Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Particulate form
Reexamination Certificate
1994-05-02
2001-10-16
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Particulate form
C424S492000, C424S401000, C424S499000, C424S493000
Reexamination Certificate
active
06303150
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates essentially to a process for the production of nanocapsules with cross-linked protein-based walls, to the nanocapsules thereby obtained and to cosmetic, pharmaceutical or food compositions in which they are present.
It is known that the encapsulation of active substances is very important either for protecting the active principle or for permitting a slow or delayed release of the active principle in the organism.
It has been proposed to encapsulate the active principles in liposomes, the latter being an interesting galenical form view their very good affinity with the cell membranes, their very good biocompatibility and their submicron size.
However, these structures have numerous limitations, to see even major disadvantages, which can be summarized in the following four points:
A poor encapsulation yield: liposomes can contain or transport different types of molecules, namely hydrophilic, lipophilic and amphiphilic molecules. However, the encapsulation yields are very low in all cases, which, coupled with the problem of diffusion of the active principles, further reduces the efficacy of the liposomes and in many cases does not permit consideration of their use in therapeutic applications.
A poor reproducibility of the liposome preparations when they are to be produced on the industrial scale.
Instability in vitro: this can manifest itself in various ways, namely chemical instability of the lipids, instability of the size of the liposomes, instability of their structure, formation of aggregates, release of the encapsulated active principles, etc.
Instability in vivo: the influence of biological fluids on the liposomes very often increases their membrane permeabilities. Depending on the administration route used, the liposomes can be in contact with biological fluids as diverse as blood, digestive juices, interstitial fluids etc. and must consequently be capable of withstanding numerous interactions. Now, contact with the majority of biological fluids results in a marked increase in the membrane permeability of the liposomes. By imperfect fusion with the cells, or by contact with salts, enzymes—lipases, phospholipases, acyltransferases—plasma constituents, bile salts or digestive juices, or by simple pH variations, the liposomes can release their active principles into the surrounding medium almost instantaneously.
It has also been proposed to encapsulate the active principles in particles or capsules with dimensions of the order of a few microns. For example, in the document FR-A-2 642 329 identified also by application Ser. No. 89 01221, the same application which forms the basis of priority of U.S. Pat. No. 5,395,620, the Applicant has proposed the preparation of microcapsules with mixed atelo-collagen/glycosaminoglyan walls for encapsulation of the active principle. This method is totally satisfactory except that it does not make it possible to prepare capsules of submicron dimensions, i.e. capsules of nanometer dimensions, called nanoparticles.
Furthermore, nanocapsules with polyacrylamide walls have been proposed, especially by Couvreur et al. in Febs Letters (1977), 84, 323-326, and nanocapsules with polymethyl and polyethyl cyanoacrylate walls have been proposed by the same authors in J. Pharm. Pharmacol. (1979), 31, 331-332. Likewise, it has been proposed in EP-A-0 274 961 to prepare nanocapsules forming colloidal systems based on a vinyl chloride/vinyl acetate copolymer, polyisobutyl cyanoacrylate and poly-(d,l)-lactic acid; in U.S. Pat. No. 4,640,709, BEESTMAN et al. have proposed the preparation, by polycondensation, of small spheres whose membranes consist of a polymeric material such as polyurea, polyamide, polysulfonamide, polyester, polycarbonate and polyurethane.
However, although the latter documents afford capsules of nanometer dimensions, there is a major problem in the fact that these particles generally have poor biocompatibility and poor biodegradation in vitro and in vivo, which may result in the accumulation of a high concentration of particles in certain organs, the toxicity of certain monomers, certain polymerization by-products or certain degradation by-products, and poor protection of the active principles when they are only adsorbed on the surface of the nanoparticles, thereby giving an inadequate delaying effect.
SUMMARY OF THE INVENTION
One object of the present invention is thus to solve the new technical problem which consists in providing a solution making it possible to produce particles of nanometer dimensions, called nanoparticles, especially in the form of nanocapsules or nanospheres exhibiting good biocompatibility, good biodegradation in vivo and zero toxicity or a very low toxicity, together with very good protection of the active principles and a significant delaying effect.
A further object of the present invention is to solve the abovementioned new technical problem in a simple and inexpensive manner which can be used on the industrial scale.
The present invention makes it possible for the first time to solve these technical problems in a simple, inexpensive and reliable manner which can be used on the industrial scale and in the field of cosmetics, pharmacy or agri-foodstuffs, by the production of particles or capsules of submicron dimensions, i.e. with a size of less than 1 &mgr;m and especially of between about 100 and 800 nanometers.
Thus, according to a first feature, the present invention provides a process for the production of capsules of very small dimensions, called nanocapsules, with crosslinked protein-based walls, which comprises preparing a very fine emulsion of said proteins called a nanoemulsion, either of the water-in-oil type or of the oil-in-water type, and forming said nanocapsules from said nanoemulsion, wherein an interfacial crosslinking reaction is carried out, (without heating,) between said proteins and a crosslinking agent comprising reactive groups capable of reacting with the reactive groups of said proteins, particularly acylatable groups, so as to produce said nanocapsules with crosslinked protein-based walls.
In one variant of this process, the viscosity difference between the liquid phases present is reduced by the addition of a viscosity modifier to one of the two phases.
In another variant of this process, the viscosity modifier is capable of modifying the viscosity by a factor of at least 4 and preferably at least 10, relative to the phase to which said modifier is added.
In another variant of this process, in the case of the formation of a water-in-oil emulsion, said viscosity modifier is added to or substituted for the oily phase so as to increase the viscosity by a factor of at least 4, relative to the viscosity of the oily phase conventionally used.
In another variant of this process, in the case of an oil-in-water emulsion, the viscosity of the aqueous phase is reduced either by reducing the proportion of protein or by adding a viscosity modifier to the aqueous phase (viscosity reducer) so as to reduce its viscosity, and preferably by a factor of at least 4, relative to the viscosity of the aqueous phase conventionally used.
In another variant of this process, the protein used is a protein with a film-forming effect which is preferably selected from the group consisting of an animal protein such as elastin, keratin, silk, albumin, milk proteins or structural proteins such as collagen, especially collagen without telopeptide, or atelocollagen a vegetable protein such as wheat, maize, oat or almond protein; and a protein originating from the marine environment, extracted especially from fish, algae or else plankton or micro-plankton.
In another variant of this process, the above-mentioned protein has a molecular weight of at least 50,000 Daltons, this protein being used by itself or in a mixture.
In another variant of this process, the proportion of protein in the emulsion solution varies between 0.1 and 5% by weight, based on the total weight of the emulsion.
In another variant of this process, the protein is initially dissolved in a b
Huc Alain Roger
Perrier Eric Jean-Luc
Coletica
Millen White Zelano & Branigan P.C.
Page Thurman K.
Pulliam A.
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