EA023000B1 - External medication for treatment of diseases of joints and soft tissues - Google Patents

Abstract

The invention relates to the field of medicine and chemical-pharmaceutical industry, in particular to transdermal medications for the treatment of diseases of joints and soft tissues, using non-steroid anti-inflammatory drugs as active ingredients. Disclosed is the external medication for the treatment of diseases of joints and soft tissues, which contains meloxicam and pharmaceutically acceptable base. Pharmaceutically acceptable base is a mixture of water, trometamol and N-methylpyrrolidone, with meloxicam being present in the form of true solution with base components. The invention makes it possible to extend the range of applied medications and obtain external medication for the treatment of diseases of joints and soft tissues, which provides the high anti-inflammatory and analgesic activity, faster development of said effects, high stability and long shelf-life.

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) - physiological COX-1 and pro-inflammatory COX-2 - has opened up new prospects for increasing the safety of NSAID therapy by creating drugs containing selective COX-2 inhibitors, which include, among others, 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 R.M. et al. // Clinical Medicine. - 1996. - No. 4 - S. 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 Medicines (Formular System). Issue V. - M .: ECHO, 2004 - 944 p.).

Currently, the global nomenclature of meloxicam preparations includes solutions for injection, tablets and rectal suppositories, while dosage forms for skin application that provide transdermal delivery of meloxicam to the lesion, unlike most NSAIDs, are absent.

Nizhpharm OJSC developed two combined soft drugs with meloxicam for cutaneous use (State Register of Russian Medicines [Electronic resource]. Access mode: NirE / dgNgoshchip / bgau.gi /). which contain meloxicam in suspension. The use of such drugs is limited to the local treatment of inflammatory skin diseases, since the suspended particles of meloxicam are not capable of transdermal penetration. )

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 cutaneous application, which has a local anti-inflammatory and analgesic effect.

From patent sources known compositions in the form of soft forms containing meloxicam (KI 2259204; KI 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. 2010102763, publication date July 27, 2011), 1,023,000 are described as becoming agents for the treatment of joint diseases, including meloxicam, dimethyl sulfoxide and an ointment base. 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.

When developing an acceptable carrier base for the active component, it was unexpectedly found that using a water, trometamol and Ν-methylpyrrolidone in combination with a non-steroidal anti-inflammatory agent, a true solution is possible. This is especially manifested with hardly soluble or water-insoluble non-steroidal anti-inflammatory drugs.

The problem to which the invention is directed, is to expand the arsenal of tools used and obtain an external agent for the treatment of diseases of joints and soft tissues, which has high stability, providing a high degree of transdermal penetration of the active component.

The problem is solved due to the fact that 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, according to the invention as a pharmaceutically acceptable base contains a mixture of water, trometamol and Ν-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, ointment or gel (preferably 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 (preferably non-steroidal and other 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 Ν-methylpyrrolidone in a concentration of from 2.0 to 30%. Additionally, the external agent may contain carbomer in a concentration of 0.5 to 5.0%.

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, a non-steroidal anti-inflammatory agent, in a preferred embodiment of the invention, meloxicam, is in the form of a true solution. 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 (Ν-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 preparation with a gel-like consistency.

Composition (g / 100 g):

Meloxicam 1,000

Excipients:

Ν-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 the optimum pH of the gel, a change in the trometamol content is allowed in the range from 1.6 to 2.6 g.

Fragrances can be used to give a pleasant smell.

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 Ν-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;

- 2,023,000 trometamol - pH flavorant and meloxicam neutralizer; lavender oil and nerolium 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.

At the stage of preclinical studies, the pharmacokinetics of meloxicam was studied during cutaneous application of a preparation obtained in accordance with the claimed invention and conventionally called Meloxicam gel for external use of 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 quantification, precision, accuracy, linearity and degree of extraction, the method used meets the established criteria.

Pharmacokinetic curves are presented in the drawing, and the calculated pharmacokinetic parameters are shown in the table.

The main pharmacokinetic parameters of meloxicam for intramuscular and cutaneous application to rabbits

Options pharmacokinetics Intramuscular introduction Cutaneous application Dose mg / kg 2 10 Stakh »NG / ML 7630.6 3379.3 Ttah »H 1,5 12 C1_, ml / h 27.31 99.32 K _e |, Ch ' ¹ 0.1263 0,0332 T / 2, H 5.49 20.87 MKT, h 7.09 26.93 ν _ζ , ml / kg 216.31 2991,05 Aiso-, v, ngch / ml 71,731.89 94514.9 AuCo ^ co, ng h / ml 73,229.60 100,682.30 Stakh / AiS O-ίΙ, Ch ¹ 0.1064 0,0358 g,% one hundred 26,4

The main pharmacokinetic parameters presented in the table 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. During skin application, meloxicam continuously circulates in the blood and slowly eliminates: MKT is 26.9 hours; K = 0.0332 h ^-1 ; T1 / 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 are different (drawing). The absorption rate of meloxicam during cutaneous application is lower than when administered intramuscularly 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 (G) 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 pharmacokinetics of meloxicam are characterized by a slow and long, but rather high tran- sumer absorption into the systemic circulation, a long time in the body 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 Meloxicam gel for external use was studied 1% compared with Voltaren Emulgel gel 1% (Novartis Consumer Health SA, Switzerland) and Nimulide gel 1% (Panacea Biotek Ltd., India), which are registered in Of 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 and 25 by 5 hours. ,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 Voltaren Emulgel Gel 1% and Nimulide Gel 1% is slower and reaches 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%, 8 day - 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 of 87.5%, 92.3% and 28.2% on the 3rd day, 110.2%, 84.7% and 49.0% on the 5th day, 68.9% on the 7th day. 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 is 1%, in general, corresponds to the activity of the drugs Voltaren Emulgel gel 1% and Nimulide gel 1%. A tendency 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 analgesic activity of the developed drug relative to both comparison drugs was established.

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 and 0.6 g / kg (in dosage form) does not affect the general condition and behavior of animals, food and water consumption, body weight dynamics, 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 multiple cutaneous application to rats at doses of 0.3 and 0.6 g / kg does not have a locally irritating effect.

According to the results of a study of ulcerogenic action, it was found that UD ₅₀ for 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 with a combination of a non-steroidal anti-inflammatory drug and an acceptable base containing water, trometamol and

- 4,023,000

Ν-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, amtolmethine 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 Ν-methylpyrrolidone allows you to get an external tool containing water-insoluble non-steroidal anti-inflammatory drugs.

Claims (7)

CLAIM 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 and Ν-methylpyrrolidone, and meloxicam is in as a true solution with the components of the base. 2. The external agent according to claim 1, characterized in that the pharmaceutically acceptable base further comprises ethanol in an amount of up to 60 wt.%. 3. The external tool according to claim 1 or 2, characterized in that it is made in the form of a gel. 4. The 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 Ν-methylpyrrolidone is in an amount of from 2.0 to 30 wt.%. 6. The 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 for treating diseases of joints and soft tissues according to claim 1 or 2, characterized in that it is in the form of a gel and contains meloxicam, Ν-methylpyrrolidone, ethanol, carbomer, trometamol, water and, if necessary, perfumes, such as neroli oil and / or lavender oil, in the following ratio, g / 100 g: Meloxicam 1,000. Excipients: Ν-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.