EP1879565A2

EP1879565A2 - Topical pharmaceutical formulation containing nimesulide

Info

Publication number: EP1879565A2
Application number: EP06705758A
Authority: EP
Inventors: Jitka Fortova; Zdenka Mrvova; Pavlina Kristenova
Original assignee: Zentiva KS
Current assignee: Zentiva KS
Priority date: 2005-04-06
Filing date: 2006-04-06
Publication date: 2008-01-23
Also published as: CZ297215B6; WO2006105741A2; WO2006105741B1; WO2006105741A3; CZ2005214A3; EA200702171A1

Abstract

The topical pharmaceutical formulation containing nimesulide contains a hydration agent, preferably propyleneglycol, a non-ionic surface-active substance and optionally other pharmaceutically acceptable additives.

Description

TOPICAL PHARMACEUTICAL FORMULATION CONTAINING NMESULIDE

Technical Field

The invention concerns a new pharamceutical formulation containing the analgetic and antirheumatic active substance nimesulide in the form of a gel.

Background Art

Nimesulide - chemically N-(4-nitro-2-phenoxyphenyl)-methanesulfonamide - the substance of formula I

I

is a known non-steroidal anti-inflammatory active substance, which is used as an analgetic, antirheumatic, or against other types of inflammations in systemic parmaceutical formulations, especially oral ones (tablets), but also in the topical form, wherein it is possible to influence the inflamed spot directly, with minimal influence on the whole organism. This reduces some undesirable effects, which are typical for non-steroidal anti-inflammatory drugs.

Generally, the topical forms can be distinguished as those oil-based (lipophilic) and hydrophilic topical forms. Another division recognizes pharmaceutical formulations wherein the active substance is in a solution or wherein it is in a dispersion.

In the case of nimesulide, it has proved more advantageous to use dispersion formulations. The reasons include, inter alia, the fact that a nimesulide solution strongly stains the skin, which can result in various problems for the patient. Oil-based dispersion systems were described in patent EP 782855 Bl . The published methods resulted in preparation of ointments, creams and oil gels.

Compared to oil-based preparations, the hydrophilic bases have the advantage that they do not grease and, therefore, do not contaminate the skin and have cooling effect on the inflamed spot, which further improves the anti-inflammatory effect and good taking of the drug by the patient. A formulation in the form of a hydrophilic gel has been described in patent EP 971708 Bl. This formulation is based on a skin penetration enhancer, which can be a lower alcohol such as ethanol or isopropanol or, preferably, diethyleneglycol monethylether. The composition further contains a high amount of water (above 40 %), a weak base and a gel base. Such composition ensures good penetration of the active substance through the skin and the above-mentioned cooling effects. However, its disadvantages include relatively frequent skin irritation, which can lead to various skin symptoms upon frequent use, such as urticaria, erythema and the like. Skin irritation works against the cooling effect and after some time from application, unpleasant itchy feeling prevails.

Disclosure of Invention

The above drawbacks have been removed by the hydrophilic composition according to the present invention. The active substance nimesulidum is suspended in a topical gel with addition of propyleneglycol and a non-ionic surface-active substance. The water-miscible solvent propyleneglycol and the surface-active substance create a system that ensures penetration of nimesulide through the skin, and thus, it ensures efficacy of the healing substance in the spot of application. In addition, propyleneglycol in the concentration used acts on the skin as an effective hydration agent and the surface-active substance by its nature helps the active substance to pass through the lipidic barrier of the top skin layers.

The subject matter of the invention includes a topical pharmaceutical formulation containing nimesulide, a hydration agent, a non-ionic surface-active substance and optionally other pharmaceutically acceptable additives.

This formulation ensures the same rate of skin penetration as the hitherto known formulas, but it decreases the possibility of skin irritation due to influence of the hydration agent. The hitherto known hydrophilic gel formulation of nimesulide is based on a skin penetration enhancer, which is a lower alcohol such as ethanol, isopropanol or, preferably, diethyleneglycol monoethylether. These organic substances have been known for long time for their fast penetration through the skin whereas in a suitable formulation, they carry along also the respective healing substance. However, fast skin penetration is associated with other effects on the skin. Usually, good solvents are used which also wash out and carry away the substances that make up the natural surface of the skin. They cause for example skin drying, its irritability or increased sensitivity to external effects (such as sun etc.). That is why there has been a lot of effort to find substances that would be gentler to the skin while being also effective with respect to enhancing skin penetration.

Therefore, the choice has led towards hydrophilic substances such as glycerol, which are gentle to the skin, but, on the other hand, they are not as effective with respect to enhancing penetration of the active substance as the prior enhancers. Surprisingly, it has turned out that if these types of substances are combined with non-ionic surface-active substances, their effect increases in the case of nimesulide so that they are equivalent to the prior substances. The surface-active agent has also another function in the composition, i.e. to form a stable suspension of nimesulide.

The amount of the active substance nimesulide in the composition according to the invention ranges from 0.5 to 20 w.%.

Preferably, liquid polyalcohols such as glycerol or propyleneglycol can be used with advantage as hydration substances, propyleneglycol being preferred. Their amounts are selected from the range of from 5 to 70 w.%, preferably more than 10 w.%.

The non-ionic surface-active substance is preferably selected from the group including macrogolglycerol-hydroxystearate, polysorbate, stearomacrogol or isosorbide dimethyl ether. Its amounts are selected from between 1 to 10 w.%. For a successful formulation, weight ratios of both main constituents are important. The hydration substance is always chosen in an excess of from 2:1 to 10:1. Advantageous ratios range from 4:1 to 6:1.

As the above mentioned suggests, combination of polyalcohols and non-ionic surface-active substances can result in achieving the effect of enhanced penetration through the skin.

The invention is further demonstrated using the following examples.

Examples

Example 1 :

Composition: weight %

(1) Nimesulide 3.00 g

(2) Methyl parahydroxybenzoate o.25 g

(3) Propyl parahydroxybenzoate o.12 g

(4) Disodium edetate 0.10 g

(5) Macrogolglycerol hydroxystearate 5.00 g

(6) Propyleneglycol 20.00 g

(7) Carbomer 1.00 g

(8) Trolamine 0.52 g

(9) Water, purified 70.01 g

Disodium edetate (4) was dissolved in purified water (9) at temperature of 25 °C under stirring with a low-speed mixer and then, the gel-producing substance of acidic nature, the carbomer (7), was suspended in the solution using a high-speed homogenizer of the stator-rotor type at 3000 RPM. Adding an adequate amount of the neutralizing agent trolamine (8), the carbomer was neutralized under intensive homogenization and in vacuo producing a clear gel. In a separate vessel, two preservative substances, methylparabene (2) and propylparabene (3) were dissolved in propyleneglycol (6) at 25 °C under intense stirring with a propeller stirrer and micronized active agent nimesulidum (1) was suspended in their solution. This suspension of (6), (2), (3), and (1) was mixed homogeneously into the ready carbopol gel of (9), (7), and (8) in vacuo using a high-speed homogenizer and finally, the surface-active substance, macrogolglycerol hydroxystearate (5), was mixed into the gel in vacuo. A homogeneous gel was obtained via final homogenization in vacuo by means of a high-speed homogenizer of the stator-rotor type at 3000 RPM.

Example 2:

Composition: Weight %

(1) Nimesulide 3.00 g

(2) Methyl parahydroxybenzoate o.25 g

(3) Propyl parahydroxybenzoate o.12 g

(4) Disodium edetate 0.10 g

(5) Macrogolglycerol hydroxystearate 7.00 g

(6) Glycerol 30.00 g

(7) Carbomer 1.00 g

(8) Trolamine 0.52 g

(9) Water, purified 58.01 g

Component (4) was dissolve in (9) and component (7) was then suspended in this solution.

With addition of an adequate amount of component (8), component (7) was neutralized producing a clear gel.

Components (2) and (3) were dissolved in component (6) and component (1) was suspended in their solution. This suspension of (6), (2), (3), and (1) was admixed homogeneously into the ready gel in vacuo and finally, component (5) was mixed into the gel in vacuo.

A homogeneous gel was obtained via final homogenization in vacuo.

Example 3:

Composition: Weight %

(1) Nimesulide 3.00 g

(2) Methyl parahydroxybenzoate o.25 g

(3) Propyl parahydroxybenzoate o.12 g (4) Disodium edetate 0.10 g

(5) Polysorbate 80 6.50 g

(6) Propyleneglycol 25.00 g

(7) Carbomer 1.00 g

(8) Trolamine 0.52 g

(9) Water, purified 63.51 g

Component (4) was dissolved in (9) and then, component (7) was suspended in the solution. With addition of an adequate amount of component (8), component (7) was neutralized producing a clear gel. Components (2) and (3) were dissolved in component (6) and component (1) was suspended in their solution. This suspension of (6), (2), (3), and (1) was admixed into the ready gel in vacuo and finally, component (5) was mixed into the gel in vacuo. A homogeneous gel was obtained via final homogenization in vacuo.

Example 4:

Composition: Weight %

(1) Nimesulide 3.00 g

(2) Methyl parahydroxybenzoate o.25 g

(3) Propyl parahydroxybenzoate o.12 g

(4) Disodium edetate 0.10 g

(5) Polysorbate 80 7.00 g

(6) Glycerol 35.00 g

(7) Carbomer 1.00 g

(8) Trolamine 0.52 g

(9) Water, purified 53.01 g

Component (4) was dissolved in (9) and then, component (7) was suspended in the solution. With addition of an adequate amount of component (8), component (7) was neutralized producing a clear gel.

Components (2) and (3) were dissolved in component (6) and component (1) was suspended in their solution. This suspension of (6), (2), (3), and (1) was admixed into the ready gel in vacuo and finally, component (5) was mixed into the gel in vacuo. A homogeneous gel was obtained via final homogenization in vacuo.

Example 5:

Composition: Weight %

(1) Nimesulide 3.00 g

(2) Methyl parahydroxybenzoate o.25 g

(3) Propyl parahydroxybenzoate o.12 g

(4) Disodium edetate 0.10 g

(5) Stearomacrogol 1050 5.50 g

(6) Propyleneglycol 27.00 g

(7) Carbomer 1.00 g

(8) Trolamine 0.52 g

(9) Water, purified 62.51 g

Example 6:

Composition: Weight %

(1) Nimesulide 3.00 g

(2) Methyl parahydroxybenzoate o.25 g

(3) Propyl parahydroxybenzoate o.12 g

(4) Disodium edetate 0.10 g

(5) Stearomacrogol 1050 6.00 g

(6) Glycerol 37.00 g

(7) Carbomer 1.00 g (8) Trolamine 0.52 g

(9) Water, purified 52.01 g

Example 7:

Composition: Weight %

(1) Nimesulide 3.00 g

(2) Methyl parahydroxybenzoate o.25 g

(3) Propyl parahydroxybenzoate o.12 g

(4) Disodium edetate 0.10 g

(5) Isosorbid dimethyl ether 5.00 g

(6) Propyleneglycol 20.00 g

(7) Carbomer 1.00 g

(8) Trolamine 0.52 g

(9) Water, purified 70.01 g

Component (4) was dissolved in (9) and then, component (7) was suspended in the solution.

Components (2) and (3) were dissolved in component (6) and component (1) was suspended in their solution. This suspension of (6), (2), (3), and (1) was admixed into the ready gel in vacuo and finally, component (5) was mixed into the gel in vacuo.

A homogeneous gel was obtained via final homogenization in vacuo. Example 8

In this Example, experimental evaluation of permeation potential of nimesulide from submitted 2 samples according to the invention and commercially available preparation Aulin gel is described. The task was solved in vitro using excided human skin and conditions imitating occlusive application. The basic and most information-comprehensive characteristic, which is, in similar cases, usually used to compare topical bio-equivalency, is represented by the value of flux J [mg/cm².^¹] of the drug through skin grafts. Determining their values for nimesulide did not pose any analytical problems in this particular case. The HPLC method used for determining nimesulide has turned out to be completely satisfactory.

Results are presented in the following table

Considering permeation of nimesulide, the gels prepared according to Examples 1 and 7 can be, in the given experimental arrangement, considered identical with the commercially available preparation AULIN® with 95% reliability.

In the following examples, where very low incidence of undesirable irritating effects on the skin is demonstrated, the preparation prepared according to the Example is called Coxtral gel; the gel prepared only from auxiliary substances, i.e. according to Example 1 but without the presence of nimesulide, is called placebo of Coxtral gel, or simply placebo. Aulin gel is the name of the gel preparation containing nimesulide registered in the Czech Republic, i.e. of the representative of the most relevant prior art.

Example 9

Test of skin irritability after a single application in rabbits The goal of the study was to determine skin irritability of nimesulide in rabbits after a single local application of the tested Coxtral gel. Placebo of Coxtral gel was used as a reference preparation. Three healthy albinoic rabbits (New Zealand White) with intact skin were included in the study. Coxtral gel and the placebo of Coxtral gel were applied locally at 0.5 g to shaved intact and/or shaved abraded skin. Local response and symptoms of erubescence and swelling were examined 24, 48 and 72 hours after application. No irritation or other changes of the skin were observed and indices of primary irritation of the tested Coxtral gel and of the placebo were zero. The potential of Coxtral gel to irritate skin was therefore evaluated as insignificant.

Example 10

Test of skin irritability after repeated application in rabbits

The goal of the study was to determine skin irritability in rabbits after repeated local application of the tested Coxtral gel. Placebo of Coxtral gel was used as a reference preparation. Three healthy albinoic rabbits (New Zealand White) with intact skin were included in the study. The preparations were repeatedly applied (in 24-hour intervals for 28 days) locally at 0.5 g to shaved intact and/or shaved abraded skin. Local response and symptoms of erubescence and swelling were examined 24 hours after previous application; the last inspection was performed 72 hours after the last application. No irritation or other changes of the skin were observed and indices of cumulated irritation of the tested Coxtral gel and placebo were zero. The potential of Coxtral gel to irritate skin was evaluated as insignificant.

Example 11

The study of skin sensitization (allergization) in guinea-pigs

The goal of the study was to determine potential of skin sensitization after repeated local application of thetested Coxtral gel. Testing was performed using 30 healthy adult guinea- pigs, which were randomly divided into two groups: tested (n=20, application of Coxtral get) and control (n=10, application of placebo of Coxtral gel). After five-day acclimatization, Coxtral gel or alternatively placebo of Coxtral gel were applied three times within the induction phase (days 0, 7 and 14); during the second phase, Coxtral gel was applied once to all animals (day 28) and during the final phase, skin reaction was evaluated twice using the Magnusson and Kligman scale. Health was monitored daily, skin changes were examined always six hours after the application of the gel and body weight was determined in days 0 and 31. No impact on health nor body weight was recorded in any group of the tested animals. During testing of locally applied Coxtral gel, no visible skin changes were observed in any group of animals. Coxtral gel did not cause any allergic reactions and it was, therefore, classified according to ,,The Classification of the Skin Sensitization Potential" as non- allergizing.

Example 12

Clinical evaluation

Clinical evaluation of analgetic and anti-inflammatory potency and tolerance of locally applied nimesulide was organized as multicentric, comparative, parallel, randomized, double-blind evaluation. The goal of the study was to prove equivalence of the tested Coxtral gel compared to the reference Aulin gel in the sense of non-inferiority. The study included 240 patients with painful acute dull injuries of the motional organs and soft tissues, who were randomly divided into two treatment groups of 120 patients and treated with the tested or reference preparation. Coxtral and Aulin gel, resp., were applied to the afflicted spot three times a day for seven days. During the study, only the total of four undesirable effects were recorded in three patients. No serious undesirable effects were observed. Occurrence of undesirable effects and their characteristics are comparable in the two groups.

Claims

C L A I M S

1. A topical pharmaceutical formulation containing nimesulide, characterized in that it contains a hydration agent, a non-ionic surface-active substance and optionally other pharmaceutically acceptable additives.

2. The topical pharmaceutical formulation according to claim 1, characterized in that the hydration agent is a polyalcohol, preferably propylene-glycol or glycerol.

3. The pharmaceutical formulation according to claim 1 or 2, characterized in that it contains 0.5 to 20 weight % of nimesulide, 5 to 70 weight % of the hydration agent and

1 to 10 weight % of the non-ionic surface-active substance.

4. The pharmaceutical formulation according to claim 3, characterized in fact that it contains more than 10 weight % of the hydration agent and that the weight ratio between the hydration agent and the non-ionic surface-active substance is within the range of2:l to 6:l.

5. The pharmaceutical formulation according to claim 4, characterized in that the weight ratio between the hydration agent and the non-ionic surface-active substance is 4:1 to 6:1.

6. The pharmaceutical formulation according to the any of the preceding claims, characterized in that the non-ionic surface-active substance is selected from the group including macrogolglycerolhydroxystearate, polysorbate, stearomacrogol and isosorbide dimethyl ether.