Oxidized celluloses containing 3-25.6% (w/w) carboxylic content represent an important class of biodegradable polymers. Ashton, U.S. Pat. No. 3,364,200 (1968). They are prepared from cellulose, the most abundant natural polymer, by treatment with an oxidant under controlled conditions. See e.g. Heinze and Glasser (1998).
Oxidized cellulose containing 16-24% is commonly and widely used in humans to stop bleeding during surgery, and to prevent the formation and reformation of postsurgical adhesions. Studies also show that such oxidized celluloses possess antibacterial activity [Abaev et al. (1986)], promote bone regeneration [Finn et al. (1992)], and are useful in periodontal therapy [Pollack et al. (1992)]. These properties have been attributed to the polyglucuronic acid structure of oxidized cellulose.
Alpaslan et al. (1997) showed that oxidized cellulose is well tolerated by soft tissues. C. C. Canvern (1996) reported that oxidized cellulose soaked with thrombin is helpful in preventing acute kinking of coronary bypass grafts and postoperative hemorrhage due to oozing from the anastomotic suture lines, devastating complications of myocardial re-vascularization. U.S. Pat. No. 5,169,840 discloses that oxidized cellulose is also useful to potentiate antibody production in response to vaccine antigens.
Oxidized cellulose has also been investigated as an immobilizing matrix for amine drugs, enzymes, and proteins. For instance, Dol'berg et al. (1974) reported the preparation, characterization and evaluation of ionic complexes of kanamycin sulfate and sulfanilamide with oxidized cellulose. Compared to free drugs, these complexes exhibited biological effects in excess of twenty days, and were readily absorbed in vivo. Adrenalone complexed with oxidized cellulose showed prolonged antiseptic and anesthetic activities and was useful for treating parodontosis. Balakleevskii (1986); Sonavaria, (1995). Firsov et al. (1987) found that the ionic complexes of lincomycin and oxidized cellulose were less irritating to the skin and mucous membranes. Implants of an ionic complex of gentamycin and oxidized cellulose showed antibiotic concentrations at the site of implantation for 30 days.
Recently, several chemotherapeutic agents, such as photrin [Kaputskii et al. (1995)], dimetpramide [Kosterova et al. (1993)], and a mixture of methotrexate and hydroxythiamine [Zimatkina (1996)], have been immobilized on oxidized cellulose and were shown to be more effective than the respective free drugs. When trypsin was immobilized on oxidized cellulose, it exhibited higher activity than when it was immobilized on phosphate or amino functionalized cellulose. Alinovskaya et al. (1989). Increased activity was also observed when proteinase, an enzyme, was immobilized on oxidized cellulose. Alinovskaya (1988).
Studies show that the carboxyl content and degree of polymerization (DP) of oxidized cellulose play important roles in the degradation of oxidized cellulose in vitro and in vivo. In general, the higher the carboxyl content, or the lower the DP, the faster the rate of degradation of oxidized cellulose. Ashton (1968). In-vitro solubilization and degradation studies have shown oxidized cellulose to be readily hydrated. About 90% of oxidized cellulose (carboxyl content 12-18%) converts to soluble substances within 21 days in a pH 7.4 buffer solution. An analysis of the resulting oxidized cellulose solution by high performance liquid chromatography (HPLC) suggests that the polymer readily undergoes chain shortening to yield oligomers. In the presence of plasma or serum, the oligomers are further hydrolyzed to small fragments, such as glucose, glucoronic acid and 2 and 3-carbon fragments. It has been suggested that the degradation of oxidized cellulose to oligomers occurs due to the presence of the carboxyl group at the C-6 position, which increases the susceptibility of the intersaccharide linkage to hydrolytic cleavage.
Dimitrijevzh et al. (1990) studied the degradation of oxidized cellulose (carboxyl content 12-18%) in vivo. They implanted oxidized cellulose onto rabbit uterine horn abrasions. Degradation was found to be rapid, and the oligomeric products produced were present primarily in the peritoneal fluid at the implantation site. No accumulation was observed in either the serum or urine. It is suggested that the degradation of oxidized cellulose involves an initial chemical depolymerization step, followed by an enzymatic hydrolysis reaction mediated by glycosidases endogenous to peritoneal macrophages.
Compared to other biodegradable polymers (e.g., poly(lactides), poly(glycolides), poly(lactide-co-glycolide) copolymers, poly (β-malic acid), etc.), oxidized cellulose has received little consideration as a potential biomaterial or drug carrier. This is because it is practically insoluble in organic solvents and water, and hence, poses little or no formulation flexibility.
Recently, U.S. Pat. No. 5,973,139 disclosed a process for producing carboxylated cellulose esters using oxidized cellulose materials containing at least 30 meq/kg, and preferably between 40 meq/kg and 70 meq/kg (about 0.14-0.3% w/w) of carboxylic content. In this process, the starting cellulose source is first esterified and then hydrolyzed to give the product. The hydroxyl content in the product ranges from 0.05 to 1.0. The carboxylated cellulose esters prepared by this method are useful in the development of coating formulations that can be applied to paper, plastic, metal, wood, gypsum board, concrete brick, masonary or galvanized sheets.
Another previous method in the art for preparing carboxylated cellulose esters uses cellulose acetate butyrate as a starting material. The carboxylic groups are then introduced by treating the polymer with ozone. Sand, 1987. A similar method is disclosed in European Patent Application No. 138,703. The disadvantage to the carboxylated cellulose esters prepared according to these references, however, is that they are not biodegradable.
The present inventors have now prepared a series of oxidized cellulose esters that not only show solubility in aqueous alkaline buffer solutions, but also dissolve in organic solvents, and/or water, depending on the nature of the ester moiety in the polymer. Since the ester linkage undergoes hydrolysis by enzymatic and chemical means in vivo and in vitro, oxidized cellulose esters of the present invention can be used to produce a variety of biodegradable controlled and/or sustained release pharmaceutical, agricultural, and veterinary compositions.
Accordingly, it is a primary object of the present invention to provide oxidized cellulose esters that exhibit solubility in aqueous alkaline solution, water and/or common organic solvents.
It is a further object of the present invention to provide oxidized cellulose esters that are biodegradable.
It is a further object of the present invention to provide a method to modify oxidized cellulose containing 3-25% carboxylic content to produce the corresponding alkyl, aryl or mixed alkyl-aryl esters.
It is a further object of the present invention to provide oxidized cellulose esters suitable for use as an implantable and/or injectable biodegradable carrier for drugs, chemicals, and biological macromolecules such as proteins and peptides.
It is yet a further object of the invention to provide oxidized cellulose esters based compositions that may serve as controlled and/or sustained-release delivery systems.
It is still a further object of the present invention to provide oxidized cellulose ester-based film forming agents suitable for producing biodegradable medicated films for use in the treatment of skin disorders.
It is a further object of the present invention to provide an oxidized cellulose ester-based coating system useful in producing enteric-coated solid pharmaceuticals.
It is yet a further object of the present invention to provide a method of producing oxidized cellulose esters that are economical to manufacture.
The methods and means of accomplishing each of the above objects will become apparent from the detailed description, preferred embodiments, and specific examples that follow hereafter.