Saran Kumar

A biodegradable injectable implant for delivering micro and macromolecules using poly (lactic-co-glycolic) acid (PLGA) copolymers

Abstract Biodegradable polymers are used in diffusion controlled, swelling controlled and chemically controlled delivery systems. In this study, PLGA copolymers were used in a formulation which forms a gel matrix immediately on contact with aqueous fluids. This property of the formulation can circumvent the need for making a surgical incision to implant the matrix. The gel matrix thus formed will release the drug slowly (over a period of weeks to months) and ultimately biodegrade depending on the composition of the polymer used. In vitro release studies using small molecules and macromolecules, such as proteins, indicate that the drug release is influenced by the concentration of the polymer, physico-chemical properties of the drug, method of incorporation of the drug in the formulation and the presence of other excipients. The drug release can therefore be modified to suit the desired release characteristics. This novel formulation design for a biodegradable injectable implant can provide prolonged release while avoiding the necessity for surgical procedures.

In vivo transdermal iontophoretic delivery of growth hormone releasing factor GRF (1–44) in hairless guinea pigs☆

Abstract The present study was undertaken to determine the effect of iontophoresis on the transdermal delivery of growth hormone releasing factor (GRF 1–44), a peptide shown to be effective in promoting linear growth in short-statured children. A reservoir patch with a conductive peptide gel was used for this purpose and the delivery of the peptide was monitored in vivo in hairless guinea pigs using a pulsed voltage generator specifically designed to provide a current limit. The current limit selected for the present study was 0.17 mA/cm 2 at 50 KHz and 50% daty cycle. The current conditions were selected based on previously performed in vitro experiments. The half life, volume of distribution and area under the curve (AUC) were determined to be 0.389 h, 8.861 and 0.453 (mg/ml) h, respectively from an intravenous administration of a 10 μg/kg dose in the same speries. Using this information, a flux of 3.16 μg/h was calculated based on a steady-state plasma concentration of about 0.20 ng/ml. This steadystate level was similar to a peak plasma level achieved after a subcutaneous dose of 10 μ/kg. An in vivo animal model, fabrication of a patch System and design of a unique pulsed voltage generator with current limiting feature have been shown, which can be used to determine the iontophoretic deiivery of compounds of interest.

Optimization of iontophoretic transdermal delivery of a peptide and a non-peptide drug

Abstract In vitro iontophoretic transdermal delivery (ITD) of a tripeptide, enalaprilat (EP) and a non-peptide, cromolyn sodium (CS), across frozen hairless guinea pig (HGP) skin were investigated. Parameters for optimization of ITD included the influence of ionic strength (μ), buffer type and size, drug loading in the donor and the effect of pH. Drug permeation into the receptor compartment was monitored using HPLC assay methods developed for the study. An optimum μ of 6.66 mM in acetate buffer was found necessary for efficient ITD of CS. An exponential decrease in the flux of CS was observed with an increasing μ. Buffer ions larger than acetate ions inhibited the transport of CS ions. With an increase in the donor concentration of CS, a hyperbolic relationship for the increase in flux was observed. For EP, permeation was not detectable when μ was increased to greater than 31 mM in phosphate-buffered solution. With an increase in pH above the p K a 1 (3.55) for EP, a linear decrease in flux was observed. Higher drug loading of EP in the donor compartment provided better permeation. Effect of freezing of HGP skin on the iontophoretic delivery of EP and CS was also evaluated. Flux values for either of the drugs studied were similar when frozen or fresh skins were used. Reversibility studies indicated that no gross current induced permeation changes occurred with the HGP skin. Passive permeation of either of the drugs investigated was negligible.

Effect of chemical enhancers and conducting gels on iontophoretic transdermal delivery of cromolyn sodium

In vitro iontophoretic transdermal delivery (ITD) at a continuous current density of 0.1 mA/cm2 of cromolyn sodium (CS) across hairless guinea pig skin (HGP) was studied with and without enhancers. CS was quantitated by a sensitive HPLC method. At a saturated drug concentration of CS in 80:20 mixture of ethanol:6.66 mM acetate buffer, an overall flux enhancement compared to buffer alone was observed. This enhancement was determined to be an additive effect of iontophoresis and ethanol. Chemical enhancers, such as anionic surfactants (e.g. sodium dodecyi sulfonate and sodium lauryl sulfate), inhibited the permeation of CS ions at concentration less than or equal to the critical micelle concentration. No significant change in flux (P > 0.05) was observed when propylene glycol was added at different concentrations to yield solutions with varying dielectric constants in the aqueous donor medium. Aqueous glycerol solution was ineffective for ITD. Conducting gels of ionic polymers, polyjel-HV® and lubrijel-MS®, decreased the flux of CS significantly (P < 0.05). Non-ionic polymers such as hydroxypropyl cellulose (Klucel-LF®) and polyvinyl alcohol did not affect the flux and may be used for ITD of CS from a transdermal patch. An optimized solution formulation for CS was incorporated in a commercially available electropatch, from which delivery rates up to 46 ± 5 μg/cm2hr−1. were achieved. The optimized formulation of CS provided about 18 fold higher flux compared to an unoptimized formulation from the electropatch. Stainless steel or Ag/AgCl electrodes showed no difference in the flux of CS from the patch. Therapeutic levels of CS in humans may be achieved by this modem non-invasive drug-delivery route.