Transdermal drug delivery: revival of fortunes?

By Barath Shankar, Research Analyst – Pharmaceuticals & Biotechnology, Frost & Sullivan

Transdermal drug delivery systems have been in use for over 20 years and had generated tremendous interest amongst pharmaceutical companies upon introduction in the early 1980’s. The interest was owing the to the advantages offered by the transdermal route, which bypassed the traditional liver metabolized route, offered higher patient compliance with the ability to control release of drugs with short half-lives and reduce adverse events associated with traditional drug delivery.

However, the promise was short-lived as several problems emerged upon development of transdermal drugs that included dose limitation, skin irritation, delayed time-of-action, site dependent absorption. The waning of interest from big-pharma resulted in limited number of transdermal delivery based drugs entering the market and several transdermal drug delivery focused companies merging with other drug delivery companies. The emergence of interest in other drug delivery routes like pulmonary further resulted in a dramatic decline in the pipeline for transdermal delivery based drugs.

However, with thinning pipelines and fewer blockbusters, pharmaceutical companies are increasingly looking to innovative drug delivery routes to extend patent life. The success of transdermal drugs, especially nicotine based transdermal products in the 90s has brought back interest amongst pharmaceutical companies and has resulted in a significant upward trend that is likely to drive the market in the future.

Technology

Transdermal drug delivery systems have evolved to suit the requirements of pipeline products by improving physical and chemical permeation of delivery systems. Renewed academic and industry interest has resulted in the development of various methods to incorporate transdermal drug delivery. While the passive transdermal delivery systems are “patch” based, the emerging “active” transdermal drug delivery platforms that incorporate innovative technologies have been discussed below. It must be noted however that several transdermal drug delivery platforms are still in development stage.

Iontophoresis
A non-invasive method of delivering the drug molecules by using a small electric current to enable charged drugs to permeate through the skin. The delivery of electric current to the skin alters its permeability that enables the increased migration of the drug into the epidermis.

Iontophoresis does not depend on concentration gradient and hence is not impacted by difference in permeability of skin in individuals. The establishment of an electric circuit through the current enables the movement of positively charged ions and drug molecules from the anode across the stratum corneum and back to the cathode. Similarly, the negatively charged molecules move from cathode through the skin and back to the anode. This movement of drug molecule is equal to the number of electrons moving between the electrodes in the exterior. Thus the drug dosage can be controlled by altering the charge delivered.

The factors that influence iontophoresis include skin pH, drug dosage, physical and chemical properties of the drug molecule, current, voltage and resistance. The application of iontophoresis has been targeted towards pain management as non-invasive, needle-free alternative.

US Food and Drug Administration approved products that incorporate iontophoresis based drug delivery systems include B.Braun Medical Inc’s LidoSite, IOMED’s Numby Stuff with Iontocaine. Future applications of iontophoresis could be to deliver the drug molecule in pulses by controlling the current.

Electric patch and micro needle
Electric patch based transdermal delivery was developed by ALZA Corporation through its E-TRANS electro transport technology. This offers higher flexibility than iontophoresis by being able to deliver a wider range of drug molecules depending on required dosage. ALZA’s Macroflux technology uses a thin titanium screen that consists of 200µm projections that create pathways to deliver the drug through the stratum corneum. Coupled with the Macroflux® transdermal technology, further enhancement of rate of drug delivery can be achieved.

Similar to the Macroflux transdermal technology is 3M’s Microstructured Transdermal System (MTS) that also incorporates micro needle technology for targeted delivery of drug molecules across the skin membrane. The drug molecule can thus be coated onto the micro projections to achieve a bolus delivery or using a reservoir to ensure continuous delivery of the drug over a specified time.

This delivery model could thus be useful for administering vaccines, small molecules and larger complex biopharmaceuticals.

Sonophoresis
The application of low level ultrasound energy or sonophoresis, for a short time period (< 90 seconds) increases permeability of the stratum corneum by creating reversible channels through the skin, permitting the delivery of drug molecules through the transdermal route. The advantage of the ultrasound delivery over micro needle is that it doesn’t require regeneration of holes in the skin that might otherwise potentially admit other compounds to go in.

SonoPrep is an ultrasonic skin permeating device developed by Sontra Medical Corporation that incorporates this technology. It has been developed for delivering SonoPrep topical anesthetic that significantly reduces time required to achieve anesthesia. Further applications of ultrasound transdermal delivery are likely to be expanded to include transdermal insulin, heparin, vaccines and continuous glucose monitoring.

Continuous glucose monitoring can be achieved as ultrasound enables the skin channels to be opened for about 12 hours with the application of a short burst. Continuous glucose monitoring is a highly critical task, especially in post-surgical patients and a technology that can monitor the absolute glucose levels and the rate of change on an hourly basis would have a tremendous impact on the market and could save valuable man-hours currently used by nurses in taking glucose measurements manually.

In diabetic patients, tight glycemic control can be achieved through continuous glucose monitoring that would improve quality of life and lead to a healthier and longer life-span.

Summary

It is very evident that transdermal drug delivery holds great promise for the future and with more companies evincing interest in this technology platform and greater collaboration amongst drug delivery and pharmaceutical companies, development of newer technologies and delivery platforms will only accelerate further and expand the horizon of transdermal drug delivery.