United States Patent:   5,998,480

Assignee:  Errekappa Eurotherapici S.P.A. (Milan, IT)

Filed:  May 4, 1998

The subject matter of this invention is a pharmaceutical preparation for topical use containing as active principle nimesulide (CAS No. 51 803-78-2) or one of its active derivatives. The invention is characterized by the fact that the preparation's base contains at least one phospholipid and at least one substance with acid reaction, specifically an acid. The figure reports the results of an ex vivo nimesulide absorption test performed with topical formulations including those which are the subject matter of this invention.

Abstract of Description of the Invention

The subject matter of this invention are topical preparations based on nimesulide containing phospholipids and organic or inorganic acids.

As is known, nimesulide(4-nitro-2-phenoxy-methan-sulfanilide) is a nonsteroidal 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 tolerability with respect to other nonsteroidal anti-inflammatories such as for example, arylalkaloid acids such as acetylsalicylic 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 absorption 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 .beta.-cyclodextrins (as described in PCT/IT91/00043, DE 4116659 and PCT/HU94/00014) 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 phospholipids.

In this specific sector there is, therefore, a demand for preparations based on nimesulide with better active principle bioavailability and absorption in 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, glycolic acid, citric acid, aqueous hydrochloric acid.

The pH of the preparation according to this invention can preferably be between 1 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, lipogel, 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.

Claim 1 of 33 Claims

1. A pharmaceutical preparation comprising nimesulide as an active ingredient, a phospholipid, and at least one acid.

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