Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Matrices
Reexamination Certificate
2000-12-19
2002-08-27
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Matrices
C424S501000, C514S772300, C514S772600, C514S785000
Reexamination Certificate
active
06440461
ABSTRACT:
BACKGROUND OF THE INVENTION
The object of the present invention is novel microspheres which are notably useful in the pharmaceutical field as particulate vectors intended for the transport of biologically active substances, in particular hydrophilic substances (peptides or proteins), with a view to an oral administration.
Another object of the invention is a method of preparing these microspheres, and pharmaceutical compositions containing them.
Within the context of the present description, the term “microspheres” is understood as signifying particles which are roughly spherical, of an average diameter of between 1 &mgr;m and 100 &mgr;m, preferably between 5 and 100 &mgr;m, and which are formed of a continuous matrix, which is more or less dense, of a support material.
These microspheres differ from the microcapsules which are constituted of a wall surrounding a cavity. It is, however, to be noted that the microspheres prepared in a multiple emulsion can comprise a collection of globules which are dispersed in the continuous network constituting them.
In this latter case, the total volume of these globules will generally represent a fraction of between 1:20 and 1:2 of the total volume of the microspheres.
Over the last years, many studies have enabled demonstrating that particulate systems based on polymers can be used for modifying the profile of release of a therapeutically active substance.
It is thus that the microspheres based on synthetic polymers, such as, for example, poly(lactic acid), poly(lactic acid-co-glycolic acid), polystyrene, poly(epsilon caprolactone), poly(methyl methacrylate), or based on methyl cellulose or ethyl cellulose have been prepared by various techniques.
However, the microspheres thus obtained are generally non-biodegradable, and when they are, they are characterised by a very delayed degradation with time.
Thus, in the case of microspheres based on poly(lactic) acid, for example, the degradation is not progressive and takes place at once after a significant time interval.
Further, the lactic polymers degrade in releasing products which are highly acidic which, not only lead to the auto-catalysis of the degradation of the polymer, but are the origin of the induction of incompatibilities with the substances encapsulated.
In the case of the other polymers used, the microspheres have an extremely low speed of degradation, even have no degradation.
The staying time in the organism of such particles can limit the repeated application thereof in man.
Finally, the known microspheres are characterised for the most by a significant hydrophobicity which promotes strong interactions and often denaturing interactions with the substance to be encapsulated, in particular when the latter is of protein or peptide nature.
SUMMARY OF THE INVENTION
It has been discovered, and this constitutes the basis of the present invention, that it was possible to prepare novel microspheres which enable remedying the drawbacks of the microspheres of the state of the art.
Thus, according to a first aspect, the object of the present application is microspheres constituted of a continuous network of a support material in which a substance is optionally dispersed, characterised in that said support material contains at least 70% by weight of a homopolymer constituted of recurring units of the following general formula (I):
in which:
R
1
represents an alkyl group having 1 to 6 carbon atoms or a (CH
2
)
m
—COOR
3
group in which m is an integer of between 1 and 5 and R
3
represents an alkyl group having 1 to 6 carbon atoms;
R
2
represents an alkyl group having 1 to 6 carbon atoms; and
n is an integer of between 1 and 5.
It has been demonstrated that on account of the chemical nature of the polymers forming their matrix, these novel microspheres:
have progressive and modulated degradation kinetics;
enable encapsulating, with great efficiency, hydrophilic substances, notably substances of biological origin.
Further, it has been observed, in an entirely surprising and unexpected manner, that these microspheres:
can induce a stimulation of the immune response when they are combined with an antigen;
enable in certain cases the suppression of hypersensitivity pathological reactions (induction of a tolerance) when they are administered via the oral route.
DETAILED DESCRIPTION OF THE INVENTION
Thus, it is the nature of the polymeric material forming the matrix of the microspheres which constitutes the originality of the present invention.
This polymeric material is essentially formed of a homopolymer constituted of recurring units of general formula (I).
Such polymers possess the remarkable property of being biocompatible and bioerodable, i.e. they can degrade chemically or biochemically by cleavage of the lateral substituents.
The speed of erosion of the microspheres in accordance with the invention being dependent upon the molecular weight of the support material, the speed can therefore by modulated simply by using a support material having a molecular weight adapted to the speed of erosion desired.
The microspheres according to the present invention thus possess a progressive and modulated bioerosion which enable, for example, the transport of a biologically active substance, dispersed in the support material, up to the location in the organism where its action will be the most efficient.
The bioerosion of the microspheres also prevents their accumulation in the organism; their use is therefore no more limited.
According to a particular characteristic, the homopolymer mentioned above is constituted of recurring units of the general formula (I) in which:
R
1
represents an alkyl group having 1 to 6 carbon atoms;
R
2
represents an alkyl group having 1 to 6 carbon atoms; and
n is a number equal to 1;
and preferably in which R
1
and R
2
represent a CH
2
—CH
3
group.
These different types of polymers of the poly(methylidene-malonate) family are particularly suitable for the encapsulation of hydrophilic substances, notably substances of biological origin, and optionally biologically active substances.
<<Biologically active molecule)) is understood as meaning, in a non-limiting manner, any molecule having a prophylactic or curative biological action, in vitro or in vivo, notably an anti-infectious agent, in particular an antiseptic, antibiotic, antiviral, antiparasitic or antimitotic agent, notably an anticancer agent.
Antibiotic or antiseptic agents which can be used can be rifampicin and colistine for example.
Didanosine, ribavirine, zidovudine, acyclovir, ganciclovir, foscarnet, vidarabine and zalcitabine can be cited in a non-limiting manner as examples of antiviral agents.
Cis-plastin and taxol can, for example, by used as anticaner agents.
According to a currently preferred embodiment of the invention, the support material of the microspheres contains:
from 90% to 99.5% by weight of a homopolymer as defined above; and
from 0.5% to 10% by weight of a copolymer comprising at least one sequence having a hydrophilic character and at least one sequence having a hydrophobic character, said sequence having hydrophobic character preferably comprising at least one recurring unit of the general formula (I).
Advantageously, the sequence having hydrophilic character of the copolymer mentioned above is selected from a poly(oxyethylene), a poly(vinyl alcohol), a poly(vinylpyrrolidone), a poly(N-2-hydroxypropyl methacrylamide), a poly(hydroxyethyl methacrylate), a hydrophilic poly(amino acid) such as a polylysine, a polysaccharide, and will preferably be a poly(oxyethylene).
The copolymer can have a block structure, preferably a di-block structure or tri-block structure, or a grafted structure.
The addition of such copolymers into the support material enables obtaining a homogeneous dispersion of the substance to be encapsulated inside each of the microspheres.
The addition also enables modulating the hydrophilic/hydrophobic ratio of the surface of the microspheres, and this enables preventing or limiting strong and often denaturing interactions with the substance to be encapsulated.
Fu
Breton Pascal
Bru-Magniez Nicole
Couvreur Patrick
Fattal Elias
Le Visage Catherine
Dennison, Schultz & Dougherty
Fubara Blessing
Page Thurman K.
Virsol
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