Browsing by Author "JAYAKRISHNAN, A"

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    A NEW METHOD FOR THE SYNTHESIS OF SMOOTH, ROUND, HYDROPHILIC PROTEIN MICROSPHERES USING LOW CONCENTRATIONS OF POLYMERIC DISPERSING AGENTS
    (JOURNAL OF MICROENCAPSULATION, 1995)
    A new method for the synthesis of protein microspheres of wide size range having good spherical geometry and hydrophilicity using very low concentrations of polymeric dispersing agents is reported. The method involves the use of around 1% solution of a biomedical grade aliphatic polyurethane in a mixture of a hexane and dichloromethane as the dispersion medium, as opposed to a 25-30% solution of polymeric dispersing agents employed by previous workers to effect steric stabilization of the protein solution droplets. The versatility of the method is demonstrated by the synthesis of albumin microspheres, as well as those of the amphiphilic protein casein, the latter being more difficult to prepare by surfactant stabilization techniques. Significant advantages of the method include the avoidance of surfactants which become adsorbed on the particles and influence tissue reactions and drug release, and the ease of removal of the polymeric stabilizer from the final product. The method may find application for the preparation of a wide range of protein and polysaccharide microspheres for medical use.
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    BIOAVAILABILITY OF THEOPHYLLINE FROM GLUTARALDEHYDE CROSS-LINKED CASEIN MICROSPHERES IN RABBITS FOLLOWING ORAL-ADMINISTRATION
    (JOURNAL OF CONTROLLED RELEASE, 1995) LATHA, MS; RATHINAM, K; Mohanan, PV; JAYAKRISHNAN, A
    Theophylline loaded bovine casein microspheres were prepared by the glutaraldehyde cross linking of an aqueous alkaline dispersion of the protein containing the drug in a non-aqueous dispersion medium. The cross-linking of the protein droplets was carried out via the organic phase by the addition of varying quantities of glutaraldehyde- saturated toluene. In vitro release of the drug was examined in simulated gastric fluid at 37 degrees C from spheres having three different cross-linking densities. The bioavailability of theophylline released from the microspheres of different cross-linking densities was studied in rabbits following single oral administration. Microspheres with higher cross-linking densities were found to sustain theophylline release even up to 24 h. The peak serum concentrations of such preparations were well within therapeutic limits. Determinations of in vitro/in vivo correlation based on the data showed that a fairly good relationship exists between in vitro and in vivo release. The study demonstrated the potential of cross-linked milk protein as a matrix for sustained release oral preparations.
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    CASEIN AS A CARRIER MATRIX FOR 5-FLUOROURACIL - DRUG-RELEASE FROM MICROSPHERES, DRUG-PROTEIN CONJUGATES AND IN-VIVO DEGRADATION OF MICROSPHERES IN RAT MUSCLE
    (JOURNAL OF PHARMACY AND PHARMACOLOGY, 1994)
    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 degrees 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 degrees 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.
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    CELL-ADHESION AND GROWTH ON SYNTHETIC HYDROGEL BEADS
    (BULLETIN OF MATERIALS SCIENCE, 1989) SHIVAKUMAR, K; NAIR, RR; JAYAKRISHNAN, A; KARTHA, CC; VALIATHAN, MS
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    CONTROLLED RELEASE OF ORAL-DRUGS FROM CROSS-LINKED POLYVINYL-ALCOHOL MICROSPHERES
    (JOURNAL OF PHARMACY AND PHARMACOLOGY, 1993)
    A new technique for the preparation of cross-linked polyvinyl alcohol (PVA) microspheres containing various drugs is described. An aqueous solution of PVA containing various concentrations of glutaraldehyde was dispersed as droplets in liquid paraffin using a suitable stabilizing agent. Cross-linking of PVA droplets with glutaraldehyde was induced by an acid catalyst (HCI) which was produced by the addition of small quantities of benzoyl chloride into the dispersion medium. Microspheres containing drugs such as aspirin, griseofulvin and nicotinic acid were prepared by carrying out the cross-linking reaction in the presence of such drugs. The drug release studies were carried out in simulated gastric and intestinal fluids without enzymes at 37-degrees-C. It was observed that increase in the cross-linking density of the microspheres reduced the drug release rate considerably, suggesting that the release profiles could be controlled by changing the cross-linking density. It was also observed that a higher rate of release was obtained from smaller beads.
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    CROSS-LINKED CHITOSAN MICROSPHERES - PREPARATION AND EVALUATION AS A MATRIX FOR THE CONTROLLED RELEASE OF PHARMACEUTICALS
    (JOURNAL OF PHARMACY AND PHARMACOLOGY, 1992)
    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-degrees-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.
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    CROSS-LINKED CHITOSAN MICROSPHERES AS CARRIERS FOR PROLONGED DELIVERY OF MACROMOLECULAR
    (JOURNAL OF BIOMATERIALS SCIENCE-POLYMER EDITION, 1994)
    Bovine serum albumin (BSA) and diphtheria toroid (DT) were loaded by passive absorption from aqueous solutions into preformed glutaraldehyde cross-linked chitosan microspheres. In vitro release of BSA under sink conditions at 37 degrees C showed that even though there was a large burst effect, there was a more or less steady increase with time thereafter for several days. Coating the BSA-loaded particles with paraffin oil or with a polymer, such as polylactic acid, modulated drug release. After the initial burst from PLA coated particles, the release rate increased with time for nearly 2 months. Preliminary immunogenicity studies on Wistar rats using DT loaded chitosan spheres showed that the antibody titres were fairly constant over a 5-month period, although very low compared to DT given on alum as control. Histological studies of placebo microspheres intramuscularly injected into rats demonstrated their tissue compatibility. Biodegradation was not complete in 6 months demonstrating the potential of cross-linked chitosan spheres as a long-acting drug delivery vehicle. The study demonstrated the possibility of incorporating biological macromolecules which are very sensitive to organic solvents, pH, temperature, ultrasound, etc. by a passive absorption technique to degradable biopolymer matrices thereby preserving their biological integrity. It is also shown that drugs passively absorbed into such matrices by taking advantage of their swelling behaviour need not necessarily be released completely in the initial 'burst' and a sustained release may be possible for macromolecules thus incorporated.
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    ENDOVASCULAR EMBOLIZATION USING HYDROGEL MICROSPHERES
    (JOURNAL OF MATERIALS SCIENCE-MATERIALS IN MEDICINE, 1994) JAYAKRISHNAN, A; MOHANTY, M; MANDALAM, R; RAO, VRK; GUPTA, AK; JOSEPH, S
    Controlled alkaline hydrolysis of crosslinked poly(methyl methacrylate) (PMMA) microspheres produced highly hydrophilic, smooth, compressible, nearly perfect microspheres having a range of water content 40-95%. These particles were found to possess many desirable properties as a material for therapeutic embolization. After successful toxicological and animal evaluation, these particles were used to treat various ailments such as arteriovenous malformations (AVM) of the brain, spinal cord, limbs, face and trunks, preoperative devascularization of tumours and in the management of severe life-threatening haemoptysis and haematemesis in clinical trials involving over 90 patients at this Institute. The results of these studies appeared to be very encouraging. The material is found to be an ideal embolic agent in all these clinical situations.
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    EVALUATION OF AN ALIPHATIC POLYURETHANE AS A MICROSPHERE MATRIX FOR SUSTAINED THEOPHYLLINE DELIVERY
    (JOURNAL OF MICROENCAPSULATION, 1995) SUBHAGA, CS; RAVI, KG; SUNNY, MC; JAYAKRISHNAN, A
    In spite of several biomedical applications of polyurethanes, very little attention has been focused on these polymers for controlled drug delivery. In this study, an aliphatic polyurethane, Tecoflex(R), was evaluated as a microsphere matrix for the controlled release of theophylline. Polyurethane microspheres containing theophylline were prepared using a solvent evaporation technique from a dichloromethane solution of the polymer containing the drug. A dilute solution of poly(vinyl alcohol) served as the dispersion medium. Microspheres of good spherical geometry having theophylline content of 35% could be prepared by the technique. The release of the drug from the microspheres was examined in simulated gastric and intestinal fluids at 37 degrees C. While a large burst effect was observed in gastric fluid, in the intestinal fluid a close to zero-order release was seen. Attempts were made to modulate the release by incorporating poly(ethylene glycol) in the matrix and also coating the spheres with paraffin wax. Preliminary data indicate that polyurethanes could be interesting matrices for controlled drug delivery.
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    GLUTARALDEHYDE CROSS-LINKED BOVINE CASEIN MICROSPHERES AS A MATRIX FOR THE CONTROLLED-RELEASE OF THEOPHYLLINE - IN-VITRO STUDIES
    (JOURNAL OF PHARMACY AND PHARMACOLOGY, 1994)
    A controlled release dosage form of theophylline in the form of microspheres using the milk protein casein as the matrix is described. Glutaraldehyde cross-linking of an aqueous alkaline solution of the protein containing the drug, dispersed in a mixture of dichloromethane/hexane having ca. 1% of an aliphatic polyurethane as the suspension stabilizer, led to the formation of the drug-loaded microspheres. Drug incorporation efficiency of around 80% could be achieved by the technique. Release profiles of the drug were examined in simulated gastric and intestinal fluids at 37 degrees C. It was observed that the release was diffusion-controlled and followed the Higuchi model. Release characteristics were influenced by the cross-linking density, particle size and the extent of loading. Data obtained indicate that the natural milk protein casein could be used as a matrix for sustained release oral dosage forms.
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    GLUTARALDEHYDE CROSS-LINKED CHITOSAN MICROSPHERES AS A LONG-ACTING BIODEGRADABLE DRUG-DELIVERY VEHICLE - STUDIES ON THE IN-VITRO RELEASE OF MITOXANTRONE AND IN-VIVO DEGRADATION OF MICROSPHERES IN RAT MUSCLE
    (BIOMATERIALS, 1995)
    Chitosan microspheres were prepared from 74% deacetylated chitin by the glutaraldehyde crosslinking of an aqueous acetic acid dispersion of chitosan in a mixture of liquid paraffin and petroleum ether stabilized using sorbitan sesquioleate as the surfactant. Cross-linking and hardening of the spherical particles were achieved by the addition of glutaraldehyde-saturated toluene through the organic phase. A relatively novel antineoplastic agent, mitoxantrone, was incorporated into the microspheres and the drug release was studied in vitro into phosphate buffer for over 4 weeks at 27 degrees C. Drug release was found to be effectively controlled by the extent of cross-linking. Only about 25% of the incorporated drug was released over 36 days from microspheres of high cross-linking density. Implantation of placebo chitosan microspheres in the skeletal muscle of rats was carried out in order to assess the biocompatibility and biodegradability of the microspheres. Histological analysis showed that the microspheres were well tolerated by the living tissue. However, no significant biodegradation of the material was noticed over a period of 3 months in the skeletal muscle of rats. Data obtained indicate the possibility of using cross-linked chitosan microspheres as a drug carrier for sustained drug release for very long periods.
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    HISTOPATHOLOGICAL EVALUATION OF POLYMETHYL METHACRYLATE AS AN EMBOLIC AGENT
    (ACTA NEUROCHIRURGICA, 1992)
    Polymethyl methacrylate (PMMA) microspheres were used as an embolic agent to reduce the vascularity in eight patients with intracranial vascular tumours. Post embolization angiograms showed 30-60% reduction in the vascularity of-the tumours. No patient developed any neurological complications in the immediate post-embolization period. These eight patients subsequently underwent surgery for the removal of their tumours. During surgery there was minimal blood loss and a good plane of cleavage was obtained between the tumour and the adjacent brain. The surgical specimens were examined histopathologically for the effects of PMMA. PMMA microspheres, in contrast to other cyano-acrylates-Isobutyl-2-cyanoacrylate (IBCA) - did not elicit either inflammatory reaction or mural angionecrosis within the wall of the embolised vessels. The histopathological studies suggest that PMMA microspheres are an inert material and can be used as an adjunct in the management of intracranial vascular tumours.
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    HYDROGEL MICROSPHERES FROM CROSSLINKED POLY(METHYL METHACRYLATE) - SYNTHESIS AND BIOCOMPATIBILITY STUDIES
    (BULLETIN OF MATERIALS SCIENCE, 1989) JAYAKRISHNAN, A; THANOO, BC; RATHINAM, K; MANDALAM, KR; RAO, VRK; LAL, AV; MOHANTY, M
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    HYDROLYZED MICROSPHERES FROM CROSS-LINKED POLYMETHYL METHACRYLATE (HYDROGEL) - A NEW EMBOLIC MATERIAL FOR INTERVENTIONAL NEURORADIOLOGY
    (JOURNAL OF NEURORADIOLOGY, 1991)
    Highly hydrophilic, perfectly smooth and spherical microspheres have been synthetized. These non-biodegradable microspheres absorb water in varying degrees and can be injected easily through microcatheters due to their slippery and compressible characteristics. The material was successfully used of embolization of 4 vascular intracranial tumours and 2 spinal vascular lesions in the cervical region, by superselective delivery. Histopathology confirmed absolute inertness of the microspheres.
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    ORAL SUSTAINED-RELEASE DRUG DELIVERY SYSTEMS USING POLYCARBONATE MICROSPHERES CAPABLE OF FLOATING ON THE GASTRIC FLUID
    (JOURNAL OF PHARMACY AND PHARMACOLOGY, 1993)
    Polycarbonate microspheres loaded with aspirin, griseofulvin and p-nitroaniline were prepared by a solvent evaporation technique. High drug loading (> 50%) was achieved by this process. Drug-loaded microspheres were found to float on simulated gastric fluid and intestinal fluid. Drug-release studies were carried out in these fluids at 37-degrees-C. Increasing the drug to polymer ratio in the microspheres increased both their mean particle size and the release rate of the drugs. It was concluded that sustained delivery of drugs could be effected using this matrix.
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    PHOTO-CROSS-LINKING OF AZIDATED POLY(VINYL CHLORIDE) COATED ONTO PLASTICIZED PVC SURFACE - ROUTE TO CONTAINING PLASTICIZER MIGRATION
    (JOURNAL OF APPLIED POLYMER SCIENCE, 1995) JAYAKRISHNAN, A; SUNNY, MC; RAJAN, MN
    The migration of phthalate esters which are commonly employed for plasticizing poly(vinyl chloride) (PVC) is a significant problem in PVC-based medical devices as well as in packaging used for food stuffs and pharmaceuticals. Medical-grade PVC resin was treated with sodium azide in dimethylformamide (DMF) to prepare the azide polymer. The polymeric azide was coated onto the surface of plasticized PVC sheets by dipping in a solution of the polymer in tetrahydrofuran (THF). Crosslinking of the azide polymer was accomplished by irradiating the surface using a 125 W UV lamp for various lengths of time. Migration of the plasticizer di-2-(ethylhexyl phthalate) (DEHP) from coated and uncoated samples was examined in n-hexane at 30 degrees C. It was found that 50-80% reduction in migration of DEHP could be effected from plasticized PVC in comparison with the controls in 72 h by this technique depending on the concentration of the coating solution, coating thickness, azide concentration, and irradiation dose. (C) 1995 John Wiley and Sons, Inc.
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    POLYMERIZATION OF 2-HYDROXYETHYL METHACRYLATE AS LARGE SIZE SPHERICAL BEADS
    (POLYMER, 1990) JAYAKRISHNAN, A; SUNNY, MC; THANOO, BC
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