TOPICAL USE-

DESCRIPTION

The subject matter of this invention are topical preparations based on

nimesulide containing phospholipids and organic or inorganic acids

As is known, nimesulide (4-nιtro-2-phenoxy-methan-sulfanιhde) is a non

steroidal anti-inflammatory drug, that has been well-known for some time, with

analgesic and antipyretic activity (BE 801812) This molecule is used in the

treatment of articular and extra-articular inflammatory conditions with pain

related to rheumatoid arthritis, as well as cataract (EP 0 532900 A) Nimesulide

has demonstrated as having a better therapeutical ratio, less gastrolesivity and, in general, better tolerabihty with respect to other non steroidal anti-

lnflammatoπes such as for example, arylalkaloid acids such as acetylsahcylic

acid, Ketoprofen, Diclofenac, Naproxen, thanks to the presence of a sulfanilide

group in its molecule Nimesulide appears to be very sparingly soluble in water

(about 0 01 mg/ml at room temperature) Nimesulide's scarce water solubility

and "wettability" can cause problems with drug release and constant

bioavailability in various pharmaceutical forms

In order to overcome such disadvantages, caused by nimesulide's low and

variable bioavailability due to its scarce absoφtion properties (correlated with

the very low solubility and bad "wetting" properties), it is possible to employ

differing techniques

Since nimesulide, a weak acid from the chemical viewpoint, is scarcely absorbed at low pH values (for example in the gastric tract), a possible initial

step is salification with alkaline or alkaline-earth bases This technique is not

usually adopted, however, due to the very high pH of the salt solutions obtained

A further method of increasing and achieving constant nimesulide

bioavailability is complexation with cyclodextrins, above all β-cyclodextπns (as

described in PCT/IT91/00043, DE 41 16659 and PCT/HU94/00 14) which

enables better solubility and quicker absorption

Another method, whose widest field of application is topical administration, is to vehicle the compound by using liposomal systems consisting of

phosphohpids

In this specific sector there is, therefore, a demand for preparations based on nimesulide with better active principle bioavailability and absorption tn the form

of pharmaceutical presentations for topical application

This invention is able to satisfy such requirement by also providing other

advantages that will become evident further on

The subject matter of this invention is a pharmaceutical preparation containing

as active ingredient nimesulide (CAS-No. 51 803-78-2) or one of its active derivatives, characterized by the fact that the base of the preparation contains at

least one phospholipid and at least one substance with an acid reaction,

specifically an acid

In the preparation according to this invention, nimesulide can be present at concentrations from 0 1 to 15%, the phospholipid from 0.1 to 10% and the acid from 0 1 to 10% of the preparation's weight.

In the preparation according to this invention, nimesulide can be present in dispersed form, the phospholipid can be a phosphatidyl acid ester, phosphatidylcholine in particular, and the acid can be an organic or an inorganic

acid, preferably chosen from the group that comprises lactic acid, salicylic acid,

glycol acid, citric acid, aqueous hydrochloric acid.

The pH of the preparation according to this invention can preferably be between

I and 7

The preparation according to this invention can contain other substances

acceptable by pharmaceutical carriers.

The preparation according to this invention can be in the form of a gel, hpogel, cream, ointment, lotion, foam, with and without propellants or pressurized gas

This invention is not limited to the pharmaceutical preparation containing nimesulide as active ingredient according to the preceding description. It is

instead extended also to the use of the above mentioned preparation for formulation of drugs for topical use in the treatment of painful articular and

extra-articular inflammation, rheumatoid arthritis, inflammation of soft tissues, whether accompanied by pain or not, and for the treatment of psoriasis and

cataract

The only figure attached shows - in an ex vivo test using a model that involves

the use of Franz cells - the active ingredient concentration the collection

medium, at the beginning of the test, after 3 hours and after 6 hours, assayed by

calculating the percentage of nimesulide which passes through the membrane

that separates the donor compartment from the receptor compartment

The manufacture of the pharmaceutical preparations according to this invention

was carried out with techniques, apparatus and excipients that are traditionally

used on a routine basis in the pharmaceutical industry such as, for example, those described in "Remington's Pharmaceutical Science Handbook", Mack

Pub Co , N Y , U S A

In vitro and ex vivo tests have been performed using the model that involves the use of Franz cells consisting of two compartments, a donor and a receptor,

separated by an artificial or natural membrane on which a thin layer of test

product is distributed Rat skin was used as membrane for the tests, whilst pH 8

phosphate buffer solution was used as medium in the receptor compartment The

active principle concentration in the collection medium was assayed, using

suitable techniques (HPLC), at the beginning of the test, after 3 and after 6

hours, with determination of the percentage of nimesulide which passed through

the membrane

The following formulations were used for the test

NlMI.SUI.IDh + NIM1 SUI.IDI- +

NIMhSUUDI ^' . +

INCJKI DII I NIMI.SUI IDL ORGANIC- l ^" l ^" OSI ^, llOI ]l ^>* DS + I'HOSI'HOM ID.S ACIDS RC1Λ IC ACIDS

Nimesulide 5 0% 5 0% 5 0% 5 0%

Phosphatidylcholine - - 3.0% 3.0%

Poiyacry lammi de-I soparaf in 4 0% 4 0% 4 0% 4 0% Laureth-7

Methyi-p-hydroxybenzoate 0 15% 0 15% 0 15% 0 15%

Propyl-p-hydroxybenzoate 0 05% 0 05% 0 05% 0 05%

Lactic acid - 3 0% - 3 0%

Purified water (q s to) 100% 100% 100% 100%

The results of an ex vivo test are reported in the figure

From the in vitro and ex vivo tests it was noted that there is a correlation between percentage of phospholipids present and the quantity of drug that

penetrates through the skin layers. Such drug quantity increased significantly by using organic acids (above all lactic acid and glycol acid) with keratolytic activity. Nimesulide's increased penetrating action, however, cannot be attributed to the sole presence of organic acids which, in the absence of

phospholipids, do not influence nimesulide absorption. The possible keratolytic activity of the organic acids is not, therefore, the primary cause of the increased absorption, but, through synergetic activity with phospholipids, it contributes towards increasing availability of a drug, such as nimesulide, that has very

scarce solubility.

The following examples represent methods of achieving a pharmaceutical preparation according to this invention:

EXAMPLE 1

Nimesulide gel - 5% concentration

Nimesulide 5 0%

Phosphatidylcholine 3 0%

Carboxyvinylpolymer (Carbopol 940) 2 0%

Methyl-p-hydroxybenzoate 0 17%

Propyl-p-hydroxybenzoate 0 03%

Lactic acid 5 0%

Purified water (q s to ) 100%

EXAMPLE 2

Nimesulide gel - 5% concentration

Nimesulide 5 0%

Phosphatidylcholine 3 0%

Polyacrylammide Isoparaffin Laureth-7 4 0%

Methyl-p-hydroxybenzoate 0 15%

Propyl-p-hydroxybenzoate 0 05%

Lactic acid 3 0%

Purified water (q s to ) 100%

EXAMPLE 3

Nimesulide cream - 3% concentration

Nimesulide 3 0%

Phosphatidylcholine 1 0%

Glycerylmonostearate self-emulsion (Arlacel 165) 7 0%

Methyl-p-hydroxybenzoate 0 15%

Propyl-p-hydroxybenzoate 0 05%

Citric acid monohydrate 3 0%

Purified water (q s to ) 100%