C.T. Hung

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 I: Physico-Chemical Characteristics

Albumin microspheres are biodegradable particles which can be readily radiolabelled and synthesized in the size range of 1 to 200 microns. During the last 30 years extensive efforts have been made towards the design and development of this carrier for the purpose of diagnosis and drug delivery. This review presents a thorough discussion on the physico-chemical characteristics of albumin microspheres.

Albumin Microspheres II: Applications in Drug Delivery

Albumin microspheres are colloidal particles which are known to sustain the release of entrapped therapeutic agent(s). The rate at which these particles metabolise in vivo can be manoeuvred by varying their synthetic conditions. These particles alter the in vivo distribution of included drugs and hence this carrier has been extensively investigated for drug delivery and targeting in laboratory animals. Attempts have also been made to use this carrier for the delivery of anti-cancer agents in patients with liver cancer. This review is focused on the experimental and clinical applications of albumin microspheres in drug delivery. An account of the toxicological properties of these particles is also presented.

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.

Targeted delivery of low dose doxorubicin hydrochloride administered via magnetic albumin microspheres in rats

The efficacy of magnetic albumin microspheres in the targeted delivery of an anti-cancer agent, doxorubicin hydrochloride, has been investigated in rats. Using the tail as a target organ, the animals were intra-arterially administered with either 0.12 mg/kg of free drug, or 0.04 mg/kg of microsphere entrapped drug in the presence of a 8000 Gauss magnet applied for 30 min at the target-site. In each group, the animals were sacrificed over a 48 h period and their various tissues analysed for drug concentration using HPLC. It was found that compared to the free drug, a one-third dose of microsphere entrapped drug resulted in almost eight times higher drug exposure (AUC0-infinity) at the target site. In addition, the drug delivery to all the non-target tissues, including liver and heart, was substantially reduced. The study confirms the efficacy of magnetic albumin microspheres in the targeted delivery of chemotherapeutic agents.

Ascending-dose study of noribogaine in healthy volunteers: Pharmacokinetics, pharmacodynamics, safety, and tolerability

Noribogaine is the active metabolite of the naturally occurring psychoactive substance ibogaine, and may help suppress withdrawal symptoms in opioid‐dependent subjects. The objectives of this Phase I study were to assess the safety, tolerability, pharmacokinetic, and pharmacodynamic profiles of noribogaine. In this ascending single‐dose, placebo‐controlled, randomized, double‐blind, parallel‐group study in 36 healthy drug‐free male volunteers, 4 cohorts (n = 9) received oral doses of 3, 10, 30, or 60 mg or matching placebo, with intensive safety and pharmacokinetic assessments out to 216 hours, along with pharmacodynamic assessments sensitive to the effects of mu‐opioid agonists. Noribogaine was rapidly absorbed, with peak concentrations occurring 2–3 hours after oral dosing, and showed dose‐linear increases of area under the concentration–time curve (AUC) and Cmax between 3 and 60 mg. The drug was slowly eliminated, with mean half‐life estimates of 28–49 hours across dose groups. Apparent volume of distribution was high (mean 1417–3086 L across dose groups). No safety or tolerability issues were identified in any cohort. No mu‐opioid agonist pharmacodynamic effects were noted in pupillometry or cold‐pressor testing. Single oral doses of noribogaine 3–60 mg were safe and well tolerated in healthy volunteers.

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.