RU2593777C1 - Gel form of nimesulide possessing anti-inflammatory and analgesic action - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention refers to medicine, particularly to pharmaceutical composition of nimesulide in gel form, having anti-inflammatory and analgesic action. Composition contains nimesulide in amount of 1 wt% and excipients: N-methylpyrrolidone, propylene glycol, carbomer, isopropyl alcohol, macrogol 400, trometamol, purified water.

EFFECT: invention implementation allows to enhance anti-inflammatory and analgesic effect, as well as reducing time and labour intensity of manufacturing process of preparation.

1 cl, 7 tbl, 9 dwg

Description

The invention relates to medicine, in particular to the pharmaceutical industry, and describes a dermal pharmaceutical composition in the form of a gel for topical use, including nimesulide and having a pronounced anti-inflammatory and analgesic effect.

Musculoskeletal pathology is attracting more and more attention of the world scientific community in connection with its widespread prevalence. WHO reports that joint pain is noted in 30% of the population. Diseases of the joints and spine occupy the 4th place in prevalence, skipping ahead only the pathology of blood circulation, respiration and digestion. Perhaps the most common symptom that forces the patient to go to the pharmacy for help is joint pain. Joint diseases are particularly relevant in connection with an increase in human life expectancy. According to epidemiological studies, joint pathology in people over the age of 40 years is noted in 50% of cases, and over 70 years in 90% of the population. About 80% of all the inhabitants of the planet experience pain in the lower back at some point in their life [NSAIDs for local use: a rational choice for joint and muscle pain / Kvitchataya AI, Yakushchenko VA, Gubchenko TD // Pharmacy - 2013. - No. 22 (893)].

Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used to treat a wide range of diseases accompanied by inflammation and pain, occupying one of the leading places in the frequency of destination and the volume of world sales [Nasonov E.L. Non-steroidal anti-inflammatory drugs (Prospects for use in medicine) - M .: Anko, 2000. - 262 p.]. Every year in the world, drugs of this group are used in 60 million outpatients and in 20% of inpatients [Nasonov E.L. Nonsteroidal anti-inflammatory drugs for rheumatic diseases: treatment standard // Russian Medical Journal. - 2001. - T. 9, No. 7-8. - S. 265-268; Brooks P.M., Day R.O. Non-steroidal anti-inflammatory drugs - differences and similarities // N. Engl. J. Med. - 1991. - Vol. 324. - P. 1716-1725]. According to various statistics, about 40% of elderly people are forced to take NSAIDs, while many of them are almost constantly due to chronic pain.

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 pharmacology of inflammation / Ed. I.L. Bonta, M.A. Bray, M.J. Parnham. - Amsterdam, New York, Oxford, 1985. - 465 p.]. The discovery of two isoforms of cyclooxygenase (COX) - the “physiological” COX-1 and the “pro-inflammatory” COX-2 [11, 12, 13] - has opened new prospects for increasing the safety of NSAID therapy by creating drugs based on selective COX-2 inhibitors, including Nimesulide belongs.

The ability of nimesulide (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 [Balabanova P.M. Nimesulide is an anti-inflammatory drug with selective inhibition of COX-2 // Russian Medical Journal. - 2001. - T.9, No. 7-8. - S. 291-294].

Nimesulide is a well-studied COX-2 selective NSAID. Based on numerous data on high therapeutic efficacy combined with good tolerance, nimesulide 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 world nomenclature of nimesulide preparations includes tablets, granules, suspension, rectal suppositories, as well as a gel dosage form for external use.

Local nimesulide gel therapy, like other NSAIDs, is widely used for localized rheumatic diseases, arthrosis of peripheral joints and spine, periarthropathy, traumatic inflammation of tendons, ligaments, muscles and joints, and the inability to take orally. In addition, local therapy of NSAIDs can reduce the frequency and severity of systemic adverse reactions, which is especially important in elderly patients [Kashevarova N.G., Alekseeva L.I. Local therapy of osteoarthrosis // Scientific and practical rheumatology. - 2006. - No. 2. - S. 22-30].

The following are known from the prior art, registered in the Russian Federation, gel-based nimesulide drugs:

- Nise ^® - manufacturer Dr. Reddy's Laboratories Ltd. (India); reg. number P N012824 / 02 of 06/20/2008;

- Nimulide - manufacturer Panacea Biotek Ltd (India); reg. number P N011525 / 04 of 10.16.2008;

- Sulaydin - manufacturer Embil Pharmaceutical Co. Ltd. (Turkey); reg. number LP-000173 dated 01/14/2011.

The most effective and widely available medicinal product containing nimesulide in the form of a gel for topical application on the Russian market is Nise ^® gel for external use 1% manufactured by Dr. Reddy's Laboratories Ltd. (India). This drug contains 1% nimesulide on a complex multicomponent cream-gel base. The drug Nise ^® gel for external use 1% is available in aluminum tubes of 20 and 50 g.

The drug Nise ^® gel for external use 1% contains the following components, mg / g:

Components Mg / g Nimesulide 10.0 N-methyl-2-pyrrolidone 250,0 Propylene glycol 100.0 Macrogol 315.5 Isopropanol 100.0 Purified water 200,0 Carbomer 940 20,0 Butylhydroxyanisole 0.2 Thiomersal 0.1 Potassium dihydrogen phosphate 0.2 Fragrance (Narcissus-938) 4.0

Thus, at present, there is a need to develop a gel dosage form of nimesulide, which allows to expand the arsenal of non-steroidal anti-inflammatory drugs of domestic production.

The technical task of the present invention is to expand the list of domestic drugs.

To achieve this goal, the authors of the present invention attempted to develop an analogue drug - Nimesulide gel for external use 1% (the drug under development), which would not be inferior to the innovative drug - Nise ^® gel for external use 1% in efficiency, safety and quality indicators ( Dr. Reddy's Laboratories Ltd., India) (reference drug, reference drug).

The leading pharmacopeias do not describe the dosage form of nimesulide.

The compatibility of nimesulide with excipients and its stability in the preparation of Nimesulide gel for external use of 1% is confirmed by the results of long-term stability studies for 12 months, accelerated stability studies for 6 months and extrapolation of test results using the upper and lower limits of acceptability in terms of "Quantitative content . Nimesulide "," Quantitative content. Isopropyl alcohol "," Quantitative content. N-methylpyrrolidone ", as well as using the upper limit of acceptability for the indicator" Impurities ".

A preparation was developed with the following content of components.

Table 1 shows the functional purpose of the auxiliary substances that make up the developed drug Nimesulide gel for external use 1%.

All excipients included in the preparation are widely used in pharmacy and in cosmetic preparations [Pharmaceutical Excipients / Edited by: Raymond C. Rowe, Paul J. Sheskey and Siân C. Owen. - London: Pharmaceutical Press. Electronic version, 2006 .; Handbook of Cosmetic Science and Technology / Andre O. Barel, Marc Paye, Howard I. Maibach: Marcel Dekker, Inc. - New York-Basel, 2001. - 903 p.].

In the preparation Nimesulide gel for external use, excipients N-methylpyrrolidone and isopropyl alcohol have a 1% antimicrobial effect.

The composition of the Nise ^® gel for external use 1% contains the antimicrobial preservative thiomersal. It is known that thiomersal, in addition to the preserving and antimicrobial action that prevents the growth of bacteria and fungi, is a compound containing mercury. Mercury has a toxic effect on the nervous, digestive and immune systems, as well as on the lungs, kidneys, skin and eyes. Thus, the use of thiomersal as an additional preservative to the authors of the present invention seems inappropriate.

The antimicrobial preservative effect of the drug Nimesulide gel for external use of 1%, containing N-methylpyrrolidone and isopropyl alcohol at the lower limit specified in the specification: 225 mg and 90 mg in 1 g of the drug, respectively, was investigated. This approach to the study of the effectiveness of antimicrobial preservatives is in line with EU standards [EMEA / CHMP / QWP / 396951/2006. - Guideline on Excipients in the Dossier for Application for Marketing Authorization of a Medicinal Product, 2007].

The research results are presented in table 2.

As follows from the results of studies on the effectiveness of antimicrobial preserving action, the developed drug exceeds the requirements of criterion A EF 7.0. (5.1.3) and the requirements of Article 34 (OFS 42-0069-07) “Determining the Effectiveness of Antimicrobial Preservatives of Medicines” of the RF Civil Fund of the XII Edition [European Pharmacopoeia 7th Edition. - Strassbourg: European Directorate for the Quality of Medicines & Health Care (EDQM) - Council of Europe, 67075 Strasbourg Cedex, France 2010. - Vol. 1., Vol. 2. - 3536 p .; State Pharmacopoeia of the Russian Federation. - M.: Publishing House "Scientific Center for Expertise of Medical Applications", 2008. - 704 p.].

Also, when developing a drug in order to predict its therapeutic equivalence with respect to a reference drug, the authors of the present invention carried out a comparison and assessment of the specific types of action and harmlessness of the developed drug and the reference drug.

Thus, in the study of osmolality, the authors of the present invention found that due to the content of hydrophilic non-aqueous solvents, the new drug is hypertonic; its freezing temperature is below -10 ° C, as a result of which the measurement of osmolality with a milliosmometer-cryostat becomes impossible.

The hypertonic properties of the drug provide its osmotic activity, which is manifested in the absorption of water by the drug through a semipermeable membrane in in vitro experiments [Guidelines for the experimental (preclinical) study of drugs for local treatment of wounds / B.M. Datsenko, SV. Biryukova, T.I. Tamm et al. - M .: Ministry of Health of the USSR, 1989. - 47 p.], As a result of which the mass of the chamber with the drug increases. The direction of this process is the opposite of the diffusion of substances into the chamber with water.

As can be seen from the data presented in FIG. 1 and table 3, according to the osmotic properties (kinetics of water absorption and mass of absorbed water), the developed drug Nimesulide gel for external use 1% is almost identical to the reference drug - Nise ^® gel for external use 1%.

When studying acute toxicity, it was found that the drug Nimesulide gel for external use of 1% with cutaneous use in rats at a dose of 3 g / kg in the dosage form does not cause the death of experimental animals and does not affect their general condition and behavior. According to the clinical symptoms of animal intoxication, the studied parameters and the level of acute toxicity, Nimesulide gel for external use 1% corresponds to the reference drug Nise ^® gel for external use 1%.

Based on the results of the pathomorphological study, it was found that the studied and reference preparations do not lead to the development of visualized changes in appearance, do not affect the relative mass of the internal organs of rats. In isolated cases, both drugs at a dose of 0.45 g / kg cause signs of hepatotoxicity and gastrotoxicity.

The drug Nimesulide gel for external use 1% and the reference drug Nise ^® gel for external use 1% do not exhibit a locally irritating effect.

In addition, the specific pharmacological activity of the studied and reference drugs in accordance with the spectrum of their pharmacological properties and indications for use was studied by indicators of anti-inflammatory and analgesic effects.

As a result of this research, the present inventors have found that despite the absence in the developed preservative drug, thiomersal and butylhydroxyanisole contained in a preparation Naiz ^® gel for topical application of 1%, it was possible to achieve effective antimicrobial preservative action, surpassing the requirements of criterion A Ph.Eur 7.0 . (5.1.3) and the requirements of Article 34 (OFS 42-0069-07) “Determining the effectiveness of antimicrobial preservatives of medicines” of the RF Civil Fund of the XII edition, as well as subject to the developed composition, an unexpected effect was achieved consisting in a significant increase in anti-inflammatory and analgesic effect, relative to the reference drug.

This result was established experimentally in the study of this effect in rats as a result of carrageenin and traumatic inflammation of the foot.

Carrageenin inflammation of the foot

Studies were carried out on 24 rats weighing 135-210 g (average 165 g). Preparations Nimesulide gel for external use 1% and Nise ^® gel for external use 1% were applied to the skin of the foot of 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, which, taking into account the average weight of the rats (165 g), was ~ 12 mg / kg calculated on the basis of nimesulide.

Exudative edema was caused 30 minutes after the first application of the preparations by subplantation injection into the right hind foot of rats of 0.08 ml of a 0.5% aqueous carrageenin solution.

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 hour, 3 hours (at the peak of edema) [Ferreira S.H. Prostaglandin hyperalgesia and the control of inflammatory pain // In: The pharmacology of inflammation / Ed. I.L. Bonta, M.A. Bray, M.J. Parnham. - Amsterdam, New York, Oxford, 1985. - P. 110.] and 5 hours after the injection of phlogistics on an electronic plethysmometer (mod. 7150, Hugo Basile, Italy). The anti-inflammatory effect was calculated by the formula:

where _k and ΔV ΔV _o - average increase in foot volume of edematous experimental and control (untreated) groups, respectively.

The threshold of pain sensitivity (PBC) was recorded 1, 3, and 5 hours after the phlogistic injection by the Randall-Selitto method with mechanical pain irritation with an analgesimeter (Hugo Basile, Italy; mod. 7200). The analgesic effect was calculated by the increase in the LBC in rats to which the compared preparations were applied, compared with the control untreated animals, calculated by the formula:

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

Traumatic inflammation of the foot.

Studies were conducted on 27 anesthetized rats weighing 130-240 g (an average of 180 g). Traumatic inflammation was caused by the impact of a load of 500 g, freely falling from a height of 40 cm onto the plantar surface of the right hind foot of rats (under the strict condition of ankle joint damage).

The preparations Nimesulide gel for external use 1% and Nise ^® gel for external use 1% were applied to the right hind (inflamed) foot of rats 2 times a day every day in a single dose of 100 mg gel / foot for 9 days (until the edema regressed completely). The total amount of gel applied per day to a rat is 200 mg, which, taking into account the average weight of the rats (180 g), was ~ 11 mg / kg based on nimesulide. The first application of drugs was performed 2 hours after the injury.

Foot volume was measured before (baseline), 2 hours after the injury and then every day 1 time per day using an electronic plethysmometer (mod. 7150, Hugo Basile, Italy). The anti-inflammatory effect was evaluated as described above, calculated by the formula I.

Analgesic activity was assessed by the Rendall-Selito method, as described above, PBC was recorded on the 1st, 3rd and 7th day of treatment, the analgesic effect was calculated by formula II.

The total anti-inflammatory and analgesic effects of the compared drugs were also calculated as the area under the time-effect curves.

Research results for carrageenin inflammation of the foot

Subplant implantation of carrageenin solution leads to the development of acute inflammatory exudative edema, which in untreated rats reaches a maximum by 3 hours. It is known that in the first 10-20 minutes, mast cells are degranulated and histamine and serotonin are released, within 1-2 hours the development of edema is supported by bradykinin and other kinins accumulating in the focus of inflammation, by the 3rd hour - prostaglandins [Trinus F. P., Mohort N.A., Klebanov B.M. Nonsteroidal anti-inflammatory drugs. - Kiev, 1975. - S. 208-209]. Thus, in the first 3 hours, the pathogenesis of carrageenan inflammation includes all the main mediators of pain and inflammation, which are directed to the effect of the studied pharmacological correctors.

The data of table 4 and FIG. 2 indicate that a 2-fold cutaneous application of both Nimesulide gel for external use of 1% and Nise ^® gel for external use of 1% has a pronounced anti-inflammatory effect, which is manifested in a decrease in the increase in the volume of the inflamed foot of rats compared with untreated control.

After 1 hour, the increase in the volume of the inflamed foot in the groups of treated rats reached significant differences with untreated control; the significance of differences with control remained throughout the observation period (up to 5 hours). There were no significant differences between the groups treated with Nimesulide gel for external use 1% and Nise ^® gel for external use 1%.

The anti-inflammatory effects of Nimesulide gel for external use of 1% and Nise ^® gel for external use of 1% by 1 hour, being equally expressed, were, respectively, 29.6% and 29.0%. In the future, the activity of the drug Nimesulide gel for external use of 1% increased slightly (by 3 hours - up to 35.0%, by 5 hours - up to 38.3%), while the effect of the drug Nise ^® gel for external use of 1% remained on that the same level, making up by 3 hours 26.6%, by 5 hours - 29.6% (table 4, Fig. 3).

The total anti-inflammatory effect, calculated as the area under the "time-effect" curve of the drug Nimesulide gel for external use of 1%, was 152.7, which is 20.9% more than the corresponding parameter of the drug Nise ^® gel for external use 1% - 126.3 .

Double application of Nimesulide gel for external use of 1%, as well as Nise ^® gel for external use of 1%, also has an analgesic effect, which manifests itself in an increase in the CBP of the inflamed foot of rats with its mechanical compression (table 5, Fig. 4).

The analgesic effect of the drug Nimesulide gel for external use of 1% after 1 hour after application was 39.1%, decreasing by 3 hours to 26.1% and lasting up to 5 hours - 26.8%. The analgesic effect of the drug Nise ^® gel for external use of 1%, being equally expressed after 1 hour with that of the drug Nimesulide gel for external use of 1% (34.7%), then decreases somewhat faster, reaching 19.3% by 3 hours, by 5 o'clock - 12.2% (table 5, Fig. 4).

The total analgesic effect, calculated as the area under the "time-effect" curve (Fig. 5) of Nimesulide gel for external use of 1% was 137.7, which is 33.8% higher than that of Nise ^® gel for external use 1% - 102.9.

The results of a study in traumatic inflammation of the foot of rats

Injury to the hind foot of rats is accompanied by the rapid development of inflammatory edema with a significant reduction in the TBC with mechanical pressure on the injured foot (Rendall-Selitto test). Traumatic edema of the foot of rats is characterized by rapid development, its maximum growth is recorded 2 hours after injury and is about 0.57 ml (table 6, Fig. 6). In the group of control untreated rats, a gradual, relatively slow regression of edema is subsequently observed. Complete normalization of the volume of the injured foot occurs in these animals on days 11-12.

The data in Table 6 and FIG. 6 indicate that the preparations Nimesulide gel for external use 1% and Nise ^® gel for external use 1%, applied to the surface of the foot of rats in a daily dose of 200 mg / foot, have a gradually developing anti-inflammatory effect. By 3 days, the increase in foot edema in the experimental groups reaches significant differences with the control in the absence of significant differences between the experimental groups

The severity of the anti-inflammatory effect in both groups increases gradually, amounting to 15.8% and 7.7% on the 2nd day of treatment, 30.6% and 32.7% on the 3rd day, 51 on the 4th day, 5% and 47.0%, on the 5th day - 61.5% and 60.9%, on the 7th day - 74.5% and 68.9%, respectively. In the future, the effect of the drug Nimesulide gel for external use 1% continues to increase, making up on the 8th day - 78.1%, on the 9th day - 85.7%, while the activity of the drug Nise ^® gel for external use 1% is maintained at the same level, accounting for 68.8% on the 8th day, and 65.7% on the 9th day (Fig. 7).

The total anti-inflammatory effect, calculated as the area under the time-effect curve (Fig. 7), for Nimesulide gel for external use, 1% was 365.7, which generally corresponds to the value of Nise ^® gel for external use, 1% - 322 , 4 (the differences are about 13%).

The developed drug Nimesulide gel for external use of 1%, as well as the comparison drug, with daily applications on the surface of the foot of rats has an analgesic effect consisting in an increase in the PBH of the injured foot of rats compared with untreated control, which was most pronounced on the 3rd day of treatment (Fig. 8, table 7).

As the data in FIG. 8 and Table 7, a day after injury to the inflamed foot, the BPH in the untreated control group was 93.8 ± 15.2 g, which did not significantly differ from that in rats treated with Nimesulide gel preparations for external use 1% (117.5 ± 14.1 g) and Nise ^® gel for external use 1% (80.0 ± 17.5 g).

The analgesic effect of Nimesulide gel for external use of 1% on day 3 was 96.1%, which is slightly higher than the activity of the Nise ^® gel for external use of 1% (79.8%), on day 7 the effects of the compared drugs were equally pronounced: 56, 7% and 55.1%, respectively (table 7, Fig. 9).

The total analgesic effect, calculated as the area under the time-effect curve (Fig. 9), for Nimesulide gel for external use, 1% was 438.8, which is 25.5% more than the corresponding indicator for Nise ^® gel for external use 1% - 349.6.

Thus, the authors of the present invention, when developing the drug Nimesulide gel for external use of 1%, obtained an unexpected anti-inflammatory and analgesic effect, significantly exceeding the same indices of the reference drug.

The authors also managed to significantly reduce the time and laboriousness of the preparation of the drug Nimesulide gel for external use of 1% compared with analogues. Reducing the duration of the process is the use of carbomer Carbopol ^® Ultrez 10 Polymer, which reduces wetting time carbomer with 4 hours (drug-analogues) to 3-5 minutes and reduces clumping when administered hydrophilic non-aqueous solvents.

The drug Nimesulide gel for external use 1% contains the following components,%:

This invention solves the problem of expanding the arsenal of non-steroidal anti-inflammatory drugs of domestic production, is new, industrially applicable, which is achieved due to the uniquely selected composition of excipients obtained experimentally.

The production technology of the drug is developed taking into account the properties of the components included in its composition, and the properties of the drug as a dispersed system. Given the properties of the components, the following main processes can be distinguished during the production of the drug:

- wetting the gelling agent with part of the purified water, introducing propylene glycol and macrogol 400 and preparing a dispersion;

- dissolution of nimesulide in N-methylpyrrolidone;

- dissolution of lavender oil in isopropyl alcohol;

- preparation of a solution of trometamol in part of purified water;

- the introduction of a solution of trometamol;

- the introduction of a solution of lavender oil in isopropyl alcohol in the dispersion of carbomer;

- the introduction of a solution of nimesulide in N-methylpyrrolidone;

- unloading bulk gel from the homogenizing reactor and transporting it to the hopper of the tube filling machine;

- dosing of gel into tubes.

In more detail, the production process of the drug Nimesulide gel for external use of 1% is as follows:

- Part of the purified water and carbomer are loaded into the reactor. A uniform dispersion of carbomer is prepared, then propylene glycol and macrogol 400 are charged and mixed until a homogeneous mass is obtained.

- Next, in the reactor, the carbomer is neutralized with a pre-prepared solution of trometamol. Get a gel-like mass.

- Then pre-dissolved essential oil in isopropyl alcohol is charged. Stir until a homogeneous mass.

- Then, the previously dissolved nimesulide in N-methylpyrrolidone is loaded into the resulting mass, homogenized and vacuum.

- The resulting gel is discharged and dosed into tubes.

Claims (1)

The gel form of nimesulide with anti-inflammatory and analgesic effects, containing nimesulide in an amount of 1 wt.% And excipients, characterized in that it has the following content of components in wt.%:
Nimesulide 1.00 N-methylpyrrolidone 25.00 Propylene glycol 10.00 Carbomer (Carbopol® 1.20 Ultrez 10 Polymer) Isopropyl alcohol 10.00 Macrogol 400 31.55 Lavender oil 0.25 Trometamol 0.09 Purified water Up to 100.00

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