Drug – bio-affecting and body treating compositions – Topical body preparation containing solid synthetic organic... – Ophthalmic preparation
Reexamination Certificate
1999-07-19
2001-05-01
Azpuru, Carlos A. (Department: 1615)
Drug, bio-affecting and body treating compositions
Topical body preparation containing solid synthetic organic...
Ophthalmic preparation
C424S443000
Reexamination Certificate
active
06224857
ABSTRACT:
This application is the national phase under 35 U.S.C. §371 of prior PCT International Application No. PCT/IB97/01288 which has an international filing date of Oct. 17, 1997 which designated the United States of America, the entire contents of which are hereby incorporated by reference.
FIELD OF THE INVENTION
The present invention relates to the use of new pharmaceutical preparations in the field of local anaesthetics and, more precisely, preparations consisting of a stoichiometrically neutral salt of a hyaluronic acid with a basic anaesthetic with local action containing aliphatic and/or aromatic amino groups with an aliquot of the carboxy groups of hyaluronic acid possibly salified with an alkaline or alkaline earth metal.
The invention also concerns some new compositions of the aforesaid type which, thanks to their specific pharmaceutical properties as described hereafter, are suitable for use as infiltrations and injections as well as for surface use.
FIELD OF THE INVENTION
European patent No 0197718 B1 granted on Dec. 15, 1993 describes the advantageous use of hyaluronic acid and molecular fractions thereof as vehicles for medicinal substances for topical use and demonstrates that associations of hyaluronic acid with known drugs in various fields of medicine give better effects than the same drugs administered on their own. That patent emphasises above all a greater degree of bioavailability than that obtained with the pharmaceutical formulations used in the past, and this advantage is illustrated especially in the ophthalmic field, where marked compatibility with the corneal epithelium was observed, with subsequent excellent tolerability with no sensitization effects, with the formation of homogeneous and stable films which are perfectly transparent, have excellent adhesive properties and guarantee prolonged bioavailability of the drug.
The above patent discusses the importance of said perfected bioavailability in the veterinary field with regard to the administration of chemotherapeutics. The patent also lists miotic, anti-inflammatory, wound healing and antimicrobial effects for ophthalmic use in the fields of both veterinary and human medicine.
DETAILED DESCRIPTION OF THE INVENTION
It has now been discovered that the use of local anaesthetics, and more precisely basic organic anaesthetics containing amino groups, if used in the form of their stoichiometrically neutral salts with hyaluronic acid, or stoichiometrically neutral salts of hyaluronic acid with such anaesthetics, resulting from partial salification of the hyaluronic acid with said aminic substances and from the salification of the remaining carboxy groups of the acid with inorganic bases deriving from alkaline or alkaline earth metals, not only offers the advantages of enhanced bioavailability and excellent tolerability, but also induce an exceptional increase in the anaesthetic effect. This result is of great importance in the ophthalinological field but can be used in other fields as well. It constitutes a specific technical effect over and above the benefits reported in the aforesaid previous patent.
In the context of the present invention, the term “hyaluronic acid” indicates a purified hyaluronic acid such as those already on the market or described in the literature or in patents such as those obtained by extraction from animal or fermentation sources, or of biotechnological origin, or molecular fractions of hyaluronic acids, likewise purified, such as those described in European patent No. 0138572 (describing commercial products known as Hyalastine and Hyalectin) or hyaluronic acids with higher molecular weights such as the fraction known as Hyaloftil, described in EP 0535200 A1, or other products available on the market. Besides the hyaluronic acid described above, its partial esters obtained according to the procedure described in EP 0216453 B1 can also be used.
The local anaesthetics for use in the preparation of salts with hyaluronic acid according to the present invention are essentially those reported in the literature and/or found on the market or used for clinical purposes, and which contain aliphatic and/or aromatic amino groups (with between 12 and 30 carbon atoms) which can be salified with an acid. While the salts of hyaluronic acid with lidocaine, dibucaine and benzocaine are known, as they are described in the aforesaid European patent No. 0197718 B1, the salts of hyaluronic acid with the following aminic-type local anaesthetics to be used according to the invention are new and constitute a particular object of the invention: tetracaine, amylocaine, bucricaine, bupivacaine, butacaine sulfate, butanilicaine, butoxycaine, carticaine, chloroprocaine, clibucaine, chlormecaine, cyclomethycaine, dimethisoquin hydrochloride, diperodon, diclocaine, ethyl p-piperidine acetylamine benzoate, ethidocaine, hexylcaine, phenacaine, fomocaine, hydroxyprocaine, hydroxytetracaine, ketocaine, oxethazaine, oxybuprocaine, paretoxycaine, piperocaine, piridocaine, pyrrocaine, pramoxine, prilocaine, procaine, propanocaine, propipocaine, propoxycaine, proxymetacaine, ropivacaine, tolycaine, trimecaine, vadocaine and, especial, benzydamine, a drug characterized by anti-inflammatory and local anaesthetic properties.
The salts of hyaluronic acid with a strong anaesthetic effect according to the present invention are above all stoichiometrically neutral salts with the abovesaid aminic bases, that is, the total salts of the polysaccharide with aminic bases. In the partial salts of the polysaccharide with said aminic bases, the degree of salification may vary within an ample range, for example between 10% and 90%, preferably between 20% and 80%, and especially between 50% and 75%, with the remaining carboxy groups of the polysaccharide are salified with one of the abovesaid ions of an alkaline or alkaline earth metal.
A preferred object of the invention is represented by the total and partial salts, as described above, of benzydamine with a hyaluronic acid. It has been observed that salts of this kind not only present a far more pronounced and longer-lasting anaesthetic effect than benzydamine or the hydrochloride thereof but also enhance the anti-inflammatory effect and, surprisingly reduce the irritating action, thus widening the gap between active and irritant concentrations or doses. Indeed, it is known that, as an anaesthetic or anti-inflammatory agent, benzydamine presents some disadvantages, such as the brevity of its topical action, as the drug quickly passes from the application site into the system, and the onset of an irritant action, which occurs at doses not far removed from those required for the desired effects.
It has further been found according to the invention that the activity of the hyaluronic acid salts with anaesthetics can vary depending upon the molecular weight of the hyaluronic acid. For one of the preferred anaesthetics, benzydamine, it was found that the product has the most improved characteristics when salified with a low molecular weight fraction of hyaluronic acid. For another preferred anaesthetic, bupivacaine, it was found that the product has the most improved characteristics when salified with a high molecular weight fraction of hyaluronic acid. It has also been found that of the alkaline and alkaline earth metals, sodium salts are the preferred monovalent salts, and calcium salts are the preferred bivalent salts.
It follows that the new benzydamine salts of the present invention, besides their advantageous application in ophthalmology, like the other anaesthetic bases mentioned previously, have proved to be new drugs with a very wide field of application, for example in inflammatory processes in the mouth or airways such as stomatitis of various origin, tonsillitis or tracheitis, in mucositis caused by radio- or chemotherapy, by sub or diagnostic intubation, such as bronchoscopy, in dental and gingival disorders in general, including teething trouble in babies, in rhinitis, in inflammatory processes affecting the auditory canal, in conjunctivitis of various origin, in proctologic
Kirschner Gunter
Romeo Aurelio
Silvestrini Bruno
Azpuru Carlos A.
Birch & Stewart Kolasch & Birch, LLP
Fidia S.p.A.
Svensson Leonard R.
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