Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form
Reexamination Certificate
2000-10-27
2002-10-15
Russel, Jeffrey E. (Department: 1653)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
C424S422000, C424S425000, C424S484000, C514S002600, C514S784000, C514S786000, C514S944000
Reexamination Certificate
active
06464987
ABSTRACT:
This application is a 371 of PCT/EP99/02551 filed Apr. 16, 1999.
The present invention relates to pharmaceutical compositions which allow the sustained release of at least one active substance, to methods for preparing these compositions, as well as to their use for administering medicinal products subcutaneously and/or intramuscularly.
The two main extravascular routes of parenteral administration are the subcutaneous and intramuscular routes. Compared to intravenous injection, these two routes of administration for the same aqueous solution of active principle generally produce a slightly delayed and slightly prolonged effect. The bioavailability of the medicinal product is also generally poorer because of a slower absorption, or binding or degradation of the medicinal product at the injection site or in the tissues traversed. Thus, TRH (thyrotropin releasing hormone, a tripeptide) has a bioavailability in mice of 67.5% after subcutaneous administration, and of 31.4% after intramuscular administration (Redding T. W. and Schally A. V., Life Sci., 12, 23 (1970)).
In order to improve bioavailability and to obtain veritable sustained-release preparations, various experimental forms have been developed.
Thus, the encapsulation by liposomes of P-18, which is a peptide with a molecular weight lower than 5000 Dalton, shows that, after intramuscular injection, the peptide remains at the injection site for 7 days (Crommelin D. J. A. and Storm G., Int. Pharm. J., 1, 179 (1987)).
Another means of sustaining the release of an active principle consists of its incorporation into an implant. These implants can be prepared from biodegradable or non-biodegradable polymers. The drawback of this form is linked to its method of subcutaneous introduction by incision or with the aid of a trocar. In addition, if a non-biodegradable polymer is used, the implant must be withdrawn by incision after diffusion of all of the active principle out of the polymer matrix. These systems have been widely developed for the administration of hormones such as LHRH (luteinizing hormone releasing hormone) and its synthetic analogues. Thus, gosereline administered in humans in the form of PLA-GA (copolymer of lactic acid and of glycolic acid) implants allows a very significant and lasting decrease in the level of testosterone in the blood to be obtained (Vogelzang N. J., Chodak G. W., Soloway M. S., Block N. L., Schellhammer P. F., Smith J. A., Caplan R. J. and Kennealey G. T., Urology, 46, 220 (1995)).
Other polymer supports can also be used: micro- or nanoparticles. In this case, only biodegradable polymers are used. In comparison to implants, these particles can be injected with the aid of a conventional syringe, but have the drawback of not being able to be withdrawn from the body in the event of a problem. A very significant and lasting decrease in the level of testosterone was also observed in humans after administration of PLA-GA microparticles containing nafarelin.
These various administration systems have the drawback of sophisticated and complex preparation which requires specific installations.
The applicant has now just discovered novel pharmaceutical compositions which are obtained by an extremely simple preparation method, and which allow sustained release of an active principle. These compositions have the property of gelling instantaneously in the presence of an aqueous phase. They can thus be judiciously used to obtain, via the subcutaneous and intramuscular routes, sustained and programmed release of medicinal products. Upon contact with mucous membranes, a gel forms under the skin or in the muscle, and the medicinal product may diffuse and be released from the gel.
Lipid compositions which undergo a phase transformation upon contact with water have already been presented in the literature.
European patent application 550960 describes compositions for topical application which are intended to prevent perspiration, comprising an antiperspirant which comprises at least one amphiphilic substance, this antiperspirant being capable of forming, in water, an insoluble liquid crystal phase with a periodicity greater than 1. In particular, Example 14 illustrates a composition which is capable of forming an inverted hexagonal crystalline phase upon contact with perspiration, and which is composed of 34 to 50% of oleic acid and of 50 to 66% of lecithin (phosphatidylcholine).
International patent application WO 94/10978 describes emulsifying compositions which are intended to replace the synthetic emulsifiers commonly used in the food, cosmetics, toiletry or pharmaceutical industry. These compositions comprise at least one membrane lipid (phospholipid), at least one natural amphiphile which is not a primary emulsifier (C
12
to C
22
fatty acid or fatty alcohol, or combination of a fatty acid and of a fatty alcohol) and, optionally, a hydrophilic medium (aliphatic alcohol such as propylene glycol). These compositions have the property of forming creams (oil-in-water emulsion) with oils or oily substances, and are capable of forming stable emulsions or creams when they are mixed with liposomes.
More particularly, Example 4 describes a composition consisting of 15% by weight of hydrogenated soy bean lecithin (phospholipid), 15% by weight of fatty acid, 45% by weight of fatty alcohol and 25% by weight of alcohol (10% of ethanol and 15% of glycerol). This composition is in the form of a soft waxy mass.
The literature also mentions fluid pharmaceutical compositions intended for treating peridontitis which are in the form of more or less viscous emulsions or suspensions, and which are administered into the periodontal pocket generally with the aid of syringes.
International patent application WO 95/34287 describes biodegradable lipid compositions in the form of L2 crystalline phases which allow the controlled release of active substances and which comprise, besides the active substance, at least one unsaturated fatty acid diacylglycerol which has 16 to 22 carbon atoms or saturated fatty acid diacylglycerol which has 14 to 22 carbon atoms, at least one phospholipid chosen from glycerophosphatides and sphingophosphatides, and, optionally, at least one polar liquid chosen from water, glycerol, ethylene glycol and propylene glycol. These compositions have the characteristic of transforming into cubic liquid crystal phases upon contact with water, which makes it possible to “mould” the active substance in the site where it is desired for the action to take place. The said document mentions, among other uses, the possibility of using such compositions for treating periodontitis. However, the effectiveness of such compositions in the treatment of periodontitis is not illustrated in that document.
European patent 429224 describes compositions which are in the form of gels containing from 1 to 99% by weight of monoolein and from 1 to 90% by weight of active substance, which are placed in the periodontal cavity. In the presence of the surrounding water, these compositions become more viscous and keep the active substance close to its site of action. The active substance is released slowly in controlled fashion.
U.S. Pat. No. 5,230,895 describes the use of compositions which are in the form of solutions or pastes which are capable of transforming into gel when they have been placed in the periodontal pocket. These compositions are biodegradable and allow the controlled release of the active substance in the site of action. They contain a mixture of glycerides and of an active substance chosen such that it is capable of forming a gel in the environment of the periodontal pocket. The compositions illustrated in the said document contain at least 70% of Myverol™ 18-92, which is a composition of sunflower monoglycerides which has a monoglyceride content of at least 90%.
U.S. Pat. No. 5,143,934 describes compositions which allow the administration, by controlled release, of an active substance in a periodontal pocket, and which comprise at least one monoglyceride and at least one plant oil in proportions which are sufficient to fo
Deleers Michel
Fanara Domenico
Vranckx Henri
Russel Jeffrey E.
UCB S.A.
Wenderoth , Lind & Ponack, L.L.P.
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