Thomas Chandy

Chitosan-as a Biomaterial

Chitosan [a (1----4) 2-amino-2-deoxy-beta-D-Glucan] is a unique polysaccharide derived from chitin. Several attempts have been made to use this biopolymer in biomedical field. The use of this material in the development of hemodialysis membranes, artificial skin, drug targetting and other applications are discussed. It appears, this novel biomolecule, biodegradable, and biocompatible, find applications in substituting or regenerating the blood/tissue interfaces. This polysaccharide having structural characteristics similar to glycosaminoglycans, seems to mimic their functional behaviour.

Chitosan/calcium–alginate beads for oral delivery of insulin

A mild chitosan/calcium alginate microencapsulation process, as applied to encapsulation of biological macromolecules such as albumin and insulin, was investigated. The microcapsules were derived by adding dropwise a protein-containing sodium alginate mixture into a chitosan–CaCl2 system. The beads containing a high concentration of entrapped bovine serum albumin (BSA) as more than 70% of the initial concentration were achieved via varying chitosan coat. It was observed that approximately 70% of the content is being released into Tris-HCl buffer, pH 7.4 within 24 h and no significant release of BSA was observed during treatment with 0.1M HCl pH 1.2 for 4 h. But the acid-treated beads had released almost all the entrapped protein into Tris-HCl pH 7.4 media within 24 h. Instead of BSA, the insulin preload was found to be very low in the chitosan/calcium alginate system; the release characteristics were similar to that of BSA. From scanning electron microscopic studies, it appears that the chitosan modifies the alginate microspheres and subsequently the protein loading. The results indicate the possibility of modifying the formulation in order to obtain the desired controlled release of bioactive peptides (insulin), for a convenient gastrointestinal tract delivery system.

Chitosan matrix for oral sustained delivery of ampicillin

Ampicillin was embedded in a chitosan matrix to develop an oral release dosage form. The in vitro release profile of ampicillin from chitosan beads and microgranules of chitosan was monitored, as a function of time, using a UV Spectrophotometer. The releasing studies were performed in a rotating shaker at 100 r.p.m., containing 0.1 M HCI buffer, pH 2.0, or 0.1 M phosphate buffer, pH 7.4, solutions, and a comparison was made between the drug loaded microbeads and microgranules. It seems that the amount and percentage of drug release was much higher in HCI solution compared with the phosphate solution, probably due to the gelation properties of the matrix at acid pH. The release rate of ampicillin from the chitosan matrix was slower for the beads as compared with the granules. From scanning electron microscopic studies, it appears that the drug forms a crystal structure within the chitosan beads, which dissolves out slowly to the dissolution medium through the micropores of the chitosan matrix. The results propose the possibility of modifying the formulation in order to obtain the desired controlled release of the drug for a convenient oral sustained delivery system.

Use of plasma glow for surface-engineering biomolecules to enhance bloodcompatibility of Dacron and PTFE vascular prosthesis.

The search for a nonthrombogenic material having patency to be used for small diameter vascular graft applications continues to be a field of extensive investigation. The purpose of the present study was to examine whether surface modification of polytetra fluoroethylene (PTFE, Teflon) and polyethylene-terephthalate (Dacron) vascular grafts might extend graft biocompatibility without modifying the graft structure. A series of surface coatings were prepared by modifying the argon plasma-treated PTFE and Dacron grafts with collagen IV and laminin and subsequently immobilizing bioactive molecules like PGE1, heparin or phosphatidyl choline via the carbodiimide functionalities. Surface analysis by Fourier transform infrared spectroscopy-attenuated total reflectance revealed the presence of new functional groups on the modified graft surfaces. In vitro studies showed that fibrinogen adsorption and platelet adhesion on modified grafts were significantly reduced. This study proposes that surface grafting of matrix components (collagen-type IV and laminin) and subsequent immobilization of bioactive molecules (PGE1, heparin or phosphatidyl choline) changed the surface conditioning of vascular grafts and subsequently improved their biocompatibility. However, more detailed in vivo studies are needed to confirm these observations.

Chitosan beads and granules for oral sustained delivery of nifedipine: in vitro studies

Nifedipine was embedded in a chitosan matrix to develop a prolonged-release form. The in vitro release profiles of nifedipine from chitosan beads and microgranules were monitored by UV spectrophotometer. The studies were performed in a rotating shaker (100 rev min-1) in 0.1 M HCl buffer (pH 2.0) or 0.1 M phosphate buffer (pH 7.4). Comparison was made between drug-loaded microbeads and microgranules. The amount and percentage of drug release were much higher in HCl than in phosphate buffer, probably due to the salt formation of the matrix (chitosan hydrochloride) at acid pH. The release rate of nifedipine from chitosan matrix was slower for beads than granules. These findings suggest the possibility of modifying the formulations to obtain the desired controlled release of the drug in an oral sustained-delivery system.

Development of chitosan/polyethylene vinyl acetate co-matrix: controlled release of aspirin-heparin for preventing cardiovascular thrombosis

Aspirin and heparin were embedded in chitosan/polyethylene vinyl acetate co-matrix to develop a prolonged release form. The in vitro release profiles of these drugs from the co-matrix system were monitored in Tris HCl buffer pH 7.4, using a UV spectrophotometer. The amount of drug release was initially much higher. followed by a constant slow release profile for a prolonged period. The initial burst release was substantially modified with styrenebutadiene coatings. From scanning electron microscopy studies it appears that the drugs diffuse out slowly to the dissolution medium through the micropores of the co-matrix. The released aspirin-heparin from the co-matrix system had shown their antiplatelet and anticoagulant functions. The results propose the possibility of delivering drug combinations, having synergestic effects for therapeutic applications.

5-Fluorouracil-loaded chitosan coated polylactic acid microspheres as biodegradable drug carriers for cerebral tumours

The development of injectable microspheres for anticancer drug delivery into the brain is a major challenge. The possibility of entrapping 5-fluorouracil (5-FU) in chitosan coated monodisperse biodegradable microspheres with a mean diameter of 10-25um was demonstrated. An emulsion of 5-FU (in water) and polylactic acid (PLA) dissolved in acetone-dichloromethane mixture was poured into an aqueous solution of chitosan (or poly-vinyl alcohol) with stirring using a high-speed homogenizer, for the formation of microspheres. 5-FU recovery in microspheres ranged from 44-66% depending on the polymer and emulsification systems used for the preparation. Scanning electron microscopy revealed that the chitosan coated microspheres had less surface micropores compared to PVA based preparations. The drug release behaviour from microspheres suspended in phosphate buffered saline exhibited a biphasic pattern. The amount of drug release was much higher initially (25%),followed by a constant slow release profile for a 30 days period of study. This chitosan coated PLA/PLGA microsphere formulation may have potential for the targeted delivery of 5-FU to treat cerebral tumours.The development of injectable microspheres for anticancer drug delivery into the brain is a major challenge. The possibility of entrapping 5-fluorouracil (5-FU) in chitosan coated monodisperse biodegradable microspheres with a mean diameter of 10-25 um was demonstrated. An emulsion of 5-FU (in water) and polylactic acid (PLA) dissolved in acetone-dichloromethane mixture was poured into an aqueous solution of chitosan (or poly-vinyl alcohol) with stirring using a high-speed homogenizer, for the formation of microspheres. 5-FU recovery in microspheres ranged from 44-66% depending on the polymer and emulsification systems used for the preparation. Scanning electron microscopy revealed that the chitosan coated microspheres had less surface micropores compared to PVA based preparations. The drug release behaviour from microspheres suspended in phosphate buffered saline exhibited a biphasic pattern. The amount of drug release was much higher initially (approximately 25%), followed by a constant slow release profile for a 30 days period of study. This chitosan coated PLA/PLGA microsphere formulation may have potential for the targeted delivery of 5-FU to treat cerebral tumours.

Biodegradable Chitosan Matrix for the Controlled Release of Steroids

Chitosan, a polysaccharide, having structural characteristics similar to glycosaminoglycans, seems to be nontoxic and bioabsorbable. This study highlights the use of chitosan matrix for controlled drug delivery systems. The steroid drugs, namely testosterone, progesterone and beta-oestradiol were mixed with chitosan and the films were prepared by evaporation technique. The in vitro release profile of these steroids from the film matrix was monitored, as a function of time, in phosphate buffered saline (PBS, pH 7.4) at 37 degree C using a U-V-spectrophotometer. The degradation, of these chitosan and drug loaded chitosan films, was also investigated by weight loss and tensile strength studies. The steroid release from chitosan films was compared with the release of these drugs from their microbeads. It appears, the films and the microbeads stayed intact during the dissolution study of 90 days and the possibility of using these systems in contraceptive applications and novel drug delivery systems are discussed.

Changes in Cisplatin Delivery Due to Surface-Coated Poly (Lactic Acid)–Poly(∊-Caprolactone)Microspheres

Smooth muscle cell proliferation plays a major role in the genesisof restenosis after angioplasty or vascular injury. Local delivery of agents capable of modulating vascular responses, have the potential to prevent restenosis. However, the development of injectable microspheres for sustained drug delivery to the arterial wall is a major challenge. We demonstrated the possibility of entrapping an antiproliferative agent, cisplatin, in a series of surface coated biodegradable microspheres composed of poly(lactic acid)– poly(caprolactone) blends, with a mean diameter of 2–10 mm. The microspheres were surface coated with poly ethylene glycol (PEG), chitosan (Chit), or alginate (Alg). A solution of cisplatin and a 50: 50 blend of polylactic acid (PLA)– polycaprolactone (PCL) dissolved in acetone–dichloromethane mixture was poured into an aqueous solution of PEG (or polyvinyl alcohol or Chit or Alg) with stirring using a high speedhomogenizer, for the formation of microspheres. Cisplatin recovery inmicrospheres ranged from 25–45% depending on the emulsification system used for the preparations. Scanning electron microscopy revealed that the PLA–PCL microspheres were spherical in shape and had a smooth surface texture. The amount of drug release was much higher initially (20–30%), this was followed by a constant slow-release profile for a 30-day period of study. It has been found that drugrelease depends on the amount of entrapped drug, on the presence of extra cisplatin in the dispensing phase, and on the polymer coatings.This PEG or Alg-coated PLA/PCL microsphere formulation may have potential for the targeted delivery of antiproliferative agents to treat restenosis.

Delivery of LMW Heparin via Surface Coated Chitosan/peg-Alginate Microspheres Prevents Thrombosis

Heparin remains the gold-standard inhibitor of the process involved in the vascular response to injury. Continued anticoagulation is achieved by subcutaneous administration of low-molecular-weight heparin (LMW Hep) or with an orally active anticoagulant such as warfarin. An oral heparin would avoid the inconvenience of subcutaneous injections and adverse events associated with warfarin. A mild chitosan/PEG/calcium alginate microencapsulation process, as applied to encapsulation of biological macromolecules such as heparin and LMW Hep was investigated. Heparin and LMW Hep entrapped alginate beads were further surface/enteric coated with chitosan and cellulose acetate phthalate (CAP) via carbodiimide (EDC) functionalities. It was observed that approximately 70% of the content is being released into Tris-HCl buffer, pH 7.4 within the initial 6 hours and no significant release of LMW Hep was observed from enteric coated microspheres (12%) during treatment with 0.1 M HCl, pH 1.0 for 4 hours. But acid treated capsules had released almost all the entrapped LMW Hep into Tris-HCl, pH 7.4 media within 6 hours. From scanning electron microscopic and swelling studies, it appeared that the surface coatings (via chitosan and CAP) had modified the alginate microspheres and subsequently the drug release. The released heparin and LMW Hep had shown their anticoagulant functions. These results established the feasibility of modifying the formulation in order to obtain the desired controlled release of bioactive agent (LMW Hep), for a convenient pH dependent delivery system.