Pramod K. Gupta

Albumin microspheres. III. Synthesis and characterization of microspheres containing adriamycin and magnetite

Abstract Adriamycin-associated bovine serum albumin microspheres (Adr-BSA), plain magnetic BSA microspheres (Fe-BSA) and adriamycin-associated magnetic BSA microspheres (Adr-Fe-BSA) were prepared by heat stabilization at different temperatures and evaluated for their size, hydration characteristics, drug and/or magnetite entrapment, Fe 3 O 4 distribution within particles and drug release properties. It was demonstrated that microspheres with a mean diameter of less than 1 μm can be prepared at temperatures between 105 and 150° C, in the presence of adriamycin and/or magnetite. Equilibrium hydration with these particles was attained in about 2 h after soaking in normal saline at 37° C. The degree to which the particles increase in size was dependent on their stabilization temperature. The entrapment of adriamycin was influenced by the presence of magnetite as well as the temperature employed during the carrier stabilization. Maximum entrapment of adriamycin in Adr-Fe-BSA microspheres, after 4 washings, was obtained at 120° C. The presence of adriamycin significantly affected the entrapment and distribution of Fe 3 O 4 in albumin microspheres. The release rate of adriamycin entrapped within Adr-BSA and Adr-Fe-BSA microspheres was dependent on the presence of magnetite as well as the stabilization temperature of the carrier.

Albumin microspheres. I: Release characteristics of adriamycin

Abstract Several models have been investigated for their appropriateness in describing the release of adriamycin from heat-stabilized bovine serum albumin microspheres. Drug release from the microspheres can be adequately described by bi-exponential first-order, bi-phasic zero-order and Higuchis square-root of time equations. Theoretical possibilities for accepting bi-phasic zero-order release characteristics are discussed.

Albumin microspheres. II. Effect of stabilization temperature on the release of adriamycin

Abstract The effect of stabilization temperature on the rate of release of adriamycin from bovine serum albumin (BSA) microspheres has been evaluated: Microspheres were prepared at 105, 120, 135 and 150°C and washed 1–4 times to remove the surface drug before the release study. Release profiles depend on the number of washing steps employed. Microspheres subjected to two or less washings exhibit a tri-phasic zero-order release of adriamycin, whereas four washings of the carrier shows a bi-phasic zero-order release pattern. The in vitro dissolution results indicate that the rate of release of adriamycin from the microspheres decreases with an increase in stabilization temperature of the carrier and the release of entrapped drug can be controlled.

Influence of Stabilization Temperature on the Entrapment of Adriamycin in Albumin Microspheres

AbstractAdriamycin associated bovine serum albumin (BSA) microspheres have been prepared by the method involving emulsion and suspension technology. Stabilization of the carrier matrix was achieved by heat treatment at 105, 120, 135 and 150°C.Following zero to four washings, each of these four batches of microspheres have been evaluated for the amount of associated adriamycin using HPLC. At high stabilization temperatures, migration of adriamycin to the microsphere surface is reduced leading to increased drug entrapment. Results demonstrate that the proportion of entrapped to total drug increases with increase in stabilization temperature of the carrier.

Factorial design based optimization of the formulation of albumin microspheres containing adriamycin.

The use of factorial design in the formulation of adriamycin-associated albumin microspheres, using the heat-stabilization technique, is illustrated. The effect of stabilization temperature, protein concentration and stabilization time on the entrapment and recovery of adriamycin in microspheres have been investigated using a 2 x 4 x 4 factorial design. The associated drug content in unwashed and four times washed microspheres was determined using HPLC. Maximum drug association and drug recovery were obtained from microspheres synthesised using 25 per cent w/v albumin solution and stabilized at 120 degrees C for 2.5 min. Under these conditions, the entrapped and total associated drug content of the microspheres was about 4 per cent and 12 per cent w/w respectively, and the drug recovery was about 75 per cent. The in vitro dissolution study carried out using dynamic dialysis revealed that the release of adriamycin from these particles follows a bi-phasic pattern. The results demonstrate that use of short stabilization time, low protein concentration and low stabilization temperature are required for the formulation of microspheres with high adriamycin content.

A physiological pharmacokinetic model describing the disposition of lead in the absence and presence of L-ascorbic acid in rats

The influence of L-ascorbic acid (As-Ac) on the multiple-tissue disposition of lead has been evaluated. Lead concentrations in femur, liver, kidney and plasma of rats were monitored over a 120h period after its intravenous bolus administration (1.0 mg/kg) in the absence and presence of As-Ac at steady state. The observed lead concentration-time data in different tissues of the rats, in the absence and presence of As-Ac, have been simulated using a physiological pharmacokinetic modelling technique. In both cases, the predicted lead concentrations in various tissues were in adequate agreement with the observed data. The model developed in the present investigation supports the previous finding that As-Ac may be useful as a prophylactic agent for lead poisoning.

Investigation of the Stability of Doxorubicin Hydrochloride Using Factorial Design

AbstractUsing drug concentration remaining at a given time as the criterion, a 24x3 factorial design has been employed to investigate the effects of temperature, light, media (aqueous or organic/aqueous), ionic strength and pH on the stability of doxorubicin hydrochloride. Following the application of first order kinetics, and assuming an additive model, the statistical significance of the factors and their interactions have been determined using analysis of variance (ANOVA) on the dependent variable ln(lnCo-InC). The results indicate that temperature, pH and media are the major factors responsible for the stability of drug. The two-way interaction between temperature and pH, and the three-way interaction between temperature, light and ionic strength are also significant. It is found that doxorubicin is more stable in non-aqueous media at low temperature and low pH values. A combination of darkness and low ionic strength is also conducive to its stability.

Albumin microspheres. V. Evaluation of parameters controlling the efficacy of magnetic microspheres in the targeted delivery of adriamycin in rats

Abstract Two studies have been carried out to investigate the effect of drug content of magnetic albumin microspheres, and the feasibility of using a low-strength magnetic field (i.e. 1000 G) in the targeted delivery of adriamycin in rats. As a part of the first study, two types of magnetic microspheres, with ~ 1 and 3% w w of adriamycin HCl, were administered via ventral caudal artery to two groups of rats (0.4 mg kg ), with the center of their tail (the target site) exposed to an 8000 G magnet for 30 min post-dose-administration. In both groups, the animals were killed over a 48 h period after dosing and the relevant tissues analyzed for adriamycin concentration using HPLC. The increase in drug content of the microspheres did not influence their efficacy in the selective delivery of drug. In the second study, two groups of rats received 0.4 mg kg adriamycin via magnetic microspheres with the tail target site exposed to a 1000 G magnet for 30 and 60 min respectively, a third group receiving an equivalent dose of microsphere-delivered drug in the absence of the magnet (control). The use of the 1000 G magnet for 30 and 60 min increased the maximum drug concentration at the target site by ~ 3 and 4-fold respectively. In addition, the magnet increased the targeting efficiency of the magnetic microspheres, vs. non-target tissues, by a factor of at least 2. The implications of altered drug content of magnetic microspheres, and variations in the magnetic field characteristics, on the drug targeting potentials of magnetic delivery systems are discussed.

Formulation and Characterization of Magnetic Polyglutaraldehyde Nanoparticles as Carriers for Poly-l-Lysine-Methotrexate

AbstractUsing the statistically optimised method, submicron magnetic polyglutaraldehyde nanoparticles (Fe-PGNP) with free surface carboxylic groups have been synthesized. A model anticancer agent methotrexate (MTX) has been chemically bonded onto the surface of these particles using poly-l-Lysine (PL) as a spacer. The drug release characteristics of the final delivery device, i.e. [Fe-PGNP]-PL-MTX, has been elucidated at 37°C in a medium containing a proteolytic enzyme. Results demonstrate that using particles containing about 8% w/w of Fe3O4, and PL-MTX conjugate constituting 256 μg MTX per mg of PL, almost 50% of the conjugate can be covalently linked onto the carrier surface. Release studies failed to demonstrate the presence of free drug. However it appears that MTX-oligopeptides are released from the carrier as a result of the enzymatic hydrolysis of biodegradable bonds. It is suggested that [Fe-PGNP]-PL-MTX may be useful in the intracellular active targeting of bonded drug(s).

Albumin microspheres. IV. Effect of protein concentration and stabilization time on the release rate of adriamycin

Abstract The effects of protein concentration and heat-stabilization time at 120 ° C on the release rate of adriamycin from microspheres have been investigated. The albumin concentration and the stabilization time of the microspheres were varied from 20 to 40% w/v and from 2.5 to 10 min, respectively. The release studies carried out using dynamic dialysis demonstrated that irrespective of the protein concentration and stabilization time, the initial release rate was significantly higher than the terminal release rate of adriamycin from these particles. Whereas variation in the albumin concentration was shown to cause comparable changes in the initial and the terminal release rate constants of adriamycin, the variation in the stabilization time predominantly affected the terminal release rate constants. The results indicate that protein concentration as well as the heat-stabilization time of albumin microspheres may be used to control the release of entrapped drug.