Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Liposomes
Reexamination Certificate
1999-04-28
2001-04-24
Kishore, Gollamudi S. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Liposomes
C424S001210, C424S009321, C424S009510, C424S417000, C424S900000, C424S489000, C424S490000, C424S491000, C424S492000, C424S493000, C424S497000, C264S004100, C264S004300, C264S004600, C428S402200
Reexamination Certificate
active
06221387
ABSTRACT:
The present invention relates to gelified microspheres, to their method of preparation and to their applications.
Microspheres, which are particles of spherical shape, the size of which ranges, generally, between 1 and 1250 &mgr;m, are composed of a support material containing the encapsulated substance and are of particular advantage, either when it is desirable to administer a medicament in a form which makes possible the controlled release of the active component over a certain period, in order to provide for a prolonged pharmacological effect, or when it is necessary to protect the said active component from premature degradation in the digestive tract.
Depending on the structure of the support material, two types of microcapsules are distinguished:
microcapsules of reservoir type, in which the support material is a solid envelope of variable thickness containing the substance to be encapsulated,
microcapsules of matrix type, also known as microspheres, in which the support material is a continuous network in which the substance to be encapsulated is dispersed.
Within the meaning of the present invention, the term microcapsule or microsphere comprises only microcapsules or microspheres of matrix type.
Many substances can be encapsulated: it can relate to chemicals, such as medicaments, or alternatively to macromolecules, such as enzymes, and also to living cells.
Microspheres are used in many fields, such as pharmaceuticals, the biotechnology industry, cosmetology, the agri-foodstuffs industry, the paper-manufacturing industry, and the like.
A number of methods for the preparation of microcapsules have been described; mention may in particular be made of:
the phase-separation method, described in particular in U.S. Pat. No. 4,675,189 and Application EP 52,510, which describes microcapsules prepared by a phase-separation technique using a coacervation agent, such as mineral oils or vegetable oils.
However, the microcapsules prepared by this method and by other analogous methods have the disadvantage of forming clusters (inter-adhesion of particles) during the preparation of the said microcapsules.
the solvent-evaporation method, described in particular in U.S. Pat. No. 4,479,911, Application EP 301,969 and Application EP 145,240; this method comprises the separate formation
of an organic phase by dissolution of a suitable polymer in a volatile water-immiscible solvent and
of an aqueous phase containing the advantageous active principle,
the addition of the aqueous phase to the organic phase, the mixing of the two phases with agitation and/or in the presence of an emulsifying agent and then the evaporation of the solvent, generally with agitation and at room temperature, in order to obtain the desired microcapsules.
Application EP 145,240 more particularly describes microcapsules produced by preparing a W/O emulsion (primary emulsion) comprising an inner aqueous layer containing a hydrophilic substance and a so-called medicament-retention substance (natural or synthetic mucilage or high-moleculer-weight compounds and more particularly gelatin) and an oily layer containing a polymer, preferably a polylactic acid or a copolymer of lactic acid and of glycolic acid or their mixtures, in a water-immiscible solvent such as dichloromethane, by then thickening or solidifying the said inner aqueous layer so as to obtain a viscosity greater than 5,000 centipoises, by then preparing a secondary W/O/W emulsion in the presence of a suitable surface-active agent and, finally, by subjecting the emulsion thus obtained to evaporation of the solvent. The process described in this Application makes it possible to obtain microcapsules with a diameter of between 0.5 and 400 &mgr;m.
However, these microcapsules or microspheres of the prior art have the major disadvantage of having diameters of the order of a &mgr;m or more (1-1250 &mgr;m); now, there exist many applications for which it is necessary and/or particularly advantageous to be able to have available particles having a significantly smaller diameter, in particular of the order of an nm or more, for example between 20 and 600 nm.
The Applicants have consequently devoted themselves to the goal of developing gelified microspheres, the diameter of which can be controlled and can reach, if necessary, 20 nm.
The subject of the present invention is microspheres, characterized in that they comprise a gelified polar core (GPC) around which are superimposed, concentrically and alternately, n lipid bilayers or a aqueous layers in the liquid state and n gelified polar layers, n being an integer, and in that they are capable of being obtained by delipidation of liposomes, called lipogelosomes® (trademark applied for on behalf of the company Lipogel and denoting liposomes with a gelified polar core), of the type containing at least one outer lipid bilayer and at least one inner polar aqueous phase containing a gelified substance.
Such microspheres advantageously:
exhibit a controllable diameter, preferably of between 20 and 600 nm,
are stable,
can enclose water-soluble active substances,
allow the preparation of both immediate-release or delayed-release forms, depending on the melting point of the gelified substance,
can be used as the basis for the attachment of ligands, of substances which are poorly recognized by the reticuloendothelial system (stealthy microspheres) or of electrically-charged compounds (electrical targeting in electrotherapy), and
are capable of being rendered stealthy (non-recognition by the reticuloendothelial system) when they exhibit a diameter of the order of 20-40 nm.
In accordance with the invention, the gelifiable substance is selected from polymerizable or non-polymerizable gelifiable compounds, such as polysaccharides, polypeptides or polyacrylamides.
The non-polymerizable gelifiable substance is preferably selected from gelatin, agarose or carragheenins and the polymerizable gelifiable substance is selected from polyacrylamide gels.
Such liposomes with a gelified polar core or lipogelosomes are described in particular in Patent EP 0,393,049, in which it is specified that they are composed of a bilayer interfacial phase, in the case of unilamellar lipogelosomes, or of a plurality of concentrically superimposed bilayer interfacial phases, in the case of multilamellar lipogelosomes, and of a gelified encapsulated inner polar aqueous phase.
This patent describes, in particular, the method for obtaining such unilamellar or multilamellar lipogelosomes: the gelified encapsulated aqueous phase results from the initial liquid aqueous phase, in which the said lipogelosomes are prepared, by conversion of the said aqueous phase into a gel, due to the presence, in the said aqueous phase, of one or a number of polymerizable or non-polymerizable gelifiable compounds; the non-encapsulated aqueous phase can, in addition, be rendered non-gelifiable by physical, chemical or enzymatic action.
The bilayer interfacial phase or phases are composed, for example, of class-4 lipids (phospholipids), optionally in combination with class-2 lipids and class-3 lipids (free cholesterol) and/or class-5 lipids.
This classification of the lipids, proposed by Professor Hauton et al., based on the partition coefficients K
D
between a polar aqueous phase and a monolayer or bilayer interfacial phase and K
C
between an interfacial phase and a hydrophobic or non-polar phase, will be used (Hauton and Lafont, Biochimie, 1987, 69, 177-204); it is also described in the abovementioned Patent EP 393,049.
Such lipogelosomes (LGS) are generally classified, according to the number of bilayers:
as small unilamellar lipogelosomes (SULGS) and as large unilamellar lipogelosomes (LULGS) and
as multilamellar lipogelosomes (MLGS).
In accordance with the invention, the stage of delipidation of the said lipogelosomes can be carried out in a number of ways and can result in gelified microspheres of controlled diameter:
surface deliDidation of unilamellar or multilamellar limoaelosomes by:
(1) extraction of the surface lipid bilayer of the said unilamellar or multilamellar li
Hauton Jacques
Salles Jean-Pierre
Kishore Gollamudi S.
Lipogel
Oblon & Spivak, McClelland, Maier & Neustadt P.C.
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