Cross-linking process of carboxylated polysaccharides

Details Cross-linking process of carboxylated polysaccharides Cross-linking process of carboxylated polysaccharides

2001-06-18

2004-05-11

Wilson, James O. (Department: 1623)

Organic compounds -- part of the class 532-570 series

Organic compounds

Carbohydrates or derivatives

C536S021000, C536S055200, C536S055300, C514S054000

Reexamination Certificate

active

06734298

ABSTRACT:

The present invention refers to a cross-linking process of carboxylated polysaccharides.
The process of the invention provides a high degree of reproducibility of the obtained products, in terms of cross-linking degree, homogeneity of the distribution of the cross-linking chains, and chemico-physical characteristics of the products and the technological characteristics of the articles obtained therefrom.
The reproducibility is particularly important for the applications in the medical, pharmaceutical and dermo-cosmetic fields.
The invention further refers to the products obtainable by said process and their applications in the medical, pharmaceutical and dermo-cosmetic field.
BACKGROUND OF THE INVENTION
The use of macromolecules in the medical/pharrnaceutical field and, more recently, in the dermatological-cosmetic field, is well established. Macromolecules are used in the preparation of pharmaceutical formulations as thickening agents, lubricants, gastro-resistant film coating agents, particularly in the preparation of capsules, gel, colloids and of different devices (e.g. contact lenses, gauzes, etc.). Macromolecules are also used in the preparation of controlled-release formulations of active ingredients.
Reviews of their characteristics and pharmaceutical uses are reported in
1) C. Hansch et Al. Editors—“Comprehensive Medicinal Chemistry”—Pergamon Press, Oxford, 1990—Vol. 1-6;
2) A. Wade and P. J. Wellers Editors—“Handbook of Pharmaceutical Excipients”—Ed. 1994—The Pharmaceutical Press.
Said macromolecules belong to different chemical families and may be either synthetic, or natural or semi-synthetic.
Examples of synthetic macromolecules include polyvinylpyrrolidone, polyoxyethylenealkyl ethers, polyvinyl alcohols, polymethacrylates. Examples of natural macromolecules include native hyaluronic acid (HY) and cellulose.
Examples of semi-synthetic macromolecules include carboxyalkylcelluloses, widely used in the food and personal care industries. These macromolecules are characterized by a linear or poorly branched structure.
A very important modification for increasing the chemical, enzymatic and mechanical strength is provided by cross-linking, which may be carried out both on synthetic and natural (more or less already modified) polymers.
Examples of cross-linked polymers include polymers used for the gastro-protection of tablets or capsules (polymethacrylates), as well as polymers used as emulsifiers, suspending agents, tablet hardeners (Carbopol), cross-linked hyaluronic acids, hereinafter discussed.
For the considered applications, and particularly for the preparation of invasive medical devices which have to be administered parenterally, said polymers must meet a number of requirements, of technical and regulatory kind.
The technical requirements include:
1) high biocompatibility;
2) resistance to enzymatic systems, both tissular or plasmatic (for injectable compositions) and gastrointestinal (for oral compositions).
In some cases a gradual degradation, for instance for the controlled release of a medicament, may be desirable.
This resistance is particularly important when the macromolecule is present in compositions/articles that must last for a long time, e.g. substitutes of the synovial liquid, films, sponges or gels as tissular antiadhesives in different kinds of surgery; in tissular engineering (artificial organs); artificial skins, in the treatment of burns and generally in aesthetic surgery;
3) moldability into different shapes (gels, films, sponges, etc.);
4) possibility to be sterilized chemically or physically without changing the product structure.
According to the regulatory requisites, the composition of the different production batches must be kept constant within very narrow limits; this implies that the production methods are standardized and that the base components have a very low intrinsic variability.
A possible cause of dishomogeneity for macromolecules derives from the dispersion of molecular weights. Said dishomogeneity becomes even higher as a consequence of cross-linking. This may be a serious drawback depending on the field of use and the applicative purposes of the final product.
EP-A-566118 (Kimberly-Clark) discloses cross-linked polysaccharides to be used as super-absorbents for diapers and similar articles.
The process described therein is based on the cross-linking of cellulose by formation of intermolecular amides, esters or ethers between polyamines, polyols or mixtures thereof and the carboxy group of polysaccharides.
The reaction is carried out by heating at about 80° C. the mixture of the polysaccharide with the polyol and/or polyamine. This process is certainly economic and suitable for large scale production where the reproducibility requirements are less stringent.
U.S. Pat. No. 5,465,055 discloses cross-linked polysaccharides (hyaluronic acid and alginic acid) obtained by esterification of COOH of the polysaccliaride and OH groups of other molecules, without insertion of cross-linking arms.
WO 91/9119 discloses microcapsules for islets of Langerhans as biohybrid organs, consisting of alginic acid cross-linked with barium ions.
EP 190215 discloses the cross-linking of different polymers (carboxylated starches, dextran, celluloses) with di- or poly-functional epoxides.
The following cross-linking agents for hyaluronic acids have been proposed:
polyfunctional epoxides are disclosed in U.S. Pat. Nos. 4,716,224, 4,772,419, 4,716,154;
polyalcohols are disclosed in U.S. Pat. No. 4,957,744;
divinylsulfone is disclosed in U.S. Pat. Nos. 4,605,691, 4,636,524;
aldehydes are disclosed in U.S. Pat. Nos. 4,713,448 and 4,582,865;
carboxamides are disclosed in U.S. Pat. No. 5,356,833;
polycarboxylic acids are disclosed in EP-A-718312.
DISCLOSURE OF THE INVENTION
The invention refers to a process for the preparation of cross-linked polysaccharides containing carboxy groups, allowing complete control of cross-linking degree as well as high reproducibility in terms of constant characteristics of the final product.
The process of the invention comprises:
a) activation of the carboxy groups of the polysacchatide by reaction with suitable carboxy activating agents in anhydrous aprotic solvent;
b) reaction of the carboxy activated polysaccharide with a polyamine.
The obtained cross-linked polysaccharide, if desired, may be subjected to sulphation or hemisuccinylation of the free hydroxy groups.
The products obtainable by the process of the invention may also be complexed with metal ions such as zinc, copper or iron ions.
The carboxy-containing polysaccharide which may be used according to the invention may be of natural, synthetic or semi-synthetic origin. Examples of said polysaccharides include Hyaluronic acids (obtained from tissues or bacteria), carboxymethyldextran, carboxymetbylcellulose, carboxymethyl-starch, alginic acids, cellulosic acid, N-carboxy-methyl or butyl glucans or chitosans; heparins with different molecular weights, optionally desulphated and succinylated, derrnatan sulphates, Chondroitin sulphates, heparan sulphates, polyacrylic acids.
Hyaluronic acids, carboxymethylcellulose, heparins, alginic acids and polyacrylic acids are particularly preferred.
Said cross-linked polymers, obtained by different methods, are known and have been proposed for several uses (see, for instance, EP 566118, WO91/9119, U.S. Pat. Nos. 5,465,055, EP 190215, EP 718312, U.S. Pat. Nos. 4,716,224 discussed above).
The carboxy activating agents are usually those used in the peptide chemistry: examples of suitable agents include carbonyldiimidazole, carbonyltriazole, chloromethylpyridylium iodide (CMP-J), hydroxybenzotriazole, p-nitrophenol p-nitropheriyltrifluoroacetate, N-hydroxysuccinimide and the like. The use of chloromethylpyridylium iodide is particularly preferred.
The polyamines have preferably the following general formula:
R
1
—NH—A—NH—R
2
wherein R
1
and R
2
, which are the same or different, are hydrogen, C
1
-C
6
alkyl, phenyl or benzyl groups, A is a C
2
-C
10
alkylene chain, preferably a C
2
-C
6
alkylene chain, optionally substituted by h

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