RU2574008C2 - Topical agent for treating joint and soft-tissue disorders - Google Patents

Abstract

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to chemical-pharmaceutical industry and represents a topical agent for treating joint and soft-tissue disorders, containing a non-steroidal anti-inflammatory agent, which is presented by meloxicam, and a pharmaceutically acceptable base containing a mixture of water, trometamol, N-methylpyrrolidone and ethanol, wherein meloxicam is taken in the form of a true solution with the base components.

EFFECT: invention provides a higher degree of transdermal penetration of the active ingredient, improved anti-inflammatory and analgesic activity, a lower risk of side effects as keratolytic, irritant action and skin dehydration, and an increase in stability of the agent.

7 cl, 15 tbl, 12 dwg

Description

The invention relates to the field of medicine and the pharmaceutical industry, in particular to transdermal preparations for the treatment of diseases of joints and soft tissues, using non-steroidal anti-inflammatory drugs as active components.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used to treat a wide range of diseases accompanied by inflammation and pain, and occupy one of the leading places according to the frequency of appointment and the volume of world sales (Nasonov E.L. Nonsteroidal anti-inflammatory drugs (Prospects for use in medicine) .- M .: Anko, 2000). Every year in the world, drugs of this group are used in 60 million outpatients and in 20% of inpatients.

The use of NSAIDs is often accompanied by a number of serious side effects (lesions of the gastrointestinal tract, impaired renal function, etc.), which causes special attention to the problem of the safety of therapy with drugs of this group. The development of side effects of NSAIDs is associated with the main mechanism of their action, namely, the inhibition of cyclooxygenase-dependent prostaglandin synthesis. The discovery of two isoforms of cyclooxygenase (COX) - the “physiological” COX-1 and the “pro-inflammatory” COX-2 - has opened up new prospects for improving the safety of NSAID therapy by creating drugs containing selective COX-2 inhibitors, including meloxicam. In addition, NSAIDs, which are COX-2 inhibitors, do not have a chondrotoxic effect and are promising for the treatment of osteoarthritis. Hereinafter, the examples cited will be based on meloxicam. However, this does not exclude the possibility of using other non-steroidal anti-inflammatory drugs, which are a selective COX-2 inhibitor and have poor solubility in water.

The ability of meloxicam (in therapeutic doses) to inhibit predominantly the synthesis of pro-inflammatory prostaglandins in the inflammatory focus while maintaining the biosynthesis of cytoprotective prostaglandins in the gastrointestinal tract and kidneys determines its high efficiency and good tolerance.

Meloxicam is one of the most fully studied, including from the standpoint of evidence-based medicine, COX-2-selective NSAIDs (New aspects of anti-inflammatory therapy of rheumatic diseases: theoretical background and clinical use of meloxicam / Nasonov E.L., Tsvetkova E.S., Balabanova PM and others // Clinical medicine. - 1996. - No. 4. - C.1-4.). On the basis of numerous data on high therapeutic efficacy in combination with good tolerance, meloxicam preparations are included in standard treatment regimens for rheumatic diseases (Federal guidelines for the use of drugs (formulary system). Issue V. - M .: ECHO, 2004. - 944 p.) .

Currently, the global nomenclature of meloxicam preparations mainly includes solutions for injection, tablets and rectal suppositories, while dosage forms for skin application that provide transdermal delivery of meloxicam to the lesion are few. Nizhpharm OJSC developed two combined soft drugs with meloxicam for skin application (State Register of Russian Medicines [Electronic resource]. Access mode: http://grls.rosminzdrav.ru/), which contain meloxicam in the form of a suspension. The use of such drugs is limited to the local treatment of inflammatory skin diseases, since suspended meloxicam particles are not capable of transdermal penetration (Martindale: The Complete Drug Reference. 35 ^th Edition / Ed. Sweetman S. - London: Pharmaceutical Press, 2008. - 1420 p.).

Therefore, these drugs are not able to have anti-inflammatory and analgesic effects on deep-seated soft tissues and joints. The dimethyl sulfoxide included in the preparations at the used concentrations does not dissolve meloxicam and cannot enhance its penetration through the skin. At the same time, topical NSAID therapy is widely used for localized rheumatic diseases, osteoarthritis, arthrosis of peripheral joints and spine, periarthropathy, traumatic inflammation of tendons, ligaments, muscles and joints, and the impossibility of oral administration. In addition, local therapy of NSAIDs can reduce the frequency and severity of systemic adverse reactions, which is especially important in elderly patients. Currently, the creation of soft dosage forms of meloxicam is the subject of active research.

The foregoing determines the relevance of creating a transdermal drug based on NSAIDs, in particular meloxicam for skin application, which has a local anti-inflammatory and analgesic effect.

From patent sources known compositions in the form of soft forms containing meloxicam (RU 2259204; RU 2259204). The compositions described in the patents are combined, based on the combined action of several active components. The presence of several active components is not always advisable for certain applications. In addition, the ointment base used does not provide a sufficient transdermal effect.

Also, in a published patent application (No. 201002763, publication date 07/27/2011), a composition for treating joint diseases, including meloxicam, dimethyl sulfoxide and an ointment base, is described. In this case, a carrier containing either carbopol 940 and water, or hydroxyethyl cellulose and water, or polyethylene glycol 400 and polyethylene glycol 4000 in various ratios and additionally contains 1.2 propylene glycol, methyl paraben and propyl paraben is used as an ointment base.

However, the composition of the ointment base will also not allow for a sufficient degree of transdermal penetration of the active component.

Foreign sources are known in which transdermal NSAID compositions are described with a list of a wide range of possible solvents and penetration enhancers of NSAIDs in the form of certain amines, amides, pyrrolidones, alcohols, etc. (for example, WO 2001/052897, US 2005/0187212, US 2005/0096371 US 5,716,609). However, these publications mainly describe the results of studies on the penetration of NSAIDs through the skin using certain penetration enhancers; there is little information related to the indicators of anti-inflammatory, analgesic, antimicrobial activity of the finished compositions, the risk of side effects, and also little information on the stability of the finished drugs, their shelf life. In this regard, the development of external formulations based on NSAIDs, which would be characterized by high rates of pharmacological activity, good characteristics of the appearance and shelf life and low risk of side effects, is relevant.

The authors of the claimed invention for the first time showed that the combination of water, trometamol and N-methylpyrrolidone (as the basis of an external drug) is characterized by a number of new, previously unknown properties associated with high anti-inflammatory, analgesic, antimicrobial activity of the finished drug and a low risk of side complications its application, as well as high stability.

In the development of an acceptable base, the carrier of the active component, in particular, it was unexpectedly discovered that when using water, trometamol and N-methylpyrrolidone in combination with a non-steroidal anti-inflammatory agent, a true solution is possible. This is especially manifested with sparingly insoluble or water-insoluble non-steroidal anti-inflammatory drugs.

The problem to which the invention is directed, is to expand the arsenal of means used and to obtain an external agent for the treatment of diseases of joints and soft tissues, providing a high degree of transdermal penetration of the active component and at the same time having a high anti-inflammatory and analgesic activity, low risk of side effects in the form of keratolytic , irritating and dehydrating skin, as well as good stability.

The problem is solved due to the fact that an external agent for the treatment of diseases of the joints and soft tissues, containing a non-steroidal anti-inflammatory agent and a pharmaceutically acceptable base, according to the invention as a pharmaceutically acceptable base contains a mixture of water, trometamol and N-methylpyrrolidone, and the non-steroidal anti-inflammatory agent is in as a true solution with the components of the base. Moreover, the pharmaceutically acceptable base additionally contains ethanol in a concentration of up to 60%, and the agent can be made in the form of a solution for external use, an ointment or a gel (preferably a gel). Also, the non-steroidal anti-inflammatory agent can be selected from the group consisting of salicylic acid derivatives, pyrazolones, butylpyrazolidines, acetic acid derivatives and related compounds, oxicams, propionic acid derivatives, phenamates, coxibs, anilides and other non-narcotic analgesics (including non-steroidal and others oxicams, or coxibs). And as a specific non-steroidal anti-inflammatory drug, meloxicam can be selected. The concentration of non-steroidal anti-inflammatory drugs can range from 0.5 to 5.0%. Trometharol can be contained in a concentration of from 0.1 to 3.5%, and N-methylpyrrolidone in a concentration of from 2.0 to 30%. Additionally, the external agent may contain carbomer in a concentration of from 0.5 to 5.0%.

Description of figures

Figure 1 shows the kinetics of the release of N-methylpyrrolidone and ethanol from the drug Meloxicam gel for external use of 1% in in vitro experiments through a semipermeable membrane at a temperature of 37 ° C.

Figure 2 presents the kinetics of water absorption through a semi-permeable membrane in experiments in vitro with Meloxicam gel for external use of 1.0% at a temperature of 25 ° C.

Figure 3 presents the UV absorption spectrum of the gel of meloxicam and placebo in methanol (λ _max1 = 364 nm). Methanol Comparison Solution.

Figure 4 presents the Spectra of solutions of meloxicam in methanol at different concentrations of meloxicam (λ _max1 = 364 nm).

In FIG. 5. The dependence of the optical density (A) of solutions of meloxicam in methanol on the concentration of meloxicam (μg / ml) is shown.

Fig. 6 shows the dependence of the optical density of solutions of meloxicam in methanol as a function of the concentration of meloxicam (% wt / v).

In FIG. 7 shows rheograms of 1% meloxicam gels (at 25 ° C) containing 0.9% Carbopol ^® Ultrez 21 Polymer, at different concentrations of trometamol and different pH. Rheograms were taken after 24 hours of gel production.

In FIG. Figure 8 shows Determination of the shelf life of the drug Meloxicam gel for external use 1% based on the quantitative determination of meloxicam using the upper and lower limits of the acceptance criteria (95-105% and 90-110%) (long-term stability tests at 25 ° C).

In FIG. Figure 9 shows the determination of the shelf life of the drug Meloxicam gel for external use of 1% based on the quantitative determination of N-methylpyrrolidone using the upper and lower limits of the acceptance criteria (95-105%) (long-term stability tests at 25 ° C).

Figure 10 shows the determination of the shelf life of the drug Meloxicam gel for external use of 1% based on the quantification of ethanol (96%) using the upper and lower limits of the acceptance criteria (95-105%) (long-term stability tests at 25 ° C) .

11 is shown. Determination of the shelf life of the drug Meloxicam gel for external use 1% based on the determination of 5-methyl-2-aminothiazole impurities using the upper limit of the acceptance criterion (0.5%) (long-term stability tests at 25 ° C).

12 shows the pharmacokinetic curves of meloxicam after cutaneous application of the gel at a dose of 10 mg / kg (1) and intramuscular injection of the solution at a dose of 2 mg / kg (2).

A substance in a dispersed dosage form with a liquid dispersion medium can be in the form of a dispersed phase in the form of a true solution (molecular or ionic), when there is no interface between the substance and the dispersion medium, and also in the form of a colloidal solution, suspension or emulsion. According to the invention, the non-steroidal anti-inflammatory agent, in the preferred embodiment of the invention is Meloxicam, is in the form of a true solution, which is due to the formation of its salt with trometamol and the composition of the solvents. The drug can be prepared on a gel basis, which, due to moderate osmotic activity and the presence of two penetration enhancers (N-methylpyrrolidone and ethanol) provides the release of meloxicam and its penetration through the skin, as established by pharmacokinetic studies. The concentration of meloxicam from 0.5 to 5.0% (the preferred concentration is 1.0-1.5%), as well as the type and composition of the gel base, are selected based on the results of screening for anti-inflammatory and analgesic effects on the model of rat carrageenin edema. The selected composition of excipients and the established pH limits provide the gel with a gel-like consistency.

Composition (g / 100 g):

Meloxicam 1,000 Excipients: N-methylpyrrolidone 15,000 Ethanol 96% (rectified ethyl alcohol) 25,000 Carbomer 0,900 Trometamol 2,100 * Purified water up to 100,000 g

*Note. If necessary, to achieve optimal gel pH, a change in trometamol content in the range from 1.6 to 2.6 g is allowed.

To give a pleasant smell, perfumes can be used:

Nerolium oil 0.015 Lavender oil 0.010

Excipients used in the composition of the drug Meloxicam gel for external use of 1% perform, including the following functional purpose:

Ethanol 96% and N-methylpyrrolidone are hydrophilic non-aqueous solvents that contribute to the dissolution and penetration of meloxicam, also playing the role of antimicrobial preservatives;

Carbomer - gelling agent;

Trometamol - pH flavorant and neutralizer of meloxicam, an amplifier that penetrates the active substance of the drug through the skin;

Lavender oil and nerolia oil - fragrances;

Purified water - solvent and dispersion medium of the gel base;

The pH of the drug should be from 7.5 to 8.9.

Meloxicam is a non-steroidal anti-inflammatory drug from the oxycam group, has anti-inflammatory and analgesic effects.

The general mechanism for the development of these effects is the ability to inhibit prostaglandin synthesis. The therapeutic effect of meloxicam is associated with selective inhibition of COX-2 synthesis compared to COX-1. Due to its high selectivity, gastropathy and impaired renal function are less likely. Unlike non-selective NSAIDs, meloxicam does not inhibit platelet aggregation induced by collagen and arachidonic acid, but significantly inhibits platelet production of thromboxane. When applied topically, the drug reduces or eliminates pain in the area of application of the gel, including pain in the joints at rest and during movement, reduces morning stiffness and swelling of the joints. Helps increase range of motion.

As already mentioned, the authors of the claimed invention for the first time showed that the combination of water, trometamol and N-methylpyrrolidone (as the basis of an external drug) is characterized by a number of new, previously unknown properties. It is these three substances that were selected from a wide range of possible solvents and transdermal penetration enhancers of NSAIDs, while it was found that the combination of these three components is necessary and sufficient to achieve the required pharmacological activity, in the absence of side effects and high quality indicators and shelf life. The exclusion or replacement of any of these three ingredients leads to a deterioration of the drug (either a decrease in anti-inflammatory or analgesic activity, or an increase in the risk of side effects, or a decrease in antimicrobial activity, or a deterioration in the appearance and shelf life, depending from mutable ingredients and / or their quantitative content).

Let us dwell in more detail on the new, previously unknown properties of the combination of the three components of the base (water, trometamol, N-methylpyrrolidone) established by the authors of this application, and evidence that this combination is necessary and sufficient. We also provide information confirming the non-obviousness of the signs of additional claims (including the additional introduction of ethanol, carbomer, as well as certain quantitative indicators).

The need to include trometamol in the composition is reflected below in Tables 1, 2 and their comments. It has been shown that without trometamol, a solvent such as N-methylpyrrolidone must be used in concentrations that could lead to side effects in the form of a keratolytic or irritating effect.

In turn, the need for inclusion in the composition of N-methylpyrrolidone is shown below in tables 3, 4, 5. It is shown that the exclusion from the composition of N-methylpyrrolidone or its replacement with ethanol leads to a decrease in anti-inflammatory and analgesic activity. A similar effect of a decrease in activity is observed when ethanol is replaced (an additional ingredient according to claim 2; the base according to claim 2 includes 4 components) with propylene glycol.

Table 5 also reflects a decrease in the analgesic effect with the additional introduction of levomenthol into the composition (and thereby confirms the sufficiency of the combination of the three claimed excipients described in claim 1).

In tables 6-10 and the comments below, information is given on the antimicrobial effect of the composition claimed as an invention. Unexpected results were obtained: the additional introduction of special preservatives (plus the three-component composition of the base of water, trometamol and N-methylpyrrolidone) does not enhance the antimicrobial effect; the combined presence of N-methylpyrrolidone and ethanol gives a synergistic effect (the latter is important for an additional claim, where ethanol is reflected as a sign). There is substantiated the absence of the need to include special preservatives in the preparation and the sufficiency of the combination of trometamol, N-methylpyrrolidone and water to achieve the desired antimicrobial effect, as well as a synergistic effect with the additional introduction of ethanol.

Figures 1, 2 and Table 11 below show the results of experiments on studying diffusion through a semi-impermeable membrane, which showed a mixed solvent structure (of three components) with a prevailing water structure and revealed such advantages of the developed composition as reducing the risk of skin dehydration during long-term application, the absence of an overdrying effect on the skin, as well as the elimination of the possibility of peak concentrations of meloxicam in the blood plasma during cutaneous use, requiring multiple applications drug during the day.

Figure 3, 4, 5, 6 and table 12 below show the results of studies of the solubility of meloxicam, proving that the NSAIDs in the claimed preparation is in a true solution state.

7 and the comments thereto, also presented below, confirm the optimality of the quantitative indicators indicated in paragraphs 8, 9 of the claims for obtaining and maintaining the gel-like structure of the preparation (in the preparation in the form of a gel).

In tables 13, 14 and Figs. 8, 9, 10, 11, 12 below are the results of a study of the stability of the claimed drug, from which it follows that the claimed combination of ingredients makes it possible to establish the shelf life within 1-2 years at a temperature of 25-30 degrees.

In general, all the following detailed research results confirm that the creation of the claimed pharmaceutical agent became possible due to the establishment of a number of new, previously unknown properties of the substances manifested by them in the described combination of ingredients.

With increasing concentrations of N-methylpyrrolidone, the solubility of meloxicam in mixed solvents increases; however, meloxicam is very slightly soluble in mixed solvents containing up to 50% N-methylpyrrolidone, and slightly soluble with a content of N-methylpyrrolidone 60-70%. The solubility of meloxicam, which may be significant for the creation of a preparation in the form of a gel, occurs only at concentrations of N-methylpyrrolidone 80-100%.

The use of N-methylpyrrolidone, which is a penetration enhancer, in a preparation at such high concentrations can lead to side effects, such as keratolytic and locally irritating effects.

As can be seen from the data presented in Tables 1-2, in the presence of trometamol, the solubility of meloxicam increases sharply and increases with increasing concentration of trometamol. The addition of 0.10-0.35% trometamol initially leads to a sharp increase in the pH of the solutions, after which an increase in the concentration of trometamol is much less likely to increase the pH of the solutions, which may be due to the salt formed between trometamol and meloxicam. The solubility of this salt increases with increasing concentration of N-methylpyrrolidone from 7.5% to 15.0%. A further increase in the concentration of N-methylpyrrolidone to 30% or the use of a mixed solvent consisting of 15% N-methylpyrrolidone, 25% ethanol (96%) and 60% purified water had practically no effect on the solubility of the resulting salt; the concentration of meloxicam in solution was determined by the content of trometamol.

It was found that with an increase in trometamol content and pH, the solubility of meloxicam in mixed solvents containing 60-70% water increases and becomes significant for the development of a gel-like preparation.

It was shown by HPLC as well as absorption spectrophotometry in the ultraviolet and visible regions that an increase in solubility is associated with the formation of a salt between meloxicam and trometamol.

Based on the results of pharmacological screening for anti-inflammatory action, the most promising use of penetration enhancers is 25% ethanol (96%) and 15% N-methylpyrrolidone; the total anti-inflammatory effect of gel samples No. 2 and No. 5 containing these penetration enhancers was 132.2% · h and 142.3% · h, respectively, which approximately corresponds to the total PVE of the Voltaren Emulgel gel 1.0%, which was 165, 8% h With the exclusion of 15% N-methylpyrrolidone from the gel composition and its replacement with ethanol 96% (sample No. 3), as well as the replacement of 96% ethanol with propylene glycol (sample No. 4), the total PVE decreases and amounts to 108% · h for gel sample No. 3 and for the gel sample No. 4 96.6% · h.

Based on the results of pharmacological screening for analgesic action, the most promising use of penetration enhancers is 25% ethanol (96%) and 15% N-methylpyrrolidone; the total analgesic effect of the gel sample No. 2 was 157.3% · h. With the exclusion of 15% N-methylpyrrolidone from the gel composition and its replacement with ethanol 96% (sample No. 3), as well as the replacement of 96% ethanol with propylene glycol (sample No. 4), the total AE decreases significantly and amounts to 60.5 for gel No. 3 % · H, and for gel sample No. 4 82.3% · h. The presence in the composition of gel No. 5 of 1% levomenthol significantly reduced its analgesic activity; AE for 3 hours was only 13.9%, and the total AE was 47.5% · h.

From the data presented in tables 6 and 7, it is seen that in both series of the drug there is a rapid death of bacteria and fungi. Already in the initial plating from the preparation of the 200312 series, viable E Coli and P. Aeruginosa cells, as well as C. Albicans, were not detected. The logarithm of the decrease in the number of CFU / g of S. Aureus in the initial seeding from the preparation of the 200312 series was 4.84, and A. Niger - 3.30. In the initial plating from the 210312 series preparation containing 0.5% phenoxyethanol, no viable cells of S. Aureus, E Coli and P. Aeruginosa, as well as C. Albicans, were found. The logarithm of the decrease in the number of CFU / g of A. Niger in the initial seeding was 2.39. After 2 days and subsequent seeding, viable cells of bacteria and fungi in the samples of both series of the drug are not detected. This effectiveness of the antimicrobial preservative effect significantly exceeds the requirements of criterion A of the European Pharmacopoeia 7.0 (5.1.3) and the requirements of the RF Civil Fund XII ed. (Article 34).

It should be noted that the effectiveness of the antimicrobial preservative effect of the preparation of the 200312 series, which does not contain phenoxyethanol, and the 210312 series, containing 0.5% phenoxyethanol, is almost the same. Two conclusions can be drawn from this:

- firstly, the additional inclusion of an antimicrobial preservative in the preparation is impractical;

- secondly, other substances have an antimicrobial preservative effect in the preparation.

According to the literature, ethanol and some other hydrophilic non-aqueous solvents can have an antimicrobial effect. It is possible that N-methylpyrrolidone also has an antimicrobial effect. Carbomers are not a breeding ground for the growth of microorganisms, but they do not interfere with their growth and reproduction.

In connection with the foregoing, it was of interest to study the antimicrobial preservative effect of 15% aqueous N-methylpyrrolidone and 25% aqueous ethanol (96%), as well as a three-component solvent containing 15% N-methylpyrrolidone, 25% ethanol (96%) and 60 % purified water. The results of a study of the effectiveness of antimicrobial preservative effects are presented in tables 8, 9 and 30.

The data presented in Tables 8, 9 and 10 indicate that both 15% aqueous solution of N-methylpyrrolidone and 25% aqueous solution of ethanol (96%) have an effective preservative effect that meets the criteria A of the European Pharmacopoeia (5.1.3) . With the combination of these two hydrophilic solvents at the indicated concentrations, a synergy of the effectiveness of the antimicrobial preservative effect is observed. Viable P. Aeruginosa cells were not detected in the initial plating from the three-component solvent, and the logarithms of decreasing the number of CFU / g were for: S. Aureus 0.23, E Coli 3.61, C. Albican 1.61 and A. Niger 0, 68. After 2 days and subsequent seeding, viable cells of bacteria and fungi in a three-component mixed solvent are not detected. This effectiveness of the antimicrobial preservative effect significantly exceeds the requirements of criterion A of the European Pharmacopoeia 7.0 (5.1.3).

The research results presented in tables 8, 9 and 10 indicate that in the preparation Meloxicam gel for external use, 1.0% antimicrobial preservative effect is exerted by N-methylpyrrolidone and ethanol. A series of the drug 200312, containing these solvents in concentrations of 14.25% and 23.75%, respectively (that is, at the lower limits specified in the specification by the draft FSP), has an antimicrobial preservative effect (Table 6), comparable to the antimicrobial preservative the action of a three-component solvent (table 10). In both cases, it significantly exceeds the requirements of criterion A of the European Pharmacopoeia 7.0 (5.1.3).

Thus, at selected concentrations, N-methylpyrrolidone and ethanol act as antimicrobial preservatives and have an effective antimicrobial preservative effect. The inclusion of additional antimicrobial preservatives in the drug is not required.

As can be seen from the data presented in Fig. 1, N-methylpyrrolidone and ethanol (96%) were prolonged and quite fully released from the drug. Within 6 hours, about 61% of each of the non-aqueous solvents is released. The prolonged release provides the gel structure of the drug. Noteworthy is the completely identical release kinetics of N-methylpyrrolidone and ethanol, despite differences in molecular weight (99.1 and 46.07, respectively) and molecular structure. It can be assumed that solvent molecules interact with each other in solution through the formation of a hydrogen bond between hydroxyl and ketone groups. To clarify this issue, polythermal determinations of the kinematic viscosity and density of mixed solvents were carried out for ethanol - N-methylpyrrolidone, and also ethanol - N-methylpyrrolidone - water. Used N-methylpyrrolidone (Pharmasolve) (ISP, USA), absolute ethyl alcohol (Megg, Germany) and these mixed solvents, which were prepared by gravimetric method. Thus, the results of the studies indicate that the three-component solvent serving as the dispersion medium for Meloxicam gel for external use of 1.0% is a strongly associated liquid, the diffusion of which through a semipermeable membrane can therefore apparently be regarded as the diffusion of a single substance. This, apparently, is responsible for the identical kinetics of diffusion of ethanol and N-methylpyrrolidone through a semipermeable membrane (Fig. 1). A mixed structure of a component solvent or a mixed structure with a prevailing water structure should not lead to dehydration of the skin with prolonged use of the drug, which could be assumed if the structure of a non-aqueous solvent predominates in it.

The predominance of the structure of non-aqueous solvents, which are penetration enhancers, could also lead to peak plasma concentrations of meloxicam during cutaneous application of the drug, which would contribute to the manifestation of side effects and would require multiple gel applications over the course of a day

As can be seen from the data presented in Table 11 and Fig. 2, Meloxicam gel for external use of 1.0% has moderate osmotic activity, absorbing about 123% of water for 6 hours. With such osmotic activity, the drug should not have a drying effect on the skin.

Figure 3, 4, 5, 6 and table 12 below show the results of studies of the solubility of meloxicam, proving that the NSAIDs in the claimed preparation is in a true solution state.

The solubility of meloxicam in water, hydrophilic non-aqueous solvents and mixed solvents was determined. In the experiment, purified water was used, and N-methylpyrrolidone, dimethyl sulfoxide, ethanol (96%), isopropanol and propylene glycol were used as hydrophilic solvents. Mixed solvents were prepared by gravimetric method.

The solubility of meloxicam was studied by the isothermal method, and the concentration of the saturated solution was determined by absorption spectrophotometry in the ultraviolet and visible regions according to the method developed by us. To this end, an excess amount of meloxicam was placed in vessels with ground stoppers, poured with a solvent of the appropriate composition and thermostated with an accuracy of ± 0.1 ° C with periodic stirring until the thermodynamic equilibrium. The establishment of thermodynamic equilibrium in the system was controlled by sampling the supernatant (solution) and measuring their optical density. The constancy of the values of the optical density of a series of consecutively selected samples indicated the onset of thermodynamic equilibrium in the studied system. Then, the solutions were kept for 3–4 h at rest at a given temperature, after which the solutions were filtered off from the precipitate at a given temperature and samples were taken for analysis.

When studying the solubility of meloxicam in mixed solvents consisting of water and a non-aqueous hydrophilic solvent, an excess of meloxicam was dissolved in a precisely weighed amount of a non-aqueous solvent, and then the required amount of water was added to obtain a solvent of a given concentration. Then they acted as described above with the words: “thermostatically controlled with an accuracy of ± 0.1 ° C with periodic stirring until the onset of thermodynamic equilibrium ...”.

The optical density was measured on a Shimadzu UV-PharmaSpec-1700 spectrophotometer in the UV region at a wavelength of 364 nm. For this, a clear saturated solution of meloxicam was diluted with methanol so that the optical density of the resulting solutions was in the range from 0.1 to 1.6. Each solubility value is the average of 3-4 measurements. The maximum relative error in the determination of solubility at a confidence level of 0.95 was 2-3%.

Based on the study of the physicochemical properties (primarily rheological properties and pH) of the gel base samples and meloxicam gels having different compositions, we selected the type of carbomer and its concentration, as well as the content of trometamol as a substance that neutralizes carbomer and causes gelation.

As can be seen from the data presented in Fig.7, rheograms of 1% meloxicam gels (at a temperature of 25 ° C) containing 0.9% Carbopol® Ultrez 21 Polymer, at trometamol concentrations from 1.55% to 3.36% and pH from 7.30 to 8.72 rheograms of gels are very close to each other, and the maximum differences in the structural viscosity of the gels generally do not exceed 10%. That is, within these pH ranges, the drug retains a gel-like consistency and has almost the same structural viscosity.

In tables 13, 14 and Figs. 8, 9, 10, 11, 12 below are the results of a study of the stability of the claimed drug, from which it follows that the claimed combination of ingredients makes it possible to establish the shelf life within 1-2 years at a temperature of 25-30 degrees.

The proposed external agent for the treatment of diseases of the joints and soft tissues is obtained as follows.

A solution of trometamol is prepared by mixing the required amount of trometamol and purified water until the trometamol is completely dissolved. N-methylpyrrolidone, meloxicam and an aqueous solution of trometamol are successively mixed, mixed until meloxicam is completely dissolved, visually controlled by the absence of undissolved particles. In the case of preparation of an external agent in the form of a gel, a carbomer dispersion is separately prepared, as well as, if necessary, an alcoholic solution of essential oils. An aqueous solution of trometamol, a solution of meloxicam, a dispersion of carbomer and an alcoholic solution of essential oils are then mixed in a homogenizing reactor.

At the stage of preclinical studies, the pharmacokinetics of meloxicam was studied during the cutaneous application of a preparation obtained in accordance with the claimed invention and conventionally called "Meloxicam gel for external use 1.0%". The comparison was carried out with the intramuscular injection of the drug Movalis solution for injection 15 mg / 1.5 ml. In addition, a specific anti-inflammatory and analgesic effect of the drug was investigated, and a harmlessness study (acute and subchronic toxicity, locally irritating, ulcerogenic and allergenic effect) was studied.

To determine meloxicam in rabbit blood plasma, an HPLC method was used with preliminary solid-phase extraction of meloxicam from animal plasma and concentration of the sample in vacuo. It is shown that according to validation parameters “selectivity”, “lower limit of quantitative determination”, “precision”, “correctness”, “linearity” and “degree of extraction” the method used meets the established criteria.

The pharmacokinetic curves are presented in Fig. 12, and the calculated pharmacokinetic parameters are shown in Table 15.

The main pharmacokinetic parameters presented in Table 1 indicate that the process of absorption of meloxicam from the gel into the blood is prolonged. The time to reach the maximum concentration, which is determined by the ratio of the rate of absorption and elimination, has a high value, which is 12 hours and characterizes the long-term and gradual absorption of meloxicam. When applied to the skin, meloxicam is continuously circulated in the blood and slowly eliminates: MRT is 26.9 hours; K _el = 0.0332 h ^-1 ; T _1/2 - 20.87 hours.

With intramuscular injection of the solution and skin application of the gel, the levels of meloxicam concentrations in the blood and the nature of the pharmacokinetic curves differ (Fig. 12). The absorption rate of meloxicam during cutaneous application is lower than by intramuscular injection, by about 3 times, the half-life is more than 3.8 times, which leads to a corresponding extension of the retention time in the body. The level of the maximum concentration of meloxicam with cutaneous application is 11 times lower than with intramuscular administration, taking into account the administered dose.

The developed drug is characterized by a fairly high degree of bioavailability for skin preparations. Its relative bioavailability (f ') is 26.4% compared with the intramuscular injection of the solution.

The pharmacokinetic profile and pharmacokinetics of meloxicam for percutaneous application of the drug Meloxicam gel for external use of 1.0% show that the peculiarity of the pharmacokinetics of meloxicam is a slow and long, but sufficiently high transdermal absorption into the systemic circulation, a long residence time and its slow elimination with a long half-life, which allows us to expect a therapeutic effect for a long time.

The study of specific types of action

The specific pharmacological (anti-inflammatory and analgesic) activity of the drug Meloxicam gel for external use was studied 1% compared with Voltaren Emulgel gel 1% (Novartis Consumer Health SA, Switzerland) and Nimulide gel 1% (Panacea Biotech Ltd, India) that are registered in Russia.

Twice cutaneous application of the compared preparations in a total dose of 200 mg of gel / foot to rats with carrageenan inflammation of the foot significantly inhibits the growth of edema and increases the pain threshold of the inflamed foot of rats. The anti-inflammatory effect of the drug Meloxicam gel 1% by 1 hour was 30.5%, 3 hours - 22.3%, 5 hours - 15.8%. The effects of Voltaren Emulgel gel 1% and Nimulide gel 1% develop more slowly and make up 14.2% and 0%, respectively, by 1 hour, 38.6% and 28.5% by 3 hours, and 36.0 by 5 hours % and 25.4%. The total anti-inflammatory effect of the drug Meloxicam gel 1% (106.2) is 1.3 times higher than the effect of the drug Nimulide gel 1% (82.4) and 1.3 times lower than the effect of the drug Voltaren Emulgel gel 1% (134.5).

The analgesic effect of the drug Meloxicam gel 1% by 3 hours was 55.3%, decreasing by 5 hours to 12.5%. The analgesic effect of the preparations Voltaren Emulgel gel 1% and Nimulide gel 1% develops more slowly and amounts to 11.5% and 30.1% by 3 hours, by 19.8% and 32.3% by 5 hours. The total analgesic effect of the drug Meloxicam gel 1% (150.8) is 3.1 times higher than the effect of the drug Voltaren Emulgel gel 1% (48.6) and 1.4 times that of the drug Nimulide gel 1% (107.6).

Compared drugs with a 9-day application to rats with traumatic inflammation of the foot at a dose of 200 mg of gel / foot / day have an anti-inflammatory effect, significantly reducing the increase in foot edema by 2 days of treatment. The anti-inflammatory effects of Meloxicam gel 1%, Voltaren Emulgel gel 1% and Nimulide gel 1% on day 2 were 27.1%, 35.0% and 19.6%, respectively, day 3 - 29.0%, 44.0% and 30.2%, 4 days - 34.9%, 49.5% and 34.2%, 5 days 52.2%, 63.8% and 43.1%, 7 days - 64.0%, 62 , 2% and 46.8%, day 8 - 68.5%, 66.7% and 61.1%, on day 9 - 66.7%, 66.7% and 76.7%. The total anti-inflammatory effect of the drug Meloxicam gel 1% (370.7) is 1.1 times lower than the effect of the drug Voltaren Emulgel gel 1% (425.5) and 1.2 times higher than the effect of the drug Nimulide gel 1% (320.0). In the same rats, the compared preparations have an analgesic effect, which is 87.5%, 92.3% and 28.2% on the 3rd day, 110.2%, 84.7% and 49.0% on the 5th day, and on the 7th day 68.9%, 52.9% and 63.0%. The total analgesic effect of the drug Meloxicam gel 1% (488.2) is 1.2 times higher than the effect of the drug Voltaren Emulgel gel 1% (406.9) and 1.5 times the effect of the drug Nimulide gel 1% (319.9).

The results obtained indicate that the anti-inflammatory and analgesic activity of the drug Meloxicam gel for external use of 1% generally corresponds to the activity of the drugs Voltaren Emulgel gel 1% and Nimulide gel 1%. A tendency was found to lower anti-inflammatory activity of the developed drug Meloxicam gel 1% relative to the drug Voltaren Emulgel gel 1% and higher anti-inflammatory activity relative to the drug Nimulide gel 1%, as well as a more pronounced analytical activity of the developed drug relative to both comparison drugs.

Harmlessness research

In the study of acute toxicity, it was found that the drug Meloxicam gel 1% for cutaneous application to rats and mice at a dose of 3.0 g / kg (dosage form), guinea pigs at a dose of 2.5 g / kg (dosage form), and with intragastric administration to mice at a dose of 5.0 g / kg (in dosage form) does not cause death and does not affect the general condition and behavior of experimental animals.

The drug Meloxicam gel 1% with prolonged daily cutaneous application to rats for 1 month at doses of 0.3 g / kg and 0.6 g / kg (in dosage form) does not affect the general condition and behavior of animals, food and water consumption, dynamics body weight, functional state of the central nervous system and electrophysiological activity of the myocardium, on biochemical parameters and on indicators characterizing peripheral blood.

Pathomorphologically, it was found that the drug, when subchronic, does not change the relative mass of the internal organs of animals. After exposure to the drug, there are no macroscopic and morphological signs of damage to the vital organs of all animals.

The drug Meloxicam gel 1% in a single cutaneous application to rabbits at a dose of 0.5 g per animal does not have a locally irritating effect. The drug Meloxicam gel 1% with repeated cutaneous application to rats at doses of 0.3 g / kg and 0.6 g / kg does not have a locally irritating effect.

According to the results of the study of ulcerogenic action, it was found that UD50 for the drug Meloxicam gel 1% is 2.30 (1.44 ÷ 3.16) g / kg (in dosage form).

The drug does not exhibit sensitizing activity, does not have an allergenic effect.

The above results were achieved by obtaining a true solution by combining a non-steroidal anti-inflammatory drug and an acceptable base containing water, trometamol and N-methylpyrrolidone in a certain ratio. In this case, a true solution is obtained both with water-soluble non-steroidal anti-inflammatory drugs, and sparingly insoluble or insoluble in water.

Currently, the choice of non-steroidal anti-inflammatory drugs (NSAIDs) is quite large. They are divided into several subgroups:

Derivatives of salicylic acid or salicylates (e.g. acetylsalicylic acid, diflunisal, lysine monoacetylsalicylate). Pyrazolones. Butylpyrazolidines (e.g. phenylbutazone, clofeson). Acetic acid derivatives and related compounds (e.g., diclofenac, ketorolac, amtolmetin guacyl, aceclofenac, acemetacin, indomethacin, sulindac, nefafenac, etodolac). Oxycams (e.g., piroxicam, tenoxicam, lornoxicam, meloxicam). Propionic acid derivatives (e.g., ibuprofen, naproxen, flurbiprofen, ketoprofen, thiaprofen acid). Phenamates (e.g., mefenamic acid, etofenamate). Coxibs (e.g., etoricoxib, rofecoxib, parecoxib, celecoxib). Other non-narcotic analgesics, including non-steroidal and other anti-inflammatory drugs (e.g. nimesulide)

Almost all non-steroidal anti-inflammatory drugs can be used in the claimed invention.

But the most interesting are oxycams and coxibs. And first of all, those that are sparingly soluble or insoluble in water (for example, meloxicam). Since only the proposed base in the form of a mixture of water, trometamol and N-methylpyrrolidone allows you to get an external tool containing water-insoluble non-steroidal anti-inflammatory drugs.

Claims (7)

1. An external agent for the treatment of diseases of joints and soft tissues, containing a non-steroidal anti-inflammatory agent and a pharmaceutically acceptable base, characterized in that the non-steroidal anti-inflammatory agent is meloxicam, a pharmaceutically acceptable base is a mixture of water, trometamol, N-methylpyrrolidone and ethanol, and meloxicam It is in the form of a true solution with the components of the base. 2. An external agent according to claim 1, characterized in that the pharmaceutically acceptable base contains ethanol in an amount of up to 60 wt.%. 3. An external agent according to claim 1 or 2, characterized in that it is made in the form of a gel. 4. An external agent according to claim 1 or 2, characterized in that meloxicam is contained in an amount of from 0.5 to 5.0 wt.%. 5. An external agent according to claim 1 or 2, characterized in that trometamol is contained in an amount of from 0.1 to 3.5 wt.%, And N-methylpyrrolidone is in an amount of from 2.0 to 30 wt.%. 6. An external agent according to claim 1 or 2, characterized in that the pharmaceutically acceptable base further comprises carbomer in an amount of from 0.5 to 5.0 wt.%. 7. An external agent according to claim 1, characterized in that it is made in the form of a gel and contains meloxicam, N-methylpyrrolidone, ethanol, carbomer, trometamol, water and, if necessary, perfumes, such as neroli oil and / or lavender oil, in the following their ratio, g / 100 g:
Meloxicam 1,000
Excipients:
N-methylpyrrolidone 15,000
Ethanol 96% (rectified ethyl alcohol) 25,000
Carbomer 0.900
Trometamol from 1.6 to 2.6 (up to pH from 7.5 to 8.9)
Nerolium oil 0.015
Lavender Oil 0.010
Purified water up to 100,000 g

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