Technologies For Skin Delivery Of Hydrophilic Molecules And Macromolecules

Abstract

ABSTRACT

TECHNOLOGIES FOR SKIN DELIVERY OF HYDROPHILIC MOLECULES AND MACROMOLECULES

Under the direction of Dr. Ajay.K.Banga, Professor and Chair of the Department of Pharmaceutical Sciences, Mercer University

Transdermal delivery can bypass first pass metabolism, increase the bioavailability of drug and usually it is a non-invasive administration method and shows better patient compliance. While the transdermal delivery has some limitations, which hinders its wide application. Skin only allow the passage of drug molecules, which should ideally be moderately lipophilic (log P between 1-3) with a molecular weight <500 Da. Stratum corneum as a lipid barrier, it blocks the delivery of drug through the skin, especially for large and hydrophilic molecules such as peptide or protein. As a result, different strategies or devices have been developed to compromise the stratum corneum and enhance the drug permeation. In our studies, we investigated the delivery of hydrophilic small molecules and large molecules in/through the skin by optimizing the formulation, developing drug delivery systems or using physical enhancement techniques, such as maltose microneedle and ablative laser. The first aim was to optimize a gel formulation of cimetidine to maximize its transdermal delivery across microporated skin. Specifically, the effect of extent of ionization in formulation on permeation of cimetidine across microporated skin was studied. Results suggest that 0.8% w/w pH 5 gel showed highest permeation through microchannels compared with other formulations. In order to assess the skin irritation potential of cimetidine carbopol gel, skin irritation test had been performed using EpidermTM-200-SIT kit and results showed 0.8% pH 5 gel is not irritate to the skin. In the second aim, we investigated the feasibility of transdermal delivery of human growth hormone (hGH) through laser-microporated dermatomed porcine ear skin. Laser-assisted microporation creates microchannels in the skin that result in the enhancement of drug delivery. The effect of fluence of laser (34.1, 45.4 and 68.1 J/cm2) and micropores density (5%, 10% and 15%) on the permeation of hGH through laser-treated skin was studied. Permeation study results showed after 48 h, application of fluence of 68.1 J/cm2 laser resulted in significantly higher permeation of drug (90.94±3.93 µg/cm2) than that from 34.1 J/cm2 group (53.13±1.75 µg/cm2, p<0.05), but not as compared to the 45.4 J/cm2 group (p>0.05). With the increase in density of micropores from 5% to 15%, permeation of hGH increased significantly from 7.1±2.63 µg/cm2 to 95.89±13.43 µg/cm2 after 48 h study. In the third aim, we developed a controlled release system using Eudragit® RS100 and polyvinyl alcohol polymer. This microsponge based drug delivery technique can incorporate both hydrophilic and hydrophobic molecules and drug release follows the mechanism of process of diffusion. Salicylic acid microsponge was prepared by quasi emulsion solvent diffusion method and dispersed into 2.0 % carbopol gel. The structure of microsponge was checked under bright microscopy and scanning electron microscopy. Characterization studies of salicylic acid microsponge including loading efficiency, production yield and entrapment efficiency was performed. We tested the drug release profiles and permeation performance from the formulation with/without microsponge using dissolution tester and vertical Franz cell. Release study and permeation study results showed incorporation of salicylic acid in the microsponge did slow down the release rate from the formulation. Microsponge system plays a very important role in controlling the release as well as the permeation of salicylic acid topically. Microsponge was proved to be a potential carrier for salicylic acid in topical acne therapy to prolong drug release, minimize skin irritation and side effects. In the fourth aim, we evaluated the deactivation efficiency of a drug disposal pouch containing granular activated carbon. This activated carbon based drug deactivation system offers a unique disposal method. The deactivation study and desorption study were carried out using diazepam, lorazepam tablets and suboxone® sublingual film. Deactivation study results showed this drug disposal pouch successfully deactivated the drug within 28 days; more than 99% of drug had been adsorbed by the activated carbon. In the desorption study, only about 1% of drug leached out from the activated carbon when it exposed to the large volume of water and organic solvent. This activated carbon based drug deactivation system may provide a convenient way for the patients to dispose their unused medications.