Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Particulate form
Patent
1995-03-08
1998-02-17
Venkat, Jyothsan
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Particulate form
424401, 428402, 42840224, 264 41, 264 46, A61K 951
Patent
active
057189056
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/FR93/00594, filed on Jun. 16, 1993.
FIELD OF THE INVENTION
The present invention relates to the preparation and the application of a novel cyclodextrin-based dispersible colloidal system in the form of spherical particles of matrix type and of size ranging from 90 to 900 nm (nanospheres), which may contain an active molecule.
BACKGROUND OF THE INVENTION
FR 2 551 072 describes micrometric capsules as a sustained-release pharmaceutical form, which are prepared from polyol esters. These microparticles are not suited to intravascular administration without entailing risks of embolization.
Submicron particles are already known, especially from BE-A-808 034, BE-A-839 748, BE-A-869 107, FR-A-2 504 408, EP-A-02 75 796 and EP-A-03 49 428.
Thus, Belgian Patents No. 808 034 and 839 748 describe submicron particles formed from polymerizable materials such as acrylic or methacrylic acid derivatives, for example methyl or butyl methacrylate, methacrylamide or a mixture of these compounds. The submicron particles formed by micellar polymerization of these various monomers have both the property of totally or partially coating the biologically active substance and the property of forming aqueous colloidal suspensions, which enable these particles thus charged with biologically active molecules to be administered parenterally.
However, the polymers of acrylic or methacrylic acid derivatives described in these patents for the preparation of submicron particles, containing a biologically active molecule, are substantially stable, such that they remain as they are for a long time in the tissues or in the cavity into which they have been administered, and this constitutes a drawback, more particularly in the case of parenteral administration in human medicine.
Belgian Patent No. 869 107 overcomes this back by describing biodegradable nanoparticles containing a biologically active molecule. The material used consists of alkyl cyanoacrylate polymers which have already been used in surgery as tissue adhesives and which are known for their biodegradability.
The major drawback thereof pertains to the structure of the particles obtained, to the toxicity of the degradation products and to the mode of incorporation of the active substance. The procedure described only makes it possible to prepare particles formed of a very dense polymer lattice. The active molecule can only be incorporated by adsorption and the proportion bound is still relatively low. Furthermore, it is difficult to control the molecular weight of the polymer constituting the nanoparticles and it is necessary, especially for the purpose of biological use, to remove the residual monomers and oligomers, the excess polymerization reactants if required (initiator and catalyst) and the surfactants if they are used at high concentration or if they are not biocompatible. However, the purification (ultracentrifugation, dialysis) often proves laborious since filtration of the nanoparticles, in view of their size, is not always possible.
Protein-based nanoparticles have also been proposed, especially by hot denaturation of a water-in-oil emulsion of a solution of a protein such as albumin, (Kramer, P. A.: J. Phar. Sci., 63 1646, 1974) or by desolvation of a solution of a protein, such as gelatin, by an inorganic salt or ethanol (Marty et al., Austr. J. Pharm. Sci., 6, 65, 1978, or Pharm. Acta Helv. 1, 53, 1978), followed, in both cases, by curing using an aldehyde. The Kramer nanoparticles have the main drawback of requiring a pre-emulsification of the aqueous solution of the macromolecular starting material in a continuous oily phase. Since this emulsion needs to be very fine, the ad hoc use of surfactants and of apparatus (sonicator, etc.) is essential in order to obtain nanoparticles of suitable size. As regards the Marty nanoparticles, they make use of considerable quantities of inorganic salts which have to be removed, as do the excess aldehyde and sulphite or metabisulphite used to neutralize the latter.
EP-A-02 75 796 and -03 49 42
Coleman Antony
Devissaguet Jean-Philippe
Duchene Dominique
Fessi Hatem
Puisieux Francis
Centre National de la Recherche Scientifique (C.N.R.S.)
Venkat Jyothsan
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