(19) & (11) EP 2 502 943 A1 (12) EUROPEAN PATENT APPLICATION (43) Date of publication: (51) Int Cl.: 26.09.2012 Bulletin 2012/39 C08F 212/08 (2006.01) C08F 222/08 (2006.01) C08F 2/02 (2006.01) (21) Application number: 12173168.1 (22) Date of filing: 30.03.2007 (84) Designated Contracting States: (72) Inventors: AT BE BG CH CY CZ DE DK EE ES FI FR GB GR • Colt, Monica HU IE IS IT LI LT LU LV MC MT NL PL PT RO SE 76300 Rehovot (IL) SI SK TR • Bucevschi, Mircea Dan Designated Extension States: 76300 Rehovot (IL) AL BA HR MK RS (74) Representative: Zeestraten, Albertus W. J. (30) Priority: 30.03.2006 US 787191 P Exter Polak & Charlouis B.V. (EP&C) P.O. Box 3241 (62) Document number(s) of the earlier application(s) in 2280 GE Rijswijk (NL) accordance with Art. 76 EPC: 07759822.5 / 2 007 824 Remarks: This application was filed on 22-06-2012 as a (71) Applicant: Exotech Bio Solutions Ltd. divisional application to the application mentioned 32100 Kiryat Gat (IL) under INID code 62. (54) Styrene-maleic anhydride copolymers for bioapplications and their preparation (57) The present invention discloses styrene-maleic maleic anhydride monomers, which makes the copoly- anhydride copolymers preparations using solventless mers particularly suitable for bioapplications. techniques. The solventless method resulted in reduced amounts of residues, such as unreacted styrene and/or EP 2 502 943 A1 Printed by Jouve, 75001 PARIS (FR) 1 EP 2 502 943 A1 2 Description study, and antimicrobial properties of acriflavine bound to SMA. Patel, H. A. et al. Die Angewandte Makromole- Related Applications kulare Chemie 1998, 263, 25-30. Patel, H. A. et al. report similar findings for SMA bound ampicillin. Patel, H. A. et [0001] This application claims the benefit of priority to 5 al. Die Angewandte Makromolekulare Chemie 1999, United States Provisional Patent Application serial 271, 24-27. In both cases, advanced purification of the number 60/787,191, filed March 30, 2006, which is here- SMA copolymer was necessary to make the composition by incorporated by reference in its entirety. suitable for bio-application. [0008] Ottenbrite, R. M. and Spiridon, D. disclose the Field of the Invention 10 use of SMA copolymers as antitumor effectors. Ot- tenbrite, R. M. and Spiridon, D demonstrate the biocom- [0002] The invention relates to, in part, styrene- maleic patibility of the SMA copolymers but only after rigorous anhydride copolymers. It relates to methods of synthe- purification steps. Ottenbrite, R. M. J. Macromol. sizing such polymers using bulk polymerization methods Sci.-Chem. 1985, A22(5-7), 819-832; Spiridon D. Poly- which yield partially hydrolysed polymers in acidic form. 15 mer International, 1997, 43, 175-181. The invention also relates to methods of preparing sty- [0009] US Pat. Nos. 3,980,663 and US Pat. No rene-maleic anhydride copolymers that have a low resid- 4,381,784 disclose using SMA copolymers as water ab- ual content of monomers (styrene and maleic acid) and sorbing materials for hygienic care. US Pat. No. which are suited to bioapplications as solutions, hydro- 3,939,108 and US Pat. No. 6,590,019 disclose SMA co- gels or solids for medical bioengineering, tissue engi- 20 polymers as an adhesive useful for bottle labeling. US neering, pharmaceutical products, hygienic care, cos- Pat. No. 5,080,888 discloses SMA copolymers in cos- metics, biotechnology, food industry, agriculture, absorb- metics. US Pat. No. 4,980,403; US Pat. No. 5,104,957; ent textiles and the like. US Pat. No. 5,480,427; and US Pat. No. 6,127,451 dis- close using SMA copolymers as biomaterials. US Pat. Background of the Invention 25 No.4,153,682; US Pat. No. 6,500,447; and US Pat. No. 6,531,160 disclose using SMA copolymers in pharma- [0003] Styrene-maleic anhydride copolymers (SMA ceutical products as drug delivery systems. copolymers) are used in numerous applications but their [0010] A condition for using SMA copolymers in a bio- use in bio-applications is hindered by their lack of purity application is that its chemical purity be as high as pos- and residual hazardous contaminates. 30 sible, while its hazardous contaminant content be as low [0004] The FDA approved SMA copolymers as indirect as possible. Contamination of SMA copolymers has two food additives for use as articles or components of arti- causes derived from the polymerization processes used: cles that contact food items (Code of Federal Regula- 1) non-reacted monomers, and 2) auxiliaries of polym- tions, Sec. 177.1820 "Styrene-maleic anhydride copoly- erization such as: organic solvents, initiators...etc. mers", Title 21, Volume 3 p 304-305, revised as of April 35 [0011] For example, SMA coplymers are prepared 1, 2000). The FDA specified that SMA copolymers have mainly by solvent based methods, but these methods are a minimum average molecular mass of 70,000 and con- also the most contaminating because, besides unreacted tain not more that 15 weight percent maleic anhydride, monomers and initiators, there is residual solvent to re- 0.3 weight percent residual styrene monomer, 0.1 weight move. See US Pat. No. 2,286,062; US Pat. No. percent residual maleic anhydride monomer, 0.00640 2,378,629; US Pat. No. 2,866,775; US Pat. No. weight percent maximum extractible fractions in distillat- 3,157,595; US Pat. No. 3,989,586; 4,105,649; and US ed water at reflux temperature for 1 hr, and 0.02 weight Pat. No. 4,126,549. The additional purification steps re- percent maximum extractible fractions in n-heptane at quired represent an important economical restriction to 73 °F for 2 hr. using SMA copolymers in bio-applications compared to [0005] Sethi, N. et al. demonstrated the biocompatibil- 45 other category of polymers. ity of SMA commercial products, but a multistep, complex [0012] Bulk polymerization is less contaminating than purification procedure was required before utilization. solution polymerization because there are no organic sol- Sethi, N. et al. Contraception 1989, 39, 217-226. The vents. See Voss, A. et al. in US Pat. No. 2,047,398; same conclusion was reported by Lohiya, N. K et al. Lo- Graves, G. D. in US Pat No. 2,205,882 and Lee Y. C. et hiya, N. K. et al. Int. J. Androl. 2000, 23, 36-42. 50 al. in US Pat No. 4,051,311 disclosing maleic anhydride [0006] Wagner J. G. et al in US Pat. No. 2,897,121 and copolymers of styrene, vinyl acetate, and others by bulk Chen, Y. R. et al in Colloids and Surfaces A: Physico- polymerization methods, with and without peroxidic initi- chem. Eng. Aspects, 2004, 242, 17-20 present the utili- ators. The content of maleic anhydride monomers is less zation of SMA copolymers as additives for a pharmaceu- than 55% by weight in the initial mixture of comonomers. tical carrier for oral administration. Although the authors 55 Baer, M. in US Pat. No. 2,971,939 presents the synthesis assert that the polymers can be used for bio-applications, of styrene maleic anhydride copolymers with a content supporting data, such as purity, is not presented. of maleic anhydride less than 12% by weight using bulk [0007] Patel, H. A. et al. disclose the synthesis, release polymerization methods. In these disclosures, a mixture 2 3 EP 2 502 943 A1 4 of styrene and peroxidic initiator is allowed to homopol- number of potential bio-applications. ymerize until a 3-5% conversion. At this point, maleic [0016] Copolymerization yields are highest (approxi- anhydride monomer is added at a constant rate to form mately 95%) when using equimolecular monomer feeds, a maleic anhydride in styrene solution. The SMA copol- and with processes that achieve good mass transfer of ymer is then extracted from the reaction mass with ben- 5 reactants (such as those achieved by polymerization in zene and ultimately separated from the solution by pre- organic solvent media). Processes that don’t use equi- cipitation with methanol. molecular monomer feeds induce a high value of con- [0013] Disadvantages with these bulk polymerization version only for the monomer which is present in the least methods include a) incomplete conversion of monomers amount. Klumperman, B. et al. Polymer 1993, 34, to copolymer due to increasing impedance of diffusion 10 1032-1037; Klumperman, B. Macromolecules, 1994, 27, of the reactants to reaction centers because of increasing 6100-6101; Klumperman, B. et al. Eur. Polym. J. 1994, reaction mass viscosity; b) purification to remove non- 30, 955-960. reacted monomer is difficult and realized by dissolution [0017] The most difficult aspect of purifying SMA co- into specific solvents (such as acetone or benzene), fol- polymers is removal of unreacted styrene because it is lowed by precipitation, extraction with alcohols or water, 15 an organic compound liquid, insoluble in water, but sol- and drying; c) generation of large amounts of reaction uble in organic solvents with high boiling points that make heat risking explosion; d) handling of reaction mass is it difficult to dry, even in high vacuum. Boundy, R. H. difficult; and e) purification solids after precipitation by "Styrene, its polymers, Copolymers and Derivatives," Re- extraction is neither cost effective nor ecologically friend- inhold Publishing Corporation, New York, 1952, pp. ly. 20 860-865. [0014] Cutter, L. A. in US Pat. No. 4,145,375 presents [0018] Unreacted maleic anhydride can be removed a process for copolymerizing styrene and maleic anhy- by simple hydrolysis with water to form maleic acid which dride which involves a sequence of operations in which has a high solubility in water (greater than 4.4 x 10 5 ppm maleic anhydride is first gradually admixed with styrene (wt) at 25°C; Yaws C.L.