A. Jayakrishnan

Cross-linked chitosan microspheres : preparation and evaluation as a matrix for the controlled release of pharmaceuticals

Abstract— Chitosan microspheres having good spherical geometry and a smooth surface were prepared by the glutaraldehyde cross‐linking of an aqueous acetic acid dispersion of chitosan in paraffin oil using dioctyl sulphosuccinate as the stabilizing agent. Microspheres having different degrees of swelling were made by varying the cross‐linking density. Microspheres were prepared by incorporating theophylline, aspirin or griseofulvin. Drug incorporation efficiencies exceeding 80% could be achieved for these drugs. In‐vitro release studies of these drugs were carried out in simulated gastric and intestinal fluids at 37°C. It was observed that the drug release rates were influenced by the cross‐linking density, particle size and initial drug loading in the microspheres.

Barium sulphate-loaded p(HEMA) microspheres as artificial emboli: Preparation and properties

Poly(2-hydroxyethyl methacrylate) p(HEMA) microspheres of good spherical geometry (diameter 90-1500 microns) encapsulated with 40-50% barium sulphate to impart radiopaque properties were prepared by a solvent evaporation process. These microspheres were cross-linked by reacting with hexamethylene diisocyanate (HMDI) or by gamma-irradiation in the presence of ethylene glycol dimethacrylate (EGDM) in n-heptane. Microspheres with a porous structure and a rough surface were also made by the incorporation of NaCl along with BaSO4. The effects of concentration of the polymer solution, concentration of the stabilizing agent, concentration of BaSO4, viscosity of the dispersion medium and ratio of the dispersed phase to the dispersion medium on the formation, stability and particle size distribution of the microspheres were investigated.

Casein as a Carrier Matrix for 5-Fluorouracil: Drug Release from Microspheres, Drug-protein Conjugates and In-vivo Degradation of Microspheres in Rat Muscle

Abstract— Glutaraldehyde cross‐linked casein microspheres were loaded with 5‐fluorouracil (5‐FU) from concentrated aqueous solutions of the drug after the microspheres were synthesized and cleaned. In‐vitro release of the drug was examined in phosphate buffer in the absence and in the presence of protease at 37°C. Drug release data showed that only about 20% of the drug is released in the absence of protease even after 5 days, while digestion of the matrix with protease released the entrapped drug completely in about 24 h. A protein‐drug conjugate was synthesized via carbamoyl linkage using 6‐(5‐FU‐1‐yl)hexyl isocyanate and the drug release was examined in phosphate buffer at 37°C. Release from the protein‐5‐FU conjugate was slower compared with the release from microspheres in the presence of protease. Implantation of placebo microspheres of different cross‐linking densities in the gluteal muscle of rats showed no adverse tissue reactions over a one‐year period. Histopathological examination of the tissues containing injected microspheres suggested that the biological life of casein microspheres in muscle is about 6 months, which is three times that of cross‐linked albumin microspheres.

Radiation grafting of hydrophilic monomers on to plasticized poly (vinyl chloride) sheets: II. Migration behaviour of the plasticizer from N-vinyl pyrrolidone grafted sheets

The grafting of N-vinyl pyrrolidone, a hydrophilic monomer, on to flexible poly(vinyl chloride) sheets used in medical applications using ionizing radiation from a 60Co source was studied. The graft yield was found to increase linearly with monomer concentration and also with increasing radiation doses. The migration of the plasticizer di-(2-ethylhexyl)phthalate into a strong organic extractant such as n-hexane was studied at different time intervals for different grafted systems of poly(vinyl chloride) at 30 degrees C. The results indicated a drastic reduction in the leaching of the plasticizer from grafted systems versus ungrafted controls. Incorporation of ethylene dimethacrylate cross-linker during grafting did not seem to affect the graft yield considerably but appeared to further reduce the plasticizer migration. Surface energy calculations of the grafted samples indicate that the surfaces are highly hydrophilic compared to ungrafted poly(vinyl chloride) and the polar and dispersion components tend to vary with increasing cross-linker concentration.

Tantalum loaded silicone microspheres as particulate emboli.

Chloroform solutions of medical grade silicone resin were cured in an aqueous dispersion medium containing poly(vinyl alcohol) (PVA) as the drop stabilizer at 40-60 degrees C to generate smooth, spherical, elastic microspheres. The microspheres were encapsulated with tantalum powder to render them radiopaque. Tantalum loaded microspheres having diameter more than 1.00 mm could be prepared by this technique. Incorporation of radiopaques such as barium sulphate and methyl iothalamate resulted in the instability of the suspension giving rise to an agglomerated product. Microspheres were grafted with hydrophilic monomers such as 2-hydroxyethyl methacrylate (HEMA) and N-vinyl pyrrolidone (NVP) using ionizing radiation from a 60Co source in an effort to make their surfaces hydrophilic. While the graft yield was very little when HEMA alone was used for grafting, a combination of HEMA/NVP in a 1:1 ratio produced better graft yields resulting in improved surface hydrophilicity. The tantalum loaded microspheres were found to be very resistant to surface modification. Microspheres could be dispersed in water with the aid of small quantities of surfactants such as Tween 20. These microspheres may find use in particulate embolization.

Polymerization of 2-hydroxyethyl methacrylate as large size spherical beads

Poly(2-hydroxyethyl methacrylate) (PHEMA) beads of fairly large size (more than 2.0mm in diameter) crosslinked with ethyleneglycol dimethacrylate (EGDM) were prepared by the suspension polymerization of 2-hydroxyethyl methacrylate (HEMA) in the presence of benzyl alcohol (BA) in 35% sodium chloride solutions using 2,2′-azobis isobutyronitrile (AIBN) as the polymerization initiator. Magnesium hydroxide formed in situ served as the suspension stabilizer during polymerization. The presence of BA afforded the preparation of clear, large size spherical beads whereas many other inert solvents such as toluene, hexane, isopropanol or cyclohexanol either yielded beads of very small size or particles of irregular shape. The effect of concentration of EGDM, Mg(OH)2 and the stirring speed on the stability of the suspension and particle size was investigated.

Synthetic hydrogel microspheres as substrata for cell adhesion and growth

SummaryCross-linked poly(methyl methacrylate) (PMMA) microspheres were subjected to alkaline hydrolysis to obtain hydrophilic microspheres having carboxyl residues distributed throughout the matrix. These microspheres were found to support the growth of human skin fibroblasts and human heart and lung cells. Further, fibroblasts grown on them were found to be comparable with those grown on the commercial tissue culture plate with respect to [14C]amino acid uptake and incorporation into proteins. The hydrolyzed PMMA microspheres may find application as a microcarrier for cell culture.

Radiation grafting of hydrophilic monomers on to plasticized poly(vinyl chloride) sheets: Part 1 Surface characterization and plasticizer migration studies

Medical-grade plasticized poly(vinyl chloride) (PVC) sheets were surface modified using gamma-radiation grafting of a combination of hydrophilic monomers based on 2-hydroxyethyl methacrylate (HEMA) and N-vinyl pyrrolidone (NVP). The modified surfaces were evaluated for their surface properties using contact angle measurements, phase-contrast photomicroscopy and scanning electron microscopy. Surface energy calculations of the modified surfaces indicated that the surfaces became highly hydrophilic when grafted with even a 1% (v/v) solution of HEMA-NVP combination in the presence of 0.005m CuSO4. Migration of the plasticizer di(2-ethylhexyl phthalate) (DEHP) from the grafted sheets was examined in hydrocarbon solvents such as n-hexane, n-heptane and n-octane and in extractant media such as cotton seed oil and polyethylene glycol-400 (PEG-400). The migration from modified sheets was found to be <4% of the migration from unmodified control sheets in hydrocarbon solvents at 30° C over a period of 5 h. Accelerated leaching studies in cotton seed oil and PEG-400 demonstrated that virtually no plasticizer migrated out in the former over a period of 96 h whereas the rate of migration in the latter medium showed only a mild reduction. The migration behaviour was Fickian in nature for grafted sheets. The method described may be useful as a simple, versatile technique for preventing plasticizer migration from plasticized PVC for medical applications.

Radiation grafting of hydrophilic monomers onto plasticized poly(vinyl chloride) sheets: Part III. Physical and mechanical properties of migration resistant sheets

Medical grade poly(vinyl chloride) (PVC) sheets were surface modified by grafting a combination of 2-hydroxyethyl methacrylate (HEMA) and N-vinyl pyrrolidone (NVP) or NVP alone using gamma radiation in an effort to retard the migration of the plasticizer from the PVC matrix. Presence of cupric ions at a concentration of 0.005m was found to be optimal in not only preventing the homopolymerization of the monomers but also producing the highest graft yield at all monomer concentrations used for grafting. The grafted PVC was characterized for its water absorption properties. Surface morphology of the grafted surface was examined using scanning electron microscopy (SEM). PVC sheets grafted on both sides as well as on one side were characterized for their physical and mechanical properties in order to assess their suitability in biomedical applications. While the tensile strength and percentage elongation values of PVC sheets grafted on both sides showed a downward trend with increasing graft yield, these properties were not drastically affected by surface modification on one side only at graft yields pertinent to prevent the migration of the plasticizer. Measurement of Shore A hardness and optical transparency of the migration resistant sheetings showed that such properties were not seriously affected by surface modification thus rendering them suitable for their intended applications.

Blood Compatibility of Surface Modified Poly(ethylene terephthalate) (PET) by Plasma Polymerized Acetobromo-α-D-glucose

Poly (ethylene terephthalate) (PET) was surface modified by plasma polymerization of acetobromo-α-D-glucose (ABG) at different radio frequency (RF) powers. Plasma polymerization was carried out by vaporizing ABG in the powder form by heating at 135°C. Surface modification resulted in improved hydrophilicity and smoothness of the surface especially at low RF powers (30—50 W), but at high RF powers, the surface was found to be etched and the hydrophilicity decreased as evidenced by atomic force microscopy (AFM) and contact angle measurements. The plasma polymerized ABG film was found to be extensively cross-linked as evidenced by its insolubility in water. Infra red (IR) and X-ray photoelectron spectroscopy (XPS) were employed to characterize the plasma polymerized ABG films. IR studies revealed that at lower RF powers, polymerization was taking place mainly by breaking up of acetoxy group while retaining the ring structures to a major extent during the polymerization process whereas at high RF powers, the rupture of ring structures was indicated. XPS indicated a reduction in the percentage of oxygen in the polymers going from low to high RF powers suggestive of complete destruction of the acetoxy group at high RF powers. Cross-cut tests showed excellent adhesive properties of the plasma polymerized ABG films onto PET. Static platelet adhesion tests using platelet rich human plasma showed significantly reduced adhesion of platelets onto modified PET surface as evidenced by scanning electron microscopy. Polymerization of glucose and its derivatives using RF plasma has not been reported so far and the preliminary results reported in this study shows that this could be an interesting approach in the surface modification of biomaterials.