Synthetic resins or natural rubbers -- part of the class 520 ser – Synthetic resins – At least one aryl ring which is part of a fused or bridged...
Reexamination Certificate
1998-09-02
2002-02-26
Yoon, Tae H. (Department: 1714)
Synthetic resins or natural rubbers -- part of the class 520 ser
Synthetic resins
At least one aryl ring which is part of a fused or bridged...
C524S916000, C523S103000, C424S439000, C424S486000, C424S501000, C525S088000, C528S354000, C528S271000, C528S361000, C528S499000, C528S501000
Reexamination Certificate
active
06350812
ABSTRACT:
The subject-matter of the invention is novel hydrogels based on triblock copolymer, their preparation and their application.
It is known that hydrogels are obtained conventionally with solid materials which swell in water by absorbing significant volumes of water. Hydrogels are generally composed of polymers which form, in water, a three-dimensional network capable of retaining in particular large molecules, such as proteins. Hydrogels can be prepared from crosslinked hydrophilic polymers.
Hydrogels have been recommended in particular as implantable pharmaceutical substrates which make possible the gradual release of drugs and in particular of macromolecules, such as proteins. Hydrogels are generally non-biodegradable and the drug is released by a diffusion phenomenon.
Provision has recently been made for the preparation of biodegradable hydrogels based on poly (hydroxyacid) -poly (ethylene glycol) -poly (hydroxyacid) triblock copolymers by using water-soluble copolymers, with acrylate endings, which are crosslinked in situ by photopolymerization of aqueous solutions of the polymer; see A. S. Sawhney et al., Macromolecules, 26, 581-587 (1993).
Document EP-A-0,092,918 describes rigid implants composed of non-crosslinked block copolymers comprising a polypeptide having a pharmacological activity. These implants gradually swell by absorbing water present in the living medium in which they are implanted.
A novel process has now been discovered which makes it possible, starting with certain triblock copolymers, to very rapidly obtain soft hydrogels containing a weight of water at least equal to the weight of triblock copolymer. These soft hydrogels can be easily deformed and can in particular pass through a hollow needle having an internal diameter of 2 mm and in particular through a hollow needle with an internal diameter of 1 mm.
Whereas hydrogels were mainly used until now for the trapping and the gradual release of hydrophilic macromolecules, the hydrogels of the present invention exhibit the distinguishing feature of being able to retain not only hydrophilic macromolecules but also hydrophobic substances.
The subject-matter of the invention is thus a hydrogel based on triblock copolymer and on water, characterized in that it is provided in the form of a soft hydrogel comprising an amount of water at least equal, by weight, to that of the copolymer and in that the said copolymer corresponds to the formula (I):
X-G-Y (I)
in which G is a non-hydroxylated hydrophilic linear polymer block comprising p repeat units, p being a number which can vary from 10 to 150,
X and Y each represent a polyester block respectively comprising m and n repeat units,
the ratio (m+n)/p being sufficiently high for the said copolymer to be insoluble in water and the said ratio (m+n)/p being chosen such that the addition of water to a solution of the copolymer in a water-miscible organic solvent causes the formation of a soft hydrogel capable of retaining an amount of water at least equal to the weight of the said copolymer.
The invention also relates to a product obtained by lyophilization of a hydrogel as defined above. Such a lyophilisate is capable of rapidly absorbing a high proportion of water and of restoring a water-swollen soft hydrogel analogous to the hydrogel from which it was produced.
The ratios (m+n)/p which are suitable can be determined in each case by routine experiments, as will be specified hereinbelow. Generally, the suitable ratios (m+n)/p are numbers between 1 and 5 approximately.
In particular, the ratio (m+n)/p can be chosen so that the said gel is capable of retaining an amount of water at least equal to twice the weight of copolymer which it contains.
The number p can vary in particular from 10 to 120 and in particular from 15 to 100.
Of course, the blocks X and Y can be alike, that is to say composed of the same repeat units.
Study of copolymers analogous to those of formula (I) shows that, when the ratio (m+n)/p is sufficiently low, the copolymers are soluble in water. When the said ratio increases, the corresponding copolymers are only slightly soluble in water and give cloudy solutions, probably due to the formation of micelles. When the said ratio increases further, the polymers become insoluble in water: brought into contact with water, the polymers, in the form of powders, do not pass into solution and no longer give rise to the formation of micelles, for example after 24 hours of contact with water at room temperature, even if the copolymers can swell slightly on contact with water.
In accordance with the discovery which forms the basis of the invention, such water-insoluble copolymers can give hydrogels starting from their solution in a water-miscible organic solvent, according to the method indicated hereinabove. However, when the length of the hydrophobic links X and Y, for the same central block G, increases (in other words, when the ratio (m+n)/p increases) beyond a certain value, the hydrogels thus obtained contain increasingly low amounts of water. It is thus easy to determine experimentally, for each type of polymer of formula (I), the value of the ratio (m+n)/p beyond which the hydrogels are no longer capable of retaining a large mass of water: in fact, with such polymers in solution in the water-miscible organic solvent, the formation of a water-swollen hydrogel is not observed when water is added but rather the formation of a precipitate of the copolymer which occupies a lower volume than that of the starting organic solution.
The optimum length of the X and Y chains can thus be determined by simple routine experiments.
For example, in the case of poly(lactic acid)poly(ethylene oxide)-poly(lactic acid) copolymers, it is observed that, when the ratio (m+n)/p is less than approximately 0.2, the copolymers are soluble in water. When the said ratio is between 0.2 and 1 approximately, the copolymers are only slightly soluble in water and give cloudy solutions. When the said ratio is greater than approximately 1, the copolymers are insoluble in water. With the latter copolymers, it is possible to obtain, starting from an organic solution of the copolymer, hydrogels capable of retaining an appreciable amount of water, when the ratio (m+n)/p is between 1 and 5 and in particular between 1 and 4 approximately. Particularly satisfactory hydrogels are obtained in particular when this ratio varies within the range from 1.5 to 3 approximately. The numbers m and n are thus such that the ratio (m+n)/p is greater than 1 and lower than a maximum value beyond which the said copolymer is no longer able to form a hydrogel capable, under the conditions indicated hereinabove, of retaining a weight of water at least equal to the weight of the said copolymer.
Other points of information on this subject will be given hereinbelow by describing the preparation of the hydrogels.
The polymer blocks which represent X and Y, in the formula (I), are hydrophobic linear polyester blocks. These are in particular aliphatic polyesters.
It is known that aliphatic polyesters can be obtained:
a) either by polycondensation of a hydroxyacid with itself or by polycondensation of several hydroxyacids,
b) or by polymerization by ring opening of lactones,
c) or by polycondensation of diacids and diols.
Among the polyesters derived from hydroxyacids, mention may in particular be made of those which derive from monomers chosen from lactic acid, glycolic acid, malic acid monoesters (for example, alkyl or aralkyl monoesters, or monoesters resulting from the monoesterification of malic acid with a hydroxylated active principle, in particular a hydrophobic active principle; see, for example, U.S. Pat. Nos. 4,320,753 and 4,265,247); lactides (D-lactide, L-lactide and D,L-lactide), glycolide, para-dioxanone, and the like. The polymer blocks represented by X and Y can also be copolymers formed by the said monomers with one another.
Among the polymers derived from diacids and diols, mention may be made, for example, of poly(ethylene glycol succinate)
Espartero-Sanchez José-Luis
Li Suming
Rashkov Iliya
Vert Michel
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