly, ketoprofen is inferior to other non-steroidal anti-inflammatory drugs (NSAIDs) in effectiveness of the analgesic and anti-inflammatory effects (in particular, diclofenac, indomethacin, naproxen (drug therapy of the inflammatory process / Sigidin Y.A., Schwartz G.Ya., Arzamastsev A.P. , Liberman S.S. M.: Medicine, 1988, 239 s). Thirdly, old carbomers (for example, Cagoro1® 940 ΝΡ or Cagoro1® 980 длительн) swell for a long time in water, require effective homogenization to prevent heterogeneity (the formation of fish eyes), and preparations based on them are sticky and, when rubbed into the skin, roll into lumps.

Known medicinal preparations in the form of a gel for skin application containing as active substance (5) - (+) - 2- (3-benzoylphenyl) propionic acid (dexketoprofen) in the form of a salt of trometamol (tromethamine), in particular the preparation Epaps1 ds1 12, 5 td / d (Мпапш Отирр, Spain) (MayFa1s: TIs Sotr1s! With Aegid KsGsgspss. 36 ' ¹ ' EFIUp / EF. 5> ss1tap 5.S. BopFop: РЬгтассийса1 Ргскк, 2009. 3694 p.). The content of dexketoprofen trometamol (in terms of dexketoprofen) in this preparation is 2 times less than in gels containing ketoprofen. When developing this drug, apparently, they proceeded from the misconception that the K (-) - enantiomer of ketoprofen is a ballast substance and does not have anti-inflammatory and analgesic effects. At the same time, the research results indicate that in gels the K (-) - enantiomer in the composition of ketoprofen racemate in the experiment has an anti-inflammatory effect at the level of (5) (+) - enantiomer and a less pronounced analgesic effect (Tables 9 and 10). Moreover, for different pathological processes, the ratio between the effectiveness of the analgesic effect of the (5) (+) - enantiomer and ketoprofen racemate turns out to be different, for example, 75:50 ., Matyp-Mo1a E., Idistoa M. s! A1 .// E. S1sh. RIagtasok 1998. Ess; 38 (12 5рр1). 5. 74-80). As a result, a gel containing 12.5 mg of dexketoprofen is inferior in effectiveness to the analgesic and anti-inflammatory effects of gels containing 2.5% ketoprofen racemate, in particular Ketonal gel 2.5% (Tables 9 and 10).

In Eurasian patent No. 002026 (hereinafter referred to as EA 002026), issued in the name of the patent holder Laboratorios Menarini S.A. (EU) and selected as a prototype of the claimed invention, a method for producing a semi-solid (soft) pharmaceutical preparation (gel or cream) containing tromethamine salt (+) - (5) -2- (3-benzoylphenyl) propionic acid (dexketoprofen trometamol) is described as a therapeutic agent, a gelling agent and a pharmacologically acceptable amine as a neutralizing agent, in which a solution of a neutralizing amine and dexketoprofen trometamol

- 1,028,759 is added to the dispersion of the gelling agent in a suitable solvent. In this case, the gelling agent is a carboxyvinyl polymer (carbomer); a neutralizing agent is tromethamine (trometamol) or diethanolamine or triethanolamine; The pH is adjusted between 5 and 7, optimally between 6 and 6.5. In Examples 1, 2, and 3, a mixture of ethanol (40.8 L) and demineralized water (57.5 L) was used as a suitable solvent for carbomer dispersion. It is declared that the pharmaceutical preparations that are the subject of the invention demonstrate advantages resulting from their high stability during storage without noticeable changes in the appearance of the product over time.

The production method described in patent EA No. 002026, and the compositions described in the examples of this patent have certain disadvantages.

Firstly, carbomers in a mixture of ethanol and water either do not swell or swell very poorly, which requires the use of homogenizers with a high rotor speed. When homogenizing a non-swollen carbomer, there is a risk for the homogeneity of the drug (the formation of fish eyes), which is greater, the higher the concentration of carbomer.

Secondly, the semi-solid dexketoprofen compositions, in particular the gels obtained by the method described in patent EA No. 002026, in the air first become opalescent and then cloudy. Initially, compositions according to patent EA No. 002026 are transparent only at a concentration of dexketoprofen of 1.25%, and when its content is increased to 2.5%, they are initially very opalescent. A change in the appearance of the preparations upon contact with air indicates that in the pH range from 6.0 to 6.5, dexketoprofen is in the form of an water-insoluble acid form and, possibly, partially in the form of a salt with the corresponding organic amine. When ethanol evaporates in air, dexketoprofen precipitates, that is, a noticeable change in the appearance of the product over a short period of time. At the same time, dexketoprofen in drugs is most poorly soluble in neutralizing carbomer with trometamol, then diethanolamine, and then triethanolamine. The same disadvantage is inherent in the analogue of the patent of the Russian Federation No. 2238722.

Thirdly, the examples given in patent EA No. 002026 suggest a concentration of 1.25% dexketoprofen trometamol (in terms of dexketoprofen), which is inferior to the analgesic and anti-inflammatory effects of the analogue drug containing 2.5% ketoprofen racemate (for example, Ketonal gel 2.5%) (tab. 9 and 10 of this description of the claimed invention). To increase the effectiveness of the action, the concentration of dexketoprofen could be increased. In the claims of the patent EA No. 002026, the quantitative content of the components is not indicated, but the patent text indicates that the production method applies to a gel containing dexketoprofen trometamol in the concentration range from 1.5 to 4.5% (which corresponds to 1-3% dexketoprofen) . At the same time, it is declared that the gel has an excellent anti-inflammatory and analgesic effect without bringing research results or references to literature sources.

In connection with the foregoing, the pharmaceutical compositions of dexketoprofen were made, which are described in patent EA 002026 as examples 1, 2 and 3, as well as the compositions of examples 1, 2 and 3, but with a 2.5% dexketoprofen content and an appropriate neutralizing agent necessary to bring pH to ~ 6.25. All these drugs, as well as the analogue according to the patent of the Russian Federation No. 2238722, change their appearance in air, which creates risks, firstly, for obtaining a high-quality drug during the production process, and secondly, for the effectiveness of the therapeutic effect during the use by the patient since suspended particles, unlike dissolved dexketoprofen, are not absorbed through the skin. The compositions of the three analogues of the patent EA 002026 are given in table. one.

Table 1

The compositions of the dexketoprofen compositions obtained by the method described in patent EA 002026

Substance Quantity, g / 100 g Example 1 Example 2 Example 3 Dexketoprofen trometamol * 1.83 * 1.83 * 1.83 * Ethanol (96%) 32.65 32.65 32.65 Lavender (essential) oil 0.10 0.10 0.10 Carbomer 980 1.49 1.49 1.49 Trometamol (tromethamine) 1.53 ** - - Diethanolamine - X 14 ** - Triethanolamine - - 1.72 ** Purified water up to 100.0 up to 100.0 up to 100.0

Note. * In terms of dexketoprofen 1.25 g / 100 g.

* The content of neutralizers (in accordance with the production method) includes an excess of about 10%, used to bring the pH of the gels to -6.25.

In the table. 2 presents the values of the structural viscosity of the compositions of the analogues according to patent EA No. 002026, the composition of which is presented in table. 1, as well as compositions containing dexketoprofen trometamol 2 times more.

- 2,028,759

table 2

Structural viscosity (η) of dexketoprofen compositions having a pH of 6.25 and obtained by the method described in patent EA 002026, with various neutralizers at a temperature of 25 ° C

Catalytic converter The content of DC,% of the mass. η (Pa s) with a shear rate gradient (ϋ _Γ ): 14.55 s' ¹ 41.64 s' ¹ 82.28 s' ¹ Trometamol (example 1) 1.25% 11.71 5.33 3.18 2,50% 5.34 2.48 1,57 Diethanolamine (example 2) 1.25% 11.82 5.33 3.23 2,50% 6.87 3.17 1.98 T rietano lamin (example 3) 1.25% 12.23 5.89 3.34 2,50% 7.50 3.46 2.17

When the dexketoprofen content is 1.25% of the composition, in particular, gels with different neutralizers obtained by the method described in patent EA 002026 have a plastic flow type and structural viscosity that characterizes a gel-like consistency at low and high shear rate gradients (Table 2 )

With an increase in the dexketoprofen content to 2.5%, the structural viscosity of compositions with different converters obtained by the method described in patent EA 002026 significantly decreases by 2.1 times, if tromethamol is used as a neutralizer, by 1.7 times in the case of diethanolamine and 1.6 times - triethanolamine. The yield curves of the preparations also change and their yield strengths decrease. During storage, the 2.5% dexketoprofen preparation, containing trometamol as a neutralizer, liquefies even more and is sweetened. The consistency of these drugs can be increased by increasing the carbomer content up to 5% and the neutralizing agent up to 3%, which is written in the text of the patent, however, with the patented method of preparation, this will increase the risks associated with the heterogeneity of the composition and increase the rolling of the drug into lumps when rubbing it into the skin.

In the table. 9 and 10 of the description of the claimed invention provides data on the effectiveness of the analgesic and anti-inflammatory effects of the analogue made according to patent EA 002026 (example 1) and containing 1.25% dexketoprofen.

As follows from the table. 9, an analogue preparation Ketonal gel 2.5% and an analogue according to patent EA 002026, containing 1.25% dexketoprofen, have different dynamics of analgesic action. The analgesic effect (AE) of the analogue according to patent EA 002026 manifests itself earlier and amounts to 20.1% after 1 h, while when using the Ketonal gel 2.5% gel after 1 h, AE is minimal and equal to 3.4% . However, by the third hour of AE, Ketonal gel 2.5% increases to 41.4% and then remains at a high level of 35.2% by the fifth hour, and in the analogue of patent EA 002026 AE, by the third hour it decreases to 16.5 % and actually lost by the fifth hour of the experiment. The total analgesic effect is reduced by 1.9 times when using dexketoprofen at a concentration of 1.25% instead of 2.5% ketoprofen racemate, that is, according to the total analgesic effect, the analogue according to patent EA 002026 is significantly inferior to the preparation analogous Ketonal gel 2.5% (table 9 of this description of the claimed invention). Apparently, the concentration of 1.25% dexketoprofen in the preparation for external use is insufficient for the manifestation of an effective analgesic effect and the manifestation of the advantages of dexketoprofen over ketoprofen racemate.

As follows from the table. 10 of this description of the claimed invention, the total anti-inflammatory effect when using instead of 2.5% ketoprofen racemate dexketoprofen at a concentration of 1.25% is reduced by 2.1 times, that is, by the total anti-inflammatory effect, the analogue of patent EA 002026 is significantly inferior to the preparation analogous Ketonal gel 2.5%.

Thus, the pharmaceutical preparation obtained according to the patent EA 002026 and containing 1.25% dexketoprofen exhibits a weak analgesic and anti-inflammatory effect, and the method of obtaining the preparation according to the patent EA 002026 and the used organic bases serving as neutralizers are not suitable for inclusion in the composition of the drug more a high concentration of dexketoprofen, necessary for the manifestation of a highly effective analgesic and anti-inflammatory effect.

At the same time, the cutaneous use of semi-solid (soft) drugs with NSAIDs is an integral part of the treatment of inflammatory diseases of the musculoskeletal system. The good tolerability of drugs containing ketoprofen has been reported in many short and long-term studies (1-12 months), which included thousands of patients, mainly suffering from osteoarthritis (V. Nasonova, Clinical evaluation of non-steroidal anti-inflammatory drugs at the end of the 20th century // Rus. Honey. 2000.V. 8, No. 17. P. 714-718; Iherre R., EoyshapTeg E. Ra1yögepe515 apb chapadezep! o £ rat ίπ O51eoag1ypy5 // Eapee1. - 2005. Yo1. 365. P. 965- 973). Gels containing 2.5% ketoprofen remain the most common drugs for external use in the treatment of osteoarthritis of the knee, since ketoprofen does not significantly affect the synthesis of proteoglycans by chondrocytes, as shown in studies of ίπ νίΐΐΌ and ίπ у1уо, does not have a catabolic effect on cartilage tissue, and in concentrations of 10 ^-4 mol / l stimulates the synthesis of proteoglycan in

- 3 028759 cells immature human cartilage (Yop1ego1da1 apy-tyatta1ogu dgid ίη gyeita o1d agShpy ang oTeoagShgg ^ Zirrog Gogh 1ye sopser geropdeg og ang popge5ropdeg ^{n /} Sha1keg Ι.8, 5Eea1eg-Kem KV Sagtodu and!.!. .e! a1 .// Lg! yy. II.it. 1987. No. 11. R. 1944-1954; Osteoarthrosis: conservative therapy: Monograph / Auth. col .: N.A. V. Dedukh et al .; Edited by N.A. Korzh, N.V. Dedukh, I.A. Zupants. Kharkov, Golden Pages, 2007.442 s).

With cutaneous application, a mild dosage form (gel, cream, ointment) can provide high efficacy of the analgesic and anti-inflammatory effects of NSAIDs while minimizing side effects.

Thus, there is a need for a medicament containing ketoprofen in a topical form that has a highly effective analgesic and effective anti-inflammatory effect, as well as stability and aesthetics of use.

The objective of this invention is the creation of a new pharmaceutical composition for external use containing a salt of dexketoprofen and an organic base and targeted additives that provide a highly effective analgesic effect, prolonged anti-inflammatory effect, stability and aesthetics of use, as well as in the development of a method for manufacturing this composition.

To solve this problem, a pharmaceutical composition for external use is proposed, which has an analgesic and anti-inflammatory effect, which contains dexketoprofen in the form of a salt with an organic base and target additives dimethyl sulfoxide, ethanol (96%), carbomer, flavor, neutralizer and purified water, in the following ratio of components , g / 100 g of the composition:

Dexketoprofen salt with an organic base (in

100% dry matter dexketoprofen) 2.00-3.00 Dimethyl sulfoxide (DMSO) 7.5-12.5 Ethanol (96%) 19.5-24.5 Carbomer 1.20-1.50 Catalytic converter 2.40-4.20 Flavoring 0.04-0.08 Purified water up to 100.0 g

In this case, the composition preferably contains dexketoprofen salt with an organic base as dexketoprofen salt trometamol, hydrophobically modified cross-linked polyacrylate carbomer Cagoro1® Engem 21 Poll as a carbomer, and as a neutralizing agent tetrahydroxypropylethylenediamine (TEi1 aromatherapy oil).

One aspect of the claimed invention is a composition of the following composition: Dexketoprofen trometamol (in terms of 100% dry matter dexketoprofen) 2.00-3.00

Dimethyl sulfoxide (DMSO) 7.5-12.5

Ethanol (96%) 19.5-24.5

SAGOROG® υΐΐτεζ 21 Po1 tag. 1.20-1.50

Tetrahydroxypropylethylenediamine (ΝειιΕοΙ® TE) 2.40-4.20

Lavender Oil 0.04-0.08

Purified water up to 100.0 g

To solve this problem, a method for producing the claimed pharmaceutical composition is also proposed, according to which a solution of a flavoring agent in a part of dimethyl sulfoxide, a solution of a salt of dexketoprofen with an organic base in a part of purified water, a solution of a neutralizer in a part of purified water are prepared separately, then a carbomer dispersion is prepared in a portion of purified water and mixed it under vacuum in series with ethanol (96%) while cooling to room temperature with a solution of flavoring, the remaining part of dimethyl sulfoxide, by dexketoprofen salt creation with an organic base, and then with a neutralizer solution until a homogeneous composition with a pH from 6.5 to 7.5 is obtained, while if necessary, the composition is kept under vacuum for degassing and then dosed into tubes.

A separate aspect is a method for producing the claimed composition, in which a solution of lavender oil in a part of DMSO, a solution of dexketoprofen trometamol in a part of purified water is prepared separately, a solution of tetrahydroxypropylethylenediamine in a part of purified water is prepared, then a dispersion of Cahporo1 ENgem 21 Pol1 is prepared in a part of purified water and the resulting dispersion is mixed under vacuum in series with ethanol (96%) while cooling to room temperature, a solution of lavender oil, DMSO, a solution of dexketoprofen trometamol, and then with p tetrahydroxypropyl the shots until a homogeneous composition with a pH of 6.5 to 7.5; if necessary, the composition is kept under vacuum for degassing and dosed into tubes.

The technical result of this invention is to provide a highly efficient

- 4,028,759 analgesic effects and effective prolonged anti-inflammatory effects, high stability and aesthetics of the skin application of the drug (lack of excessive stickiness and rolling into lumps when rubbing the drug into the skin), as well as eliminating risks to the quality of the drug and the effectiveness of the action associated with heterogeneity of structure and dexketoprofen precipitation upon contact of the drug with air. As reflected in the table. 9 and 10 of this description of the claimed invention, in comparison with the prototype (EA 002026), the analgesic and anti-inflammatory effect increases several times.

The components of the composition have the following functional purpose.

Dexketoprofen trometamol and DMSO are active substances that, when used on the skin, have analgesic and anti-inflammatory effects.

DMSO, ethanol (96%) and purified water are solvents, and DMSO and ethanol (96%) are penetration enhancers of dexketoprofen and antimicrobial preservatives.

Сапьоро1® Ригем 21 Ро1утег serves as a gelling agent, which is capable of rapid swelling in water without additional homogenization at high rotor speeds.

Tetrahydroxypropylethylenediamine (Kei1go1® TE) is an organic base that serves as a pH regulator and a neutralizer, allowing to obtain compositions in which dexketoprofen does not precipitate in the presence of carbomer in contact with air.

Lavender oil is a flavor.

Сапьоро1® υΐΙΤΌζ 21 Ро1утег, unlike Сапьоро1® 940/980 ΝΡ and other old carbomers, quickly swells in water during the process without homogenization. Therefore, the use of a Clogoro1 ® υ1ΐΤΌζ 21 Ро1утег as a gelling agent, which belongs to the new generation of carbomers, allows its dispersion in water to be obtained quickly, without homogenization and without adding ethanol as a wetting agent. With this manufacturing method, the risk of producing a heterogeneous gel associated with the formation of so-called fish eyes is eliminated, and the process is significantly simplified in comparison with the method for producing analogues of patent EA 002026. With this manufacturing method, no decomposition products of dexketoprofen are formed: ketoprofen admixture A, ketoprofen ethyl ether and unidentified impurities.

The claimed ratio of dexketoprofen trometamol and target additives in the composition of the pharmaceutical composition is found experimentally, it is optimal and allows to obtain a technical result that matches the intended purpose.

Table 3

Structural viscosity (at different shear rate gradients (Ώ _Γ ) and a temperature of 25 ° C) of compositions containing 2.5% dexketoprofen trometamol (in terms of dexketoprofen), at various concentrations of (C) Cagoro1® υ1ΐΤΌζ 21 Ро1утег and pH -7, 0 (Zhi1go1® TE neutralizer)

from,% Structural viscosity (Pa-s) at: A = 14.55 s ¹ / ± = 41.64 s ¹ A = 82.28 s' 0.9 2.28 1.14 0.76 1,1 5.56 2.69 1.77 1,2 8.78 4.16 2,57 1.3 12.28 5.82 3,59 1.4 13.75 6.55 4.03 1,5 15.27 7.24 4.47

As follows from the table. 3, the concentration of Saporo® Eigem 21 Ploite to 1.1% is insufficient for gel formation. The content of Cagoro1® υ1ΐΤΌζ 21 Po1utag from 1.2 to 1.5% at pH -7.0 provides an optimal gel-like consistency and allows standardizing the structural viscosity within ± 30% of the structural viscosity at an optimum concentration of 1.3% for gelation of this carbomer. Concentrations of Saporo1 ® υ1ίτβζ 21 Ро1teg over 1.5% are excessive and may contribute to the rolling of the drug into lumps when rubbed into the skin.

Unlike Cagoro1® 940/980 ΝΡ and Cagoro1® 934/978 ΝΡ, the use of a hydrophobically modified cross-linked polyacrylate carbomer Cagoro1® υ1ΐτβζ 21 Ро1teg as a gelling agent allows it to be used in a lower concentration (optimally 1.30%), and also stickiness and rolling the drug into lumps when rubbing into the skin.

The tromethamol, diethanolamine, and triethanolamine neutralizers used as part of the analogues proved to be unsuitable as pH regulators in the drug with dexketoprofen trometamol.

- 5,028,759

Table 4

Structural viscosity (at different shear rate gradients ( _{Γ Γ} ) and a temperature of 25 ° C) of compositions containing 2.5% dexketoprofen trometamol (in terms of dexketoprofen) and 1.3% Cagoro1®

ENge / 21 Ro1uteg when neutralized with various organic bases to a pH of -7.0

Catalytic converter pH gel Structural viscosity (Pa-s) at: I), = 14.55 s ¹ 1), = 41.64 s ¹ I), = 82.28 s ¹ Tetrahydroxypropylethylenediamine (ΝθΗγοΙ® TE) ~ 6.5 10.19 4.84 3.02 ~ 7.0 12.28 5.82 3,59 ~ 7.5 13.64 6.47 4.03 Trometamol ~ 6.5 1,57 0.81 0.55 ~ 7.0 2.19 1,11 0.73 ~ 7.5 4.66 2.24 1.44 Diethanolamine ~ 6.5 5.28 2.54 1,63 ~ 7.0 5.30 2,55 1,64 ~ 7.5 8.85 4.18 2.66 T rietano l amine ~ 6.5 6.91 3.36 2.14 ~ 7.0 8.84 4.18 2.65 ~ 7.5 9.90 4.72 2.99

The value of structural viscosity characterizes the efficiency of gelation. As follows from the table. 4, the greatest gelling efficiency in the pH range from 6.5 to 7.5, in which dexketoprofen is the most stable, is observed when tetrahydroxypropylethylenediamine (No. and1go1® TE) is used as a neutralizer and pH regulator. Thus, the structural viscosity of the gel at an optimum pH of -7.0 and _{Γ Γ} = 14.55 s ^-1 in the case of neutralization of Cagoro1® EIGe / 21 with tetrahydroxypropylethylenediamine (Nu1go1® TE) is 5.6 times higher than when neutralized with trometamol, 2.3 times diethanolamine and 1.4 times triethanolamine. Stable gels with trometamol at pH from 6.5 to 7.5 were not formed. Within the pH range from 6.5 to 7.5, transparent homogeneous gels with very weak opalescence were formed only when using Ni1go1® TE as a neutralizer. When using trometamol, triethanolamine and diethanolamine in the indicated pH range, either cloudy gels or gels with strong opalescence were formed, indicating incomplete solubility of dexketoprofen.

In the monograph Keolorgo ep Se1 of the British Pharmacopoeia, the pH of ketoprofen gels is normalized from 5.0 to 7.5, which should ensure the stability of ketoprofen during storage. In this case, the main product of the modification is ketoprofen ethyl ether, which is allowed no more than 4%.

In the table. Figure 5 shows the results of screening studies to select the optimal pH range based on the determination of the decomposition products of dexketoprofen (ketoprofen impurities A of ketoprofen ethyl ester and unidentified impurities) in dexketoprofen gels having different pH values, during storage for three months at a temperature of 25 and 30 ° FROM.

Table 5

The impurity content in dexketoprofen preparations during storage at a temperature of 25 ° C and 30 ° C

Foreign matter pH of drugs 5.5 6.0 ⁶ ' ^{5 7} ° 7.5 7.8 Source analysis Ketoprofen impurity A,% BUT but but but but but Ketoprofen ethyl ether (CEE),% 0,03 0.02 but but but but Unidentified impurity,% but BUT but but but but Analysis after 3 months of storage at a temperature of 25 ; ° s Ketoprofen impurity A,% but but but but but but Ketoprofen ethyl ether (CEE),% 0,07 0.05 but but but but Unidentified impurity,% BUT BUT but but but but at a temperature of 30 | ° s Ketoprofen impurity A,% but but but but but but Ketoprofen ethyl ether (CEE),% 0.12 0.09 0.02 0.01 but but Unidentified impurity,% BUT BUT but but but but Note. BUT - not detected.

As follows from the table. 5, in preparations with a pH of 6.0 and below ketoprofen, ethyl ether is formed during manufacture (during the process) and then accumulates during storage the higher, the higher the temperature. In preparations having a pH of 6.5-7.5, ketoprofen ethyl ether and other impurities during the initial analysis and during storage at a temperature of 25 ° C for 3 months

- 6,028,759 discovered. At a temperature of 30 ° C, after three months at pH 6.5 and 7.0, only traces of ketoprofen ethyl ether appear.

Thus, during the manufacture of a pharmaceutical composition having a pH in the range of 6.5 to 7.5, no decomposition products of dexketoprofen are formed. When storing the manufactured pharmaceutical composition, dexketoprofen in its composition is highly stable. After two years of storage at temperatures of 25 and 30 ° C ketoprofen, impurity A does not form; the content of ketoprofen ethyl ester does not exceed 0.1% after storage for 2 years at a temperature of 25 ° C and 0.2% at a temperature of 30 ° C with an upper limit of 4.0% established for this impurity in the monograph Keolorgoy Oe1 of the British Pharmacopoeia. The content of any unidentified impurity did not exceed 0.05% during storage - the limit to which the impurity content is not taken into account. The research results indicate the optimality of pH values in the range from 6.5 to 7.5 and the composition of the composition, which provides a pH in these ranges.

A mixed solvent consisting of DMSO, ethanol (96%) and water performs several functions.

1. It is a liquid medium in which dexketoprofen trometamol is soluble in the temperature range from 2 to 25 ° C. So, in 1.0 g of a mixed solvent consisting of 11.0 g of DMSO, 24.0 g of ethanol (96%) and 65.0 g of purified water and simulating the composition of the dispersion medium of the pharmaceutical composition with an optimal ratio of components, at temperatures of 2 and 25 ° C, respectively, 0.12 and 0.40 g of dexketoprofen trometamol are dissolved (in terms of dexketoprofen). Given that the concentration of dexketoprofen in the developed product is 2.5% (0.025 g / g), it can be argued that in the form of salt it will be in the dissolved state of the drug, which is a prerequisite for the release of dexketoprofen from the gel and its passive diffusion through the skin with the manifestation of an effective analgesic and anti-inflammatory effect.

2. Gives the compositions hyperosmolality, which ensures the release of dexketoprofen and the absorption of the drug, in particular gel, water. The release of ketoprofen and dexketoprofen from gel samples was determined in experiments ΐη ugo by dialysis through a cellophane membrane at a temperature of (32.0 ± 0.1) ° С. The gel mass in the chamber was 3.0 g; the release took place in a chamber containing 50 ml of purified water. The quantitative content of ketoprofen and dexketoprofen in the dialysate was determined by liquid chromatography. The research results are presented in table. 6.

Table 6

The concentration (C) in the dialysate of dexketoprofen and ketoprofen released from the drug into the chamber with water at a temperature of 32 ° C in опыη experiments by dialysis through a cellophane membrane

An object C (mg / ml) through: 0.5 h 1 hour 2h Sp 4h 5h 6 h Dexketoprofen Gel 2.5% 0,039 0,062 0,110 0.163 0.188 0.210 0.230 Ketonal gel 2.5% 0,037 0,060 0.106 0.151 0.187 0.210 0.230

The kinetics of water absorption by drugs, in particular gels, was determined in experiments йη ugo by dialysis through a cellophane membrane at (32.0 ± 0.1) ° С. The gel mass in the chamber was 3.0 g. The pharmaceutical composition in the form of a gel with the optimal content of the components and the Ketonal analogue drug, 2.5%, containing 100 g of 28.5 g of ethanol (96%) in 100 g were examined. The research results are presented in table. 7.

Table 7

Mass (t) of water (in% of the mass of the drug) absorbed by the drug at a temperature of 32 ° C in experiments ΐη

An object w %) across: 0.5 h 1 hour 2h Sp 4h 5h 6 h Dexketoprofen Gel 2.5% 20.3 39.7 52.0 63.0 71.0 81.5 84.5 Ketonal gel 2.5% 22.6 41D 53,2 64.8 74.9 85.6 89.0

As follows from the table. 6 and 7, the composition of the drug dexketoprofen 2.5% provides the release of dexketoprofen and the absorption of water by the drug. Moreover, the kinetics of dexketoprofen release and the kinetics of water absorption are almost identical for the developed pharmaceutical composition and the Ketonal gel analogue 2.5%.

3. DMSO and ethanol (96%) provide the drug with the proper antimicrobial preservative effect (Table 8).

- 7,028,759

Table 8

The effectiveness of the antimicrobial preservative effect of the pharmaceutical composition when the content of DMSO and ethanol (96%) is 10% less than their optimal content

Exposition EF requirements The number of microorganisms, CFU / g (1o§ decrease) Number bacteria CFU / g logarithm decrease Number mushrooms CFU / g logarithm decrease 5. aigeez ATCC 6538 E. so! / ATCC 25922 R. aegidosis ATCC 9027 from. a1ysapz ATCC 10231 BUT. Bgaschetgs (ηίξβτ) ATCC 16404 Source load 1x10 ⁵ 1x10 ⁶ 1x10 ⁵ 1x10 ⁶ 3.60x10 ⁵ 2.12x10 ⁶ 5.65x10 ⁵ 2.00x10 ⁵ 2.90x10 ⁵ Source seeding - - 4.50x10 ⁵ (-0D0) BUT 415 (3.13) 2.05x10 ⁵ (-0.01) 2.70x10 ⁵ (0.03) 2 days 2 - BUT but BUT BUT fifteen (4.29) 7 days 3 - but but but but BUT 14 days - 2 but but but but but 28 days WELL WELL but but but but but

Note: NU - there is no increase in the number of test microorganisms compared to the number of viable test microorganisms in the previous control point.

BUT - no viable cells of the test microorganisms were found: less than 10 CFU / g for 8. aigeis, R. aegidtosis, E. eOE and C. aFyuapz, less than 5 CFU / g for A. bazepeps (tdeg).

As follows from the table. 8, viable E. coE cells were not detected in the initial plating and subsequently; the logarithm of the decrease in the number of viable R. aegidtosis cells in the initial plating was 3.13; during subsequent plating, viable R. aegidtosis cells were not detected. In the initial seeding, the number of viable cells was 8. aigeis, C. aFuapz, and A. where it remained almost unchanged. On the 2nd day and subsequently viable cells 8. aigeis and C. aFyuapz were not found. On the 2nd day there was a decrease in the number of viable cells of A. tdeg by 4.29 orders of magnitude; after 7 days and subsequently up to 28 days inclusive, viable A. cells were not detected.

This antimicrobial preservative effect exceeds the requirements of criterion A of the European Pharmacopoeia (5.1.3) (Eigoreap Ryogtasoroe1a. 8 ¹¹ 'EPEop. ) In the presence of DMSO and ethanol (96%), the inclusion of other antimicrobial preservatives in the pharmaceutical composition is not required.

4. DMSO and ethanol (96%) are penetration enhancers that provide the transdermal absorption of dexketoprofen, which is necessary to provide analgesic and anti-inflammatory effects.

5. DMSO is also an active substance, which can have analgesic and anti-inflammatory effects in case of cutaneous application (Magypya1e: Thye Sotr1e1e Egid Kegegepsa. 36 ^L EFeop / Ei. 8 \\ ee1tap 8.S. Yopyop: Ryagtaseisa Prz. )

As a flavoring (fragrance) taken lavender oil in concentrations at which it masks the smell of ethanol and DMSO. In the manufacture of the composition, lavender oil is readily soluble in DMSO and does not cause gel opalescence.

Purified water was used as a solvent for dexketoprofen trometamol and excipients.

We give specific examples of the invention.

Example 1. The quantitative indicators of several ingredients below the values of the claims.

Further in the table. 9 and 10 show the inappropriateness of such a reduction in the content of components (therapeutic effects are lower than in such a comparison drug as Ketonal gel).

In part of DMSO (in an amount of about 5% of its weight), lavender oil is dissolved with stirring. In part of the purified water (in an amount of about 17% of its mass), dexketoprofen trometamol is dissolved with stirring. In part of the purified water (in an amount of about 15% of its mass), tetrahydroxypropylethylenediamine is dissolved with stirring. A portion of purified water (about 68% of its mass) is charged into a vacuum reactor equipped with a stirrer, and CagLoro1® ®Γβζ 21 Po1uteg (hereinafter carbomer) is left without stirring until the carbomer is completely wetted and then mixed until a uniform dispersion is obtained. Ethanol (96%) is charged into a vacuum reactor with a carbomer dispersion and stirred under vacuum until a uniform dispersion is obtained, cooling the dispersion to a temperature of 18-25 ° C. A solution of lavender oil and DMSO (in an amount of about 95% of its weight) is loaded into the reactor and stirred under vacuum. Into the reactor in portions or at slow feed

- 8 028759 load the solution of dexketoprofen trometamol and mix under vacuum. A tetrahydroxypropylethylenediamine solution is charged in portions or at a slow feed to the reactor and stirred under vacuum. If necessary, for degassing, the composition is kept without stirring under vacuum from -0.05 to -0.07 MPa in depth. The manufactured product is dosed in aluminum tubes with an internal protective coating, after which the tail of the tubes is folded.

The drug has such a ratio of components, g / 100 g of the composition:

Dexketoprofen trometamol 1.50 (in terms of 100% dry matter dexketoprofen)

DMSO 5.00

Ethanol (96%) 27.00

СапЬоро1® υΐίτβζ 21 Ро1ушег 1.10

Tetrahydroxypropylethylenediamine (up to pH ~ 7.0) 2.80

Lavender Oil 0.04

Purified water up to 100.00

Note. The total content of DMSO and ethanol (96%) is 32.00 g.

Example 2. The inventive drug is produced analogously to example 1 with the following ratio of components, g / 100 g of the composition:

Dexketoprofen trometamol 2.00 (in terms of 100% dry matter dexketoprofen)

DMSO 7.50

Ethanol (96%) 24.50

Sagoro1® Zigeg 21 Pogusheg 1.20

Tetrahydroxypropylethylenediamine (up to pH ~ 7.0) 3.00

Lavender Oil 0.05

Purified water up to 100.00

Note. The total content of DMSO and ethanol (96%) is 32.00 g.

Example 3. The inventive drug is produced analogously to example 1 with the following ratio of components, g / 100 g of the composition:

Dexketoprofen trometamol 2.50 (in terms of 100% dry matter dexketoprofen)

Dimethyl sulfoxide 10.00

Ethanol (96%) 22.00

SAGORO1® TSIGEG 21 POGUTEG 1.30

Tetrahydroxypropylethylenediamine (up to pH ~ 7.0) 3.30

Lavender Oil 0.06

Purified water up to 100.00

Note. The total content of DMSO and ethanol (96%) is 32.00 g.

Example 4. The inventive drug is manufactured analogously to example 1 with the following ratio of components, g / 100 g of the composition:

Dexketoprofen trometamol 3.00 (in terms of 100% dry matter dexketoprofen)

Dimethyl sulfoxide 12.50

Ethanol (96%) 19.50

SAGORO1® ZIGeg 21 Poyeg 1.50

Tetrahydroxypropylethylenediamine (up to pH ~ 7.0) 3.80

Lavender Oil 0.08

Purified water up to 100.00

Note. The total content of DMSO and ethanol (96%) is 32.00 g.

For comparative pharmacological studies, analogues of Ketonal gel 2.5% (Salyutas Pharma GmbH for Sandoz, Germany) containing analogues were used.

2.5% ketoprofen, carbomer, triethanolamine, ethanol (96%) 28.5 g, paraben or parabens, lavender oil and purified water to 100 g;

the analogue according to patent EA 002026, the composition and method of preparation of which is described in example 1 of patent EA 002026; the composition of this analogue (g / 100 g) is shown in table. 1. For research in accordance with the technology described in patent EA 002026, a series of 3 kg was manufactured in an RP-500 vacuum homogenizing reactor simulating industrial equipment (Promvit company; ^^^. Rhoshu P. sosh.ia);

as well as experimental samples of pharmaceutical compositions with the following compositions.

Composition 1. In a part of ethanol (96%) (in an amount of about 5% of its mass), lavender oil is dissolved with stirring. In part of the purified water (in an amount of about 17% of its mass), dexketoprofen trometamol is dissolved with stirring. In part of the purified water (in an amount of about 15% of its mass), tetrahydroxypropylethylenediamine is dissolved with stirring. A portion of the purified water (in the amount of about 68% of its mass) is charged into a vacuum reactor equipped with a stirrer, and Cagoro1® υΐΐΐΌζ 21 Ро1утег (hereinafter carbomer) is left without stirring until the carbomer is completely wetted and then mixed until a homogeneous dispersion is obtained. A portion of ethanol (96%) (in the amount of about 95% of its weight), a solution of lavender oil are loaded into a vacuum reactor containing a carbomer dispersion, a solution of lavender oil is stirred under vacuum until a uniform dispersion is obtained, cooling the dispersion to a temperature of 18-25 ° C. Then, a dexketoprofen trometamol solution is loaded in portions or at a slow feed into the reactor and stirred under vacuum. A tetrahydroxypropylethylenediamine solution is charged in portions or at a slow feed to the reactor and stirred under vacuum. If necessary, for degassing, the composition is kept without stirring under vacuum from -0.05 to -0.07 MPa in depth. The manufactured product is dosed in aluminum tubes with an internal protective coating, after which the tail of the tubes is folded.

The pharmaceutical composition has such a ratio of components, g / 100 g of the composition: Dexketoprofen trometamol 1.50 (in terms of 100% dry matter dexketoprofen)

Ethanol (96%) 32.00

SAGORO1® INGEG 21 PO1UTEG 1.10

Tetrahydroxypropylethylenediamine (up to pH ~ 7.0) 2.80

Lavender Oil 0.04

2.00

32.00

1.20

3.00

0.05 to 100.00

Purified water up to 100.00

Composition 2. The pharmaceutical composition is prepared analogously to analogue 1 with such a ratio of components, g / 100 g of the composition:

Dexketoprofen trometamol (in terms of 100% dry matter dexketoprofen)

Ethanol (96%)

Sagoro1® Ineg 21 Po1uteg

Tetrahydroxypropylethylenediamine (up to pH ~ 7.0)

Lavender Oil Purified Water

Composition 3. The pharmaceutical composition is prepared analogously to analogue 1 with such a ratio of components, g / 100 g of the composition:

Dexketoprofen trometamol (in terms of 100% dry matter dexketoprofen)

Ethanol (96%)

SAGORO1® INGEG 21 PO1UTEG

Tetrahydroxypropylethylenediamine (up to pH ~ 7.0)

Lavender oil

2,50

32.00

1.30

3.30 0.06

Purified water up to 100.00

Composition 4. In part DMSO (in an amount of about 5% of its weight), lavender oil is dissolved with stirring. In part of the purified water (in an amount of about 15% of its mass), tetrahydroxypropylethylenediamine is dissolved with stirring. A portion of purified water (about 85% of its mass) is charged into a vacuum reactor equipped with a stirrer, and CagLoro1® 1L1gem 21 Ro1uteg (hereinafter carbomer) is left without stirring until the carbomer is completely wetted and then mixed until a uniform dispersion is obtained. Ethanol (96%) is charged into a vacuum reactor with a carbomer dispersion and stirred under vacuum until a uniform dispersion is obtained, cooling the dispersion to a temperature of 18-25 ° C. A solution of lavender oil and DMSO (in an amount of about 95% of its weight) is loaded into the reactor and stirred under vacuum. A tetrahydroxypropylethylenediamine solution is charged in portions or at a slow feed to the reactor and stirred under vacuum. If necessary, for degassing, the composition is kept without stirring under vacuum from -0.05 to -0.07 MPa in depth. The fabricated drug is dosed into aluminum tubes with an internal protective coating, after which the tail of the tubes is folded. The resulting preparation has the following ratio of components, g / 100 g of composition:

dmso 10.00 Ethanol (96%) 22.00 SAGORO1® INGEG 21 PO1UTEG 1.30 Tetrahydroxypropylethylenediamine (up to pH ~ 7.0) 1.90 Lavender oil 0.06 Purified water up to 100.00

- 10,028,759

Note. The total content of DMSO and ethanol (96%) is 32.00 g.

Compositions 1-3 contain different concentrations of dexketoprofen from 1.5% to 2.5% and do not contain DMSO, which distinguishes them from examples 1-3, and composition No. 4 contains 10% DMSO, but does not contain dexketoprofen, which distinguishes it from Example 3. In all cases, the content of the penetration enhancer of ethanol (96%) or a mixture of ethanol (96%) with DMSO remains the same 32 wt.%.

All manufactured preparations of dexketoprofen according to examples 1-4, as well as preparations with compositions 14 were transparent or slightly opalescent, both initially and after 1 h in air. At the same time, the gel analogue according to patent EA 002026, having a pH of ~ 6.25, in 5-10 minutes in air became very opalescent, and then a turbid white gel.

The anti-inflammatory and analgesic effects of the drugs were studied on the model of acute aseptic carrageenin inflammation of the foot of rats (Schwartz G.Ya., Syubaev R.D. Methodical recommendations for preclinical study of non-steroidal anti-inflammatory drugs // Guide for preclinical studies of drugs. Part 1. / Edited by A.N. Mironov, M. Grif and Co., 2012.P. 746-758; Uode1 I.S., Uode1 Sh.N. Ν.Υ., 1997.R. 197-199). The experiment was conducted on nonlinear sexually mature male rats weighing 165-255 g.

Comparable samples of the preparations, the compositions of which are indicated in examples 1-4, as well as the samples used for comparison with compositions 1-4, the preparation analogue Ketonal gel 2.5% and the preparation analogue 1.25% according to patent EA 002026 were applied to the skin of the foot rats to the ankle joint in an amount of 100 mg, twice 30 minutes before and immediately after injection of the phlogogenic agent; the total amount of gel applied to the rat was 200 mg.

Exudative edema was caused by subplantar injection into the right hind foot of rats 0.08 ml of a 0.5% aqueous solution of carrageenin 30 minutes after the first application of drugs. The threshold of pain sensitivity (PBC) was recorded 1 h, 3 h, and 5 h after injection of the phlogistic by the Rendall-Selitto method with mechanical pain irritation with an analgesimeter (mod. 7200, Hugo Basile, Italy). The analgesic effect (AE) was calculated by the increase in CBP in rats to which the drugs were applied, compared with control untreated animals, calculated by the formula

where E _about and E _to - threshold pressure force on the foot (g) in the experimental and control groups, respectively.

The anti-inflammatory effect was evaluated by the degree of inhibition of the growth of foot edema on the background of drugs compared with the control group of untreated animals. Foot volume was measured before and after 1 h, 3 h (at the peak of edema) and 5 h after phlogistic injection using an electronic plethysmometer (mod. 7150, Hugo Basile, Italy). Anti-inflammatory effect (PE) was calculated by the formula

where LU _to and LU _about - the average increase in the volume of the edematous foot in the control and experimental groups, respectively.

The total analgesic effect (Σ AE) and the total anti-inflammatory effect (Σ PE) of the drugs were calculated as the area under the time-effect curves. The relative total analgesic effect and the relative total anti-inflammatory effect of the drugs were also calculated relative to the total analgesic effect and the total anti-inflammatory effect of the Ketonal gel analogue drug 2.5%, each of which was taken as 1.00.

Statistical processing of the results was carried out by methods generally accepted in pharmacology (R. Salimov. Statistical processing of the results of preclinical trials // Manual on the experimental (preclinical) study of new pharmacological substances. M., 2000. P. 349-355; Lapach S.N., Chubenko A.V., Babich P.N. Statistical methods in biological research using Ехсе1. - K. Morion. 2000. 320 p.), Calculating the average values of indicators (x) and standard error (3 x). The significance of differences between the mean values was determined by ί student criterion. The probability of the results was evaluated at a significance level of at least 95% (p <0.05).

The results of studies of the analgesic effect (AE) of pharmaceutical compositions and their analogues are given in table. nine.

As follows from the table. 9, the total analgesic effect of dexketoprofen in the preparations increases with an increase in its content from 1.5 to 2.5% (formulations 1, 2 and 3). Dexketoprofen, included in a concentration of 2.5% (composition 3), has a more effective analgesic effect in the experiment during cutaneous application compared with the preparation Ketonal gel 2.5% containing 2.5% ketoprofen racemate. The analgesic effect manifests itself earlier and amounts to 25.2% after 1 h, while when using the Ketonal drug, 2.5% gel after 1 h AE is minimal and equal to 3.4%. The total analgesic effect when using dexketoprofen instead of ketoprofen at a concentration of 2.5% increases by 1.34 times. However, in concentrations of less than 2.5%, dexketoprofen in the preparations (formulations 1 and 2) in the experiment has a lower total AE; in this case, AE manifests itself rapidly within 1 hour, but by 5 hours it is practically lost (Table 9). In addition, according to the total anti-inflammatory effect, composition 3 has no advantages over the preparation Ketonal gel 2.5% (Table 10).

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Table 9

The analgesic effect (AE) of the claimed pharmaceutical compositions with dexketoprofen and their analogues in a model of acute aseptic carrageenin inflammation of the foot of rats

An object AE (%) through: ΣΑ3, % H Relative ΣΑ3 1 hour Sp 5h Dexketoprofen 1.5% (Example 1) DMSO 5.0% 19.0 33.1 16,2 110.9 0.90 Dexketoprofen 2.0% (Example 2) DMSO 7.5% 22.8 58.6 35.6 187.0 1,52 Dexketoprofen 2.5% (Example 3) DMSO 10.0% 26.2 70.9 33,2 214.3 1.74 Dexketoprofen 3.0% (Example 4) DMSO 12.5% 22.8 74.0 32,0 214.2 1.74 Dexketoprofen 1.5% (composition 1) DMSO 0% 24.2 18.8 0.4 74.3 0.60 Dexketoprofen 2.0% (composition 2) DMSO 0% 23.8 34.7 2,4 108,5 0.88 Dexketoprofen 2.5% (composition 3) DMSO 0% 25,2 48.6 30,2 165.2 1.34 Dexketoprofen 0% (composition 4) DMSO 10.0% 0 12.0 2,4 20,4 0.17 Ketonal gel 2.5% 3.4 41,4 35,2 123.1 1.00 Analog drug 1.25% by patent EA 002026, example 1 of the patent 20.1 16.5 1,6 64.8 0.53

The analogue preparation according to the patent EA 002026, containing 1.25% dexketoprofen, is 1.9 times inferior in the total analgesic effect to the analogue preparation Ketonal gel 2.5%, containing 2.5% ketoprofen racemate. That is, the concentration of dexketoprofen 1.25% is insufficient for the manifestation of a highly effective analgesic effect.

Thus, the use of dexketoprofen instead of ketoprofen in the preparations does not fully meet the purpose of the invention and does not allow to achieve the planned technical result.

The inclusion of DMSO in the composition of the preparations potentiates their analgesic effect when the dexketoprofen content is from 1.5 to 2.5% (examples 1, 2 and 3) (table. 9). With an increase in the content of dexketoprofen from 1.5 to 2.5% and DMSO from 5.0 to 10.0%, the total AE also increases at a concentration of dexketoprofen of 2.0% and DMSO of 7.5% (example 2) 1.52 times exceeds the total AE of the drug-analog Ketonal gel 2.5%. A pharmaceutical composition containing 2.5% dexketoprofen and 10.0% DMSO (Example 3) is 1.74 times higher than the total AE of the Ketonal gel analogue drug 2.5%. With an increase in the content of dexketoprofen to 3.0% and DMSO to 12.5% (Example 4), the total AE does not increase, but remains at the same level, exceeding 1.74 times this indicator for the Ketonal gel analogue drug 2.5% .

In the absence of dexketoprofen, a preparation containing 10% DMSO (composition 4) has an insignificant analgesic effect; total AE is only 20.4% -h. The increase in the effectiveness of the analgesic effect of dexketoprofen in the presence of DMSO is not a result of the summation of their analgesic effects. So, for compounds 3 and 4, in total Σ AE is (165.2 + 20.4) = 185.6% -h, while for example 3 Σ AE is 214.3% -h, which is 28 more 7% When comparing the sum of Σ AE for compounds 2 and 4 with Σ AE for example 2, the difference is even greater and amounts to 58.1% -h. In the case of example 1, there is also a potentiation of the effectiveness of the analgesic effect of dexketoprofen, but at a concentration of 1.5% the objective of the invention and the planned technical result are not achieved, since Σ AE is less than that of the analog drug Ketonal gel 2.5% (table 9) .

The developed pharmaceutical composition in an experiment on rats provided a high analgesic effect, which is 1.52-1.74 times more than that of the Ketonal gel analogue drug 2.5% and 2.89-3.31 times more than that of analogue of 1.25% according to patent EA 002026 (Table 9), which, possibly 12,028,759, can, when used in humans, also achieve a more effective analgesic effect.

Table 10

Anti-inflammatory effect (PE) of the claimed pharmaceutical compositions with dexketoprofen and their analogues in a model of acute aseptic carrageenin inflammation of the foot of rats

An object PE (%) through: ΣΠ3, % H Relative ΣΠ3 1 hour Sp 5h Dexketoprofen 1.5% (example 1) DMSO 5.0% 22.7 44.8 40,2 163.9 0.71 Dexketoprofen 2.0% 36.3 54.7 56.8 220.7 0.96 (example 2) DMSO 7.5% Dexketoprofen 2.5% (Example 3) DMSO 10.0% 48.1 56.7 63.9 249.5 1.09 Dexketoprofen 3.0% (Example 4) DMSO 12.5% 47.8 58.5 64.6 253.3 1.10 Dexketoprofen 1.5% (composition 1) DMSO 0% 8.6 38.1 28.9 118.0 0.51 Dexketoprofen 2.0% (composition 2) DMSO 0% 39.8 54.3 35.9 204.2 0.89 Dexketoprofen 2.5% (composition 3) DMSO 0% 46.1 52.8 38.5 213.3 0.93 Dexketoprofen 0% (composition 4) DMSO 10.0% 1,2 6.5 2.0 14.8 0.06 Ketonal gel 2.5% 46.9 57.2 44.7 229.5 1.00 An analogue drug of 1.25% according to patent 002026, example 1 patent 6.8 36,4 25,2 108,2 0.47

As follows from the table. 10, the total anti-inflammatory effect of dexketoprofen in the preparations increases with an increase in its content from 1.5 to 2.5% (formulations 1, 2 and 3). Dexketoprofen, included in a concentration of 2.5% (composition 3), does not have a more effective anti-inflammatory effect in the experiment during cutaneous application compared with the analogue drug Ketonal gel 2.5% containing 2.5% ketoprofen racemate. The relative Σ PE of composition 3 is 0.93, that is, Σ PE is at the level of the Ketonal gel analogue drug 2.5%. According to the total anti-inflammatory effect, the 1.25% analogue preparation according to EA 002026 is more than 2 times inferior to the Ketonalgel analogue drug 2.5% (Table 10).

The analog drug Ketonal gel 2.5% and analog drugs containing 1.5 to 2.5% dexketoprofen (formulations 1, 2 and 3) have a similar dynamics of the anti-inflammatory effect, which initially increases, passes through a maximum of about 3 h and then decreases to 5 hours (table. 10).

The inclusion of DMSO in the preparations slightly potentiates the effectiveness of their anti-inflammatory action with a dexketoprofen content of from 1.5 to 2.5% (examples 1, 2 and 3) (Table 10). When the concentration of dexketoprofen is 1.5% and DMSO is 5.0% (Example 1), the preparation in the experiment has a lower total PE than the analogue drug Ketonal gel 2.5%; in this case, PE after 1 h is 2 times less than that of the Ketonal gel analogue drug 2.5% (Table 10). The total PE with an increase in the content of dexketoprofen from 1.5 to 2.5% and DMSO from 5.0 to 10.0% increases and with a concentration of dexketoprofen 2.5% and DMSO 10.0% (example 3) 1.09 times (by 9%) exceeds the total PE of the drug analog Ketonal gel 2.5%. With a further increase in the content of dexketoprofen to 3.0% and DMSO to 12.5% (Example 4), the relative Σ PE practically does not increase and remains at about the same level of 1.10.

The total anti-inflammatory effect of the pharmaceutical composition according to example 3 is 2.31 times greater than that of the drug analogue of the patent 002026 (table. 10).

It can be stated that in the range of dexketoprofen concentrations from 2.0 to 3.0% and DMSO from 7.5 to 12.5%, the total PE is approximately at the level of the Ketonal gel analogue drug 2.5% (Table 10). However, for the claimed pharmaceutical compositions (examples 2, 3 and 4), the dynamics of PE changes. If the maximum anti-inflammatory effect of Ketonal gel 2.5% falls on 3 hours, then the dynamics of the anti-inflammatory activity of dexketoprofen preparations is 2.0%, 2.5% and 3.0%, containing 7.5%, 10.0% and 12, respectively , 5% DMSO, is characterized by a high and stable anti-inflammatory effect of up to 5 hours (Table 10). That is, DMSO prolongs the anti-inflammatory effect of drugs containing 2.0%, 2.5% and 3.0% dexketoprofen, which is a significant advantage over the equivalent drug Ketonal gel 2.5%. The prolongation of an effective anti-inflammatory action is not associated with the PE of DMSO itself (composition 4), which passes through a maximum of 3 hours. Moreover, the total PE of the drug containing 10% DMSO in the absence of dexketoprofen (composition 4) is only 14.8% -h and is not comparable with the total PE of the preparations with dexketoprofen and ketoprofen.

The developed pharmaceutical composition in the experiment allows us to maintain a high level of anti-inflammatory activity in rats for a long time, which, possibly, will allow us to achieve a longer interval between the use of the drug and a higher anti-inflammatory effect in humans than when using analog drugs.

Thus, preclinical studies have confirmed that the claimed drug in accordance with the invention has a highly effective analgesic activity and a prolonged effective anti-inflammatory effect. The purpose of the invention and the technical result regarding analgesic and anti-inflammatory effects are achieved in the concentration range of dexketoprofen from 2.0 to 3.0% and DMSO from 7.5 to 12.5%.

The obtained pharmaceutical composition containing dexketoprofen (§ (+) - the enantiomer of ketoprofen) in the form of a salt with an organic base and target additives DMSO, ethanol (96%), Cagloro1® ϋΐίίβζ 21 Po1uteg, tetrahydroxypropylethylenediamine (No. Schgo1® TE), lavender oil purified, meets pharmacopoeial regulatory requirements regarding the quality, uniformity, content of dexketoprofen, DMSO and ethanol, the content of impurities and microbiological purity and has a shelf life of more than 3 years in the pH range from 6.5 to 7.5. The method of obtaining this composition described in example 1 is justified.

The claimed pharmaceutical composition is in the form for external use, the cutaneous application of which is aesthetically pleasing, when rubbed into the skin, it does not roll into lumps and excess stickiness is eliminated at a concentration of Cahporo1® υΗΐΌζ 21 Ро1утег from 1.20 to 1.50% and a tetrahydroxypropylethylenediamine neutralizer of 2 , 40 to 4.20%. Dexketoprofen in the composition of the composition is chemically stable, and the composition is resistant to delamination and change of appearance not only in the package (in tubes), but also in contact with air for a long time, which eliminates the risks to its stability during the process and the effectiveness of the drug when use by patients.

Thus, all of the above indicates the achievement of the goals of the invention and the achievement of a technical result, which consists in creating a new pharmaceutical composition for external use containing dexketoprofen trometamol and targeted additives that provide a highly effective analgesic effect and effective prolonged anti-inflammatory effect, a high level of stability and aesthetics skin application (lack of excess stickiness and rolling into lumps rubbing the drug into the skin), as well as eliminating risks to the quality of the drug and the effectiveness of the action associated with the heterogeneity of the composition and the precipitation of dexketoprofen in the sediment upon contact of the drug with air.

Claims (8)

CLAIM 1. A pharmaceutical composition for external use that has an analgesic and anti-inflammatory effect, which contains dexketoprofen in the form of a salt with an organic base and target additives dimethyl sulfoxide, ethanol (96%), carbomer, flavor, neutralizer and purified water, in the following ratio, g / 100 g of the composition: dexketoprofen salt with an organic base (in terms of 100% dry matter dexketoprofen) - 2.00-3.00, dimethyl sulfoxide (DMSO) - 7.5-12.5, ethanol (96%) - 19.5 -24.5, carbomer - 1.20-1.50, neutralizer - 2.40-4.20 , flavoring - 0.04-0.08, purified water - up to 100.0 g. 2. The pharmaceutical composition according to claim 1, characterized in that, as a dexketoprofen salt with an organic base, it contains dexketoprofen trometamol. 3. The pharmaceutical composition according to claim 1, characterized in that, as a carbomer, it preferably comprises a hydrophobically modified cross-linked polyacrylate carbomer Cagoro1 ® υ 1ι ^ еζ 21 Ро1утег. 4. The pharmaceutical composition according to claim 1, characterized in that as a neutralizer it preferably contains tetrahydroxypropylethylenediamine (No. Shgo1® TE), which adjusts the pH of the composition to 6.5-7.5. 5. The pharmaceutical composition according to claim 1, characterized in that it preferably contains lavender oil as a flavoring. 6. The pharmaceutical composition according to claim 1, having the following composition in the following ratio of components, g / 100 g of the composition: dexketoprofen trometamol (in terms of 100% dry matter dexketoprofen) - 2.00-3.00, dimethyl sulfoxide (DMSO) - 7 5-12.5, ethanol (96%) - 19.5-24.5, Cagoro1® - 14 028759 υΐίΓβζ 21 Ро1утег - 1.20-1.50, tetrahydroxypropylethylenediamine (ΝοιιΙγοΙ® TE) - 2.40-4.20, lavender oil - 0.04-0.08, purified water - up to 100.0 g. 7. A method of obtaining a pharmaceutical composition according to any one of claims 1 to 6, in which a solution of a flavoring agent in a portion of dimethyl sulfoxide, a solution of a salt of dexketoprofen with an organic base in a portion of purified water, a solution of a neutralizer in a portion of purified water are prepared separately, then a dispersion of carbomer in a portion of water is prepared purified and mixed under vacuum successively with ethanol (96%) while cooling to room temperature, a flavor solution, the remaining part of dimethyl sulfoxide, a solution of dexketoprofen salt with organic base, and then with a solution of a catalyst to obtain a homogeneous composition with a pH of from 6.5 to 7.5, while if necessary, withstand the composition under vacuum for degassing and then dose it into tubes. 8. The method according to claim 7 of obtaining the pharmaceutical composition according to claim 6, in which a solution of lavender oil in a part of dimethyl sulfoxide, a solution of dexketoprofen trometamol in a part of purified water, a solution of tetrahydroxypropylethylenediamine in a part of purified water are prepared separately, then a dispersion of carbomer in a part of purified water is prepared and mix it under vacuum in series with ethanol (96%) while cooling to room temperature, a solution of lavender oil, the remaining part of dimethyl sulfoxide, a solution of dexketoprofen trometamol, and then m tetrahydroxypropyl solution to obtain a homogeneous composition with a pH of 6.5 to 7.5, wherein the composition is maintained, if necessary under vacuum for degassing and then dosed into its tube.