HK1025265B - Nimesulide gel systems for topical use - Google Patents

Description

Nimesulide gel systems for topical application

The present invention relates to a nimesulide topical formulation based on a gel system.

Nimesulide is a known anti-inflammatory agent whose therapeutic effect has been proven for some time, but which has the drawback of having poor chemical-physical characteristics; the main obstacle to the use of nimesulide in topical formulations is in fact its insolubility in water and, on the other hand, its poor solubility in the solvents/raw materials commonly used in such formulations.

Some nimesulide formulations for external use are described in WO 96/11002; said formulations consist of a dispersion of the active ingredient particles in one component, which, in the case of creams, comprises: a hydrophilic polymer, an oily substance, a surfactant, an alkaline substance and water.

The application is silent about gel systems, especially those in which the active ingredient is dispersed in a non-aqueous solvent; furthermore, the formulation proposed in WO 96/11002 does not solve some of the problems associated with the stability of the system and the bioavailability of the active ingredient.

It has now been found that the combination of a gel based on a carboxyvinyl polymer or other suitable gelling agent with a dispersion of nimesulide in a solvent selected from ethanol, isopropanol or diethylene glycol monoethyl ether gives significant advantages in terms of stability of the system and in terms of release and absorption of the active ingredient, thus improving bioavailability.

Gelation is preferably obtained by neutralization of the carboxyvinyl polymer resin in acidic form (which behaves chemically as a weak acid); as regards the bases used for this neutralization, the use of weak bases, such as triethanolamine or diisopropanolamine (in an acid/base equivalent ratio of 1: 1), has proved particularly successful.

The carboxyvinyl polymer (e.g. carbomer) used in the gelling process is obtained starting from acrylic/methacrylic acid and is used in an amount ranging from 0.1% to 5% by weight, preferably from 0.5% to 2.5%. Alternatively, polyacrylamide-isoparaffins known under the trade name Sepigel (Sepic) (in amounts ranging from 0.5 to 10 wt%) can be advantageously used as gelling agents.

The use of non-aqueous solvents in the preparation of the gel system of the present invention undoubtedly includes advantages in the chemical-physical characteristics of nimesulide and in the release and absorption properties. In particular, the present invention relates to the use of solvents such as ethanol, isopropanol and diethylene glycol monoethyl ether, which proved to be particularly effective in increasing the absorption of the active ingredient due to its solubilizing effect on the lipid skin barrier.

The dissolution effect, which, although it promotes the absorption of nimesulide, adversely affects the hydration of the skin, is compensated by the film-forming and tactile-forming properties of gels based on carboxyvinyl polymers.

The viscosity and pH of the compositions of the invention may vary within wide ranges: the viscosity is several centipoise to 100.000 or more, and the preferable pH range is 5 to 7. The amount of water may range from 40% to 95% by weight, while the amount of solvent (also in terms of its effect on the evaporation of the aqueous phase) is from 5% to 20% by weight, preferably about 10%, for ethanol and isopropanol; on the other hand, in the case of diethylene glycol monoethyl ether, the diffusion and permeation properties are associated with a concentration of 5 to 40 wt%, preferably about 15%.

The active ingredient nimesulide may be dispersed over a wide concentration range, preferably 0.5 to 7 wt%.

The compositions of the invention may also comprise lipophilic excipients, for example glyceryl caprylate/glyceryl caprate with 8 ethylene oxide units per molecule of glycerate, which improve both the absorption characteristics and the final coverage, and the "skin feel" characteristics.

Suitable preservative systems and lipophilic materials suitable for limiting any undesired effects at shallow layers caused by defatting (delipidation) of the solvent may further be applied.

The preservative system provides microbial protection using a wide range of antibacterial agents (e.g., imidazolidinyl urea and balanced paraben mixtures); a further safeguard of stability is the presence of a chelating agent (e.g. EDTA) which is capable of chelating any harmful ions to maintain a suitable viscosity index.

In view of the high percentage of water present, it should be suggested that EDTA guarantees an enhanced antimicrobial effect on the preservative system.

The composition of the present invention may further comprise an emollient/humectant such as cetyl esters 1-15 wt%, cholesterol 0.3-0.5 wt%, glycerin 1-30 wt%, isopropyl myristate 1-10 wt%, isopropyl palmitate 0.05-5.5 wt%, lecithin 1-20 wt%, lanolin alcohol 0.5-15 wt%, petrolatum 4-95 wt%, soybean lipid 1-20 wt%; and skin absorption enhancer such as 2-pyrrolidone 0.1-10 Wt%, propylene glycol 5-50 Wt%, and pyrrolidone derivative 0.1-10 Wt%.

The compositions of the present invention may be prepared by a process comprising:

-preparing a dispersed phase comprising a carboxyvinyl polymer gellant;

-adding said alcoholic solvent, dispersing the active ingredient nimesulide, adding preservatives and stabilizers;

-neutralizing the resin with a selected base.

As the system in which diethylene glycol monoethyl ether is the solvent, the following can be mentioned as a scheme of the process:

-preparing an aqueous phase containing a water-soluble preservative and a homogeneously dispersed carboxyvinyl polymer;

-preparing a phase containing preservatives (parabens) in diethylene glycol monoethyl ether and dispersing the active ingredient, adding a phase comprising caprylic/capric glycerides having 8 ethylene oxide units per molecule of glycerate;

-preparing a dispersion, suspending a phase containing said active ingredient in an aqueous phase containing said carboxyvinyl polymer;

-preparing a stabilizer suitably soluble in said aqueous phase;

-neutralizing the resin with a selected base.

The composition of the invention has the following advantages:

-the ability to dissolve nimesulide;

-rapidity and release mechanism of the gel carrier;

-the ability to promote absorption;

-reduction of the dehydration phenomena induced.

The compositions of the invention proved to be well tolerated both in animals (rabbits and guinea pigs) and in clinical studies.

The efficacy of the compositions of the invention has been tested using well-known pharmacological tests (e.g. UV-induced erythema in guinea pigs, croton oil-induced inflammation of guinea pig ears, carrageenan-induced granuloma in rats).

Applications of¹⁴Damping of CCutaneous absorption was studied in rats and in human volunteers, in none of these cases significant concentrations of the nimesulide system were observed.

The composition of the invention was also tested clinically on 200 patients with tendonitis of the upper limb or with benign ankle sprain in a controlled double blind experimental design.

The composition of the invention proved to be effective in a statistically significant manner compared to placebo.

The following are examples of some formulations obtained by the process of the invention:

example 1

Phase composition% w/w

Proper amount of A-phase purified water

Imidazolidinyl urea 0.20

EDTA tetrasodium salt 0.10

Phase B Carbomer (CARBOPOL)1382) 1.20

C-phase mixed parabens 0.20

Vaseline 1.00

D phase Isopropanol 10.00

E-phase nimesulide-

F phase purified water 10.00

Triethanolamine 0.60

The formulation was prepared at four nimesulide concentrations (i.e. 2, 3, 4, 5% w/w, each concentration in 3 different 5kg batches).

The a + B phase (i.e. the dispersion of carbopol in a solution of water and preservative) was obtained by swelling the gel at room temperature for two days until a homogeneous dispersion was reached. Phase C was prepared in a paddle mixer of the type Gianke & Kunkel PM43 heated on a water bath.

After the addition of isopropanol, homogenization was carried out using a homogenizer model Guarniero Mantelli F43CV 2.

Alternatively, the entire preparation can be carried out: carbopol was dispersed in water by a turbine under vacuum, mixed with a paddle after addition of phase C, and homogenized again by a turbine under vacuum after addition of isopropanol.

"Paracombin" (a powdery mixture of methyl, ethyl, propyl, and butyl parabens) was used as preservative. Methyl, ethyl and propyl parabens are cited in the italian pharmacopoeia (version XI). Butyl paraben is cited in USP XXIII.

The mixture was added with the preservative imidazolidinyl urea.

Example 2

％w/w

Water 83.40

Ethanol 10.00

Nimesulide 3.00

Carbomer (carbopol 1382) 1.40

Vaseline 1.00

Triethanolamine 0.70

Imidazolidinyl urea 0.20

0.20 of methyl, ethyl and propyl p-hydroxybenzoate

Tetrasodium EDTA 0.10

Chemical-physical Properties preparation at room temperature at 40 deg.C for 45 days and then 45 days
	Opaque and opaque appearance white gel
pH 5.00 5.03 4.98

No signs of separation or viscosity reduction were observed.

Example 3

％w/w

Water 83.40

Isopropanol 10.00

Nimesulide 3.00

Carbomer (carbopol 1382) 1.40

Vaseline 1.00

Triethanolamine 0.60

Imidazolidinyl urea 0.20

0.20 of methyl, ethyl and propyl p-hydroxybenzoate

Tetrasodium EDTA 0.10

Chemical-physical Properties preparation at room temperature at 40 deg.C for 45 days and then 45 days
	Opaque and opaque appearance white gel
pH 5.00 5.03 5.01

No signs of separation or viscosity reduction were observed.

Example 4

Phase composition% w/w

Proper amount of A-phase purified water

Having 8 ethylene oxides per molecule of glycerate

Unit of glyceryl caprylate/glyceryl caprate 2.00

Imidazolidinyl urea 0.20

EDTA tetrasodium salt 0.10

Phase B carbomer (carbopol 940) 1.00

C-phase mixed parabens 0.20

Diethylene glycol monoethyl ether 15.00

Nimesulide-

D phase purified water 10.00

Triethanolamine 0.50

The formulation was prepared at four nimesulide concentrations (i.e., 2%, 3%, 4%, 5% w/w, each concentration in 3 different 5kg batches).

Example 5

％w/w

Water 83.40

Diethylene glycol monoethyl ether 15.00

Nimesulide 3.00

Carbomer (carbopol 940) 1.00

PEG-8 glyceryl caprylate/glyceryl caprate 2.00

Triethanolamine 0.50

Imidazolidinyl urea 0.20

0.20 of methyl, ethyl and propyl p-hydroxybenzoate

Tetrasodium EDTA 0.10

Chemical-physical Properties preparation at room temperature at 40 deg.C for 45 days and then 45 days
	Opaque and opaque appearance white gel
pH 5.20 5.18 5.21

No signs of separation or viscosity reduction were observed.

Claims (11)

1. A nimesulide topical pharmaceutical composition in the form of a gel system, the pharmaceutical composition comprising: a carboxyvinyl polymer or polyacrylamide-isoparaffin neutralized with a weak base aqueous solution, and a solvent selected from ethanol, isopropanol, diethylene glycol monoethyl ether, the water content being in the range of 40 to 95 wt%.

2. The pharmaceutical composition of claim 1, wherein the ethanol and isopropanol concentrations used are in the range of 5 wt% to 20 wt%.

3. The pharmaceutical composition of claim 2, wherein the concentration is 10 wt%.

4. The pharmaceutical composition of claim 1, wherein diethylene glycol monoethyl ether is used in a concentration range of 5 wt% to 40 wt%.

5. The pharmaceutical composition of claim 4, wherein the concentration is 15 wt%.

6. The pharmaceutical composition of any one of claims 1 to 5, wherein the weak base used to neutralize the carboxyvinyl polymer is triethanolamine or diisopropanolamine.

7. The pharmaceutical composition of claim 6, wherein the active ingredient nimesulide is dispersed at a concentration in the range of 0.5 to 7 wt%.

8. The pharmaceutical composition of claim 7, further comprising an additive selected from the group consisting of emollients, humectants, absorption enhancers, preservatives.

9. The pharmaceutical composition of claim 8, wherein the preservative is imidazolidinyl urea, parabens, and EDTA.

10. A process for preparing the pharmaceutical composition of claim 1, comprising:

-preparing a dispersed phase comprising a carboxyvinyl polymer gellant;

-adding said alcoholic solvent, dispersing the active ingredient nimesulide, adding preservatives and stabilizers;

-neutralizing the resin with a selected base.

11. A process for preparing the pharmaceutical composition of claim 4, comprising:

-preparing an aqueous phase containing a water-soluble preservative and a homogeneously dispersed carboxyvinyl polymer;

-preparing a phase containing parabens in diethylene glycol monoethyl ether as preservative and dispersing the active ingredient, adding a phase comprising caprylic/capric glycerides having 8 ethylene oxide units per molecule of glycerate;

-preparing a dispersion, suspending a phase containing said active ingredient in an aqueous phase containing said carboxyvinyl polymer;

-preparing a stabilizer suitably soluble in said aqueous phase;

-neutralizing the resin with a selected base.