Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Implant or insert
Reexamination Certificate
2000-03-14
2002-02-12
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Implant or insert
C424S489000, C514S772300
Reexamination Certificate
active
06346263
ABSTRACT:
The present invention relates to a new type of biodegradable particulate matrix and the methods of its preparation.
Both in the fields of pharmacy and cosmetology, the use of numerous active principles remains sensitive and can be contemplated only for putting in place vectorization strategies. To cause a compound to penetrate and react in the interior of a biological or biochemical system, there exist a certain number of processes. It is however necessary to have a particulate vector in which the active principle is incorporated so as to be able to modify its behavior.
Thus the incorporation in a vector permits:
modifying the biodistribution of compounds having marked toxicity for a tissue
modifying the release mode and time of resonance at the site of administration and/or of action
improving the low solubility of certain molecules in physiological media
imparting a certain protection and increasing the half life of the molecule incorporated in the case of compounds having a too low half life in the organism or in the biological or biochemical systems.
The concept of vector must here by understood in the broad sense, which is to say that it comprises molecules playing a support role, for example when they are incorporated in a composition, either as such, or for the transport, presentation and/or stabilization of the active principle.
These strategies of vectorization are based on the use of particulate vectors obtained by techniques of solvent evaporation, polymerization in emulsion, or coacervation (patent WO 93.02712). These are the vectors based on polymers, polyamides, polypeptides, polyacrylates and derivatives, these are also the microparticles of peptidic origin, gelatins, alginates, polyamides obtained by gelification or by interfacial polymerization. All these techniques are well known to those skilled in the art. They are discussed in “Dossier Bioencapsulation, Biofutur, 1994 No. 132 p 1545”. These vectors are for the most part difficult to be industrialized and remain troublesome. It must be emphasized that the techniques of evaporation lead to vectors containing traces of residual solvents and have for certain ones a toxicity which is not zero. Finally, there can be distinguished the liposomes widely used in cosmetology and for which the first pharmaceutical applications are arising but whose physico-chemical stability is still limited.
These different types of technologies have permitted obtaining several interesting results for solving certain problems of biodistribution and pharmacokinetics. Thus the forms of LHRH with timed release have been used as particles of polylactic/glycolic copolymer. Finally, the liposome forms of Doxorubicine, which are characterized by a modified biodistribution permitting avoiding the phenomenon of acute cardiotoxicity as described by “Bally et al. Cancer Chemotherapy and Pharmacology (1990) No. 27 p13-19” “Vaage et al, International Journal of Cancer (1992) No. 51 p 942-948”. However, for numerous molecules, there exists no particulate vector having high capacity for incorporation, being modulable and easy to use industrially.
The ideal vector permitting the internal incorporation of molecules would have the following characteristics:
a particulate structure easily obtained without resort to conventional techniques difficult to employ, evaporation of solvent or gelification or interfacial covalent crosslinkage.
a high capacity for internal incorporation of molecules, followed by a high dispersability in aqueous media.
high stability of incorporation.
easy control and modulation of the release parameters.
ease of surface derivitization without risk of modification of the structure of the active principle.
Such a particulate vector must satisfy a certain number of requirements relating particularly to its useful load, its biocompatibility, its non-toxicity and its biodegradability. It must not upset the physiological equilibria and must not be immunogenic.
The only vectors which approximate this list of requirements are microparticles of copolymer of lactic/glycolic acid and the biodegradable ionic matrices.
The matrix of these microparticles is constituted by biodegradable polyesters of lactic acid and glycolic acid, two intermediaries of cellular metabolism. The speed of biodegradation is a maximum for a lactic/glycolic ratio of 1/1 by weight. These particular matrices are essentially prepared by the method known to those skilled in the art, so-called evaporation in solvent described in the patent “WO 93-02712”, and by “BENOIT in New Pharmaceutical Forms. Technological, Biopharmaceutical and Medical Aspects, P. BURI et al editors, LAVOISIER Editions Tec and Doc 1985 page 632”. To obtain an internal charge of the particle with this type of technology, it is necessary to incorporate the active principle with the polymer upon the initial dispersion phase in organic solvent. The solubility of the active principle in the organic solvent determines the maximum capacity of incorporation in the particle. This process implies the presence of the active principle throughout the process for synthesizing the particles, which is troublesome for radioactive and/or toxic products. For this type of vector, the release of the active principle depends on the speed of biodegradation of the particle and also on the properties of solubilization or diffusion of the molecule, hence on its physical condition.
In practice, for numerous molecules, speed of release is not constant with time and can be fairly long, which limits the use of this type of vector. As to the control of the size of the particles, this technology does not permit the industrial preparation of particles of a size below 200 nm, which considerably limits the therapeutic uses and particularly limits the possibilities of parenteral administration. Finally, those skilled in the art know that it is impossible, with this synthesis technique, totally to eliminate the residual traces of solvent, which remains problematic.
The biodegradable ionic matrices, also called ion exchange resins, are constituted by a three-dimensional network which is hydrophilic, swellable, not soluble in water and derived by an ion exchange capacity generally comprised between 0.1 and 10 mEq/g.
In particular, two families of resins can be distinguished: synthetic resins and resins obtained from natural and/or derived polymers.
The synthetic exchange resins are obtained by polymerization or copolymerization, in emulsion or reverse emulsion, of monomers comprising ionic functions, as described in the patent WO 93/07862. The natures of these resins as well as their size, porosity of ionic matrix, ion exchange capacity, rate of swelling, are controlled by different parameters of the synthesis process such as the quantity of water, the speed of agitation, and quantity and type of solvent, the quantity, type and concentration of the monomers. The monomers used at present are:
monoethylenic unsaturated monomers such as styrenes, styrene sulfanates, vinyl derivatives, acrylic and methacrylic esters. The monoethylenic unsaturated monomers with a protonic or basic function, include vinyl-pyridine and its derivatives, acrylate derivatives and methacrylate derivatives such as methacrylamidopropylhydroxyethyldimethylammonium acetate or chloride.
the unsaturated polyethylenic monomers include ethylene glycol diacrylates, ethylene glycol methacrylates, ethylene glycol or glycerol polyvinyls, divinylcetones, divinylsulfides, vinyl derivatives with carboxylate or sulfate functions, vinyl derivatives with pyridine or ammonium functions. However, the use of these polymers remains sensitive because of their limited or zero biodegradability. Finally, there cannot be totally eliminated, in the present state of the art, traces of residual solvents and of residual monomers, which can give rise to problems of toxicity.
The natural polymer resins are generally obtained from polysaccharides, naturally derived by ionic functions, for example chitosan, hyaluronic acids, alginates, carrogeeran. The technologies most often used are based on the
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