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Novel Heparin-Like Sulfated Polysaccharides

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Novel Heparin-Like Sulfated Polysaccharides ^ ^ ^ ^ I ^ ^ ^ ^ ^ ^ II ^ ^ ^ II ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ I ^ European Patent Office Office europeen des brevets EP 0 940 410 A1 EUROPEAN PATENT APPLICATION (43) Date of publication: (51) |nt CI * C08B 37/08, A61 K 31/73, 08.09.1999 Bulletin 1999/36 A61 K 47/36 A61 1_ 27/00 (21) Application number: 99200468.9 (22) Date of filing: 23.03.1995 (84) Designated Contracting States: • Magnani, Agnese AT BE CH DE DK ES FR GB GR IE IT LI LU MC NL 153010 San Rocco A. Philli (IT) PT SE • Cialdi, Gloria Deceased (IT) (30) Priority: 23.03.1994 IT PD940054 (74) Representative: (62) Document number(s) of the earlier application(s) in Crump, Julian Richard John et al accordance with Art. 76 EPC: FJ Cleveland, 9591 31 58.2 / 0 702 699 40-43 Chancery Lane London WC2A1JQ(GB) (71) Applicant: FIDIA ADVANCED BIOPOLYMERS S.R.L. Remarks: 72100 Brindisi (IT) »This application was filed on 18 - 02 - 1999 as a divisional application to the application mentioned (72) Inventors: under INID code 62. • Barbucci, Rolando »The application is published incomplete (there is no 53100 Siena (IT) claim number 9)as filed (Article 93 (2) EPC). (54) Novel heparin-like sulfated polysaccharides (57) The invention provides sulfated derivatives of jects and pharmaceutical compositions comprising polysaccharides such as hyaluronic acid and hyaluronic these derivatives. The invention further provides for the acid esters exhbiting anticoagulant, antithrombotic and use of these derivatives in the manufacture of pharma- angiogenic activity, for use in the biomedical area. The ceutical compositions, biomedical objects, biomaterials, invention further provides complex ions, biomedical ob- and controlled drug release systems. F/0.1 Hyal(x)S03 CH2OS03 coa 0<a£ 1 ;N "03S0a r HNCOCH3 < O Hyal2S03 Hyal2.5S03 Hval3.0S03 Hyal3.5S03 WBCT=oo WBCT= 00 O ^> TT= control TT= 30.0 TT= 38.3 TT= 00 O) -2 -1 o Img = 2.6 x 10 mgHep 1mg= 1.3x10 mgHep 1mg= 1.6x10 mgHep a. LU Printed by Jouve, 75001 PARIS (FR) EP0 940 410 A1 Description BACKGROUND OF THE INVENTION 5 Field of the Invention [0001] The present invention relates to the homogeneous sulfation of polysaccharides and semisynthetic derivatives thereof, in particular glycosaminoglycans such as hyaluronic acid and its esters and tetraalkylammonium salts, for the preparation of new biomaterials useful in biomedical, health care, and pharmaceutical applications, and to such bio- 10 materials perse. Such sulfated derivatives exhibit antithrombotic activity as evidenced by the lengthening of both the thrombin time and the whole blood clotting time. Moreover, the absence of hemolysis and the growth and shape of endothelial cells placed in contact with such sulfated derivatives indicate that these materials are promising heparin- like compounds. is Description of Related Art [0002] Many molecules of biological origin are polyelectrolytes, and their interactions are very important in a wide variety of biochemical reactions. Consequently, synthetic and/or semisynthetic polyelectrolytes have been in use for some time now. These polyelectrolytes mimic the biological characteristics of natural polyelectrolytes, and can have 20 somewhat different characteristics compared to the starting material. [0003] Polyelectrolytes of biological origin include sulfated polysaccharides, and in particular, heparin and its deriv- atives (D.A. Lane and U. Lindahl, Eds., Heparin-Chemical and Biological Properties, Clinical Applications, Edward Arnold, London), which play an important role in cell-substrate interactions, particularly in the process of viral activity inhibition, in the process of blood coagulation, in lipid removal, etc. 25 [0004] Heparin is the most biologically reactive member of the family of sulfated glycosaminoglycans. It is well known for its antithrombotic and anticoagulant properties. In fact, it is extensively used in the management of cardiovascular diseases and contributes enormously to the success of open heart surgery. Nevertheless, the structure of heparin is not simple and, due to the number of variations, is not entirely known. Commercial heparins consist of a spectrum of 21 heparins (Nader et al. (1 974) Biochem. Biophys. Res. Commun. 57:488) ranging in molecular weights from 3,000 30 to 37,500 in varying anticoagulant activities. [0005] The blood anticoagulant activity of heparin is attributed to structural features, e.g., degree of sulfation, degree of dissociation, particular sequences of COO" and SO"3 groups, as well as to molecular shape and size. These factors appear to be related to biological activity by virtue of their importance in the ion binding capacity of heparin (Stivala et al. (1967) Arch. Biochem. Biophys. 122:40). By virtue of its highly negatively charged nature, heparin has a strong 35 affinity for cations, and its activity is pH-dependent. [0006] Most of the readily available natural polysaccharides have been sulfated in an attempt to obtain heparin an- alogues (Hoffman et al. (982) Carbohydrate Res. 2:115; Kindness et al. (1980) Brit. J. Pharmac. 69:675; Horton et al. (1973) Carbohydrate Res. 30:349; Okadaetal. (1979) Makromol. Chem. 180:813; Kikuchi etal. (1979) Nippon Kagaku Kaishi 1 : 1 27; Manzac etal. (1981) Proc. Third M.I.S.A.O. 5:504), and recently, sulfate, carboxylic, and sulfonate groups 40 were attached to synthetic polymers such as polystyrene (Kanmaugue et al. (1985) Biomaterials 6:297) and poly- urethane (Ito et al.(1992) Biomaterials 13:131). The anticoagulant activities of these materials were much lower than that heparin, and were dependent on the type and binding of the substituents, the degree of substitution, and sequenc- es. [0007] Some chemical reactions are known which make it possible to sulfate polysaccharides (WO 88/00211 ; EP 0 45 340 628; Nagasawa et al. (1986) Carbohydrate Research 158:183-190), but it has not yet been possible to obtain sulfated polysaccharides which, besides the chemical and chemical-physical characteristics peculiar to such polysac- charides, also possess new characteristics, such as anticoagulant activity. [0008] FR-A-2584728 discloses a process for sulfating a glycosaminoglucan in the form of a salt that is soluble in an organic medium. FR-A-2584728 discloses that the glycosaminoglucan is preferably selected from dermatan sulfate, so the chondroitins, the chondroitin sulfate or hyaluronic acid. A degree of sulfation in the range 2 to 4 is disclosed for the sulfated glycosaminoglycans in general. [0009] US-A-2599172 discloses sulfuric acid esters of hyaluronic acid and processes for preparing such esters by esterification with chlorosulfonic acid and fuming sulfuric acid, particularly at low temperature. [0010] WO-A-89/07932 discloses the use of a sulfated saccharide or a salt or a complex thereof as an ingredient in 55 topical preparations for the prophylactic or treatment of diseases or conditions of the tooth or tooth-supporting tissue. Preferably, the sulfated saccharide is a polysulfated or persulfated saccharide, e.g. sucralfate (sucrose oktakis) hydro- gen sulfate (aluminium complex) or a sodium and/or potassium salt of sucrose oktakis (hydrogen sulfate). The prep- aration may be in the form of a solution, suspension, salve, paste, powder, gel, cream, dental fixative, periodontal 2 EP0 940 410 A1 implant, chewing gum, chewable tablet, effervescent tablet or lozenge. SUMMARY OF THE INVENTION 5 [0011] The present approach to studying the structural properties associated with the anticoagulant properties of polysaccharides was first to choose polymers possessing well-defined chemical groups consisting of regular repeating units, and secondly to modify their chemical structure. [0012] Such molecules must therefore: 10 (1) Contain regular sequences of monomeric units, and (2) Be chemically modifiable without destroying their structure. [0013] Hyaluronic acid, the major component of the mammalian extracellular matrix, consists of alternating units of N-acetylglucosamine and glucuronic acid residues, and therefore seems a suitable macromolecule. is [0014] The sulfation of alcoholic hydroxyls present in the polymeric chain of a polysaccharide or of one of its semi- synthetic derivatives by the use of a suitable sulfating agent can lead to the formation of new derivatives with chemical- physical characteristics, but most of all biological characteristics, which are different from those of the starting material. [0015] The polyelectrolyte polysaccharides which can be used as substrates in the present invention include gly- cosaminoglycans. First and foremost among these is hyaluronic acid and the semisynthetic derivatives thereof. Some 20 particularly important semisynthetic derivatives of hyaluronic acid are esters thereof with alcohols of the aliphatic, araliphatic, heterocyclic and cycloaliphatic series, designated "HYAFF," that are described in U.S. Patents 4,851 ,521 , 4,965,353, and 5,202,431, and EP 0 216 453. Sulfation of such pre-processed biomaterials is a novel feature of the present invention. In this case, the sulfation reaction no longer occurs in the homogeneous phase, but rather on the surface of the biomaterial in the heterogeneous phase, activating the exposed hydroxyl groups toward the reaction 25 solvent. [0016] The degree of sulfation that can be obtained directly on the biomaterial is an important characteristic, and requires careful kinetic control. To avoid the solubilization of the biomaterial, induced by the increased hydrophilic nature of the polymer which constitutes the matrix, the number of -S03 groups per dimeric unit must not exceed
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