Transdermal versus subcutaneous leuprolide: a comparison of acute pharmacodynamic effect.

Transdermal administration of peptides has been limited by the barrier properties of the skin. We compared the acute luteinizing hormone (LH) response to subcutaneous and transdermal administration of an LH-releasing hormone agonist (leuprolide). Eighteen volunteers received 5 mg leuprolide added to electrically powered patches delivering a current of 0.22 microA (transdermally). One week later, they received a 5 mg subcutaneous dose. LH response was measured. The area under the curve for LH response, maximum LH response, and time to maximum LH response were similar. Time to first response was shorter (147 +/- 108 minutes [transdermally] and 73 +/- 74 minutes [subcutaneously]; p less than 0.05), and the area under the curve for the first 150 minutes was greater (3655 +/- 2246 mIU.min/ml [transdermally] and 8666 +/- 4067 mIU.min/ml [subcutaneously]; p less than 0.05) for subcutaneous delivery. No major adverse effects were seen. This electrically powered transdermal technique merits further study.

Transdermal delivery of human insulin to albino rabbits using electrical current.

The transdermal route of administration for medication has many potential advantages over other routes of administration. However, the stratum corneum is an effective barrier to the absorption of most chemicals from the external environment into the body. To evaluate techniques for alteration of transdermal permeability, the authors studied the effect of low levels of electrical current on transport of a protein across the stratum corneum. Transcutaneous insulin absorption was used as an indicator of altered permeability. Twenty-six albino rabbits had acute diabetes mellitus induced by the intravenous administration of 125 mg/kg of alloxan. The animals then received either cutaneous patches containing insulin and an electrical current of 0.4 mA (active) or patches containing an equal amount of insulin but without electrical current (passive). At 10 and 12 hours after the placement of the patches, animals with active patches had significant elevations in serum insulin levels (p less than .05) and reduction in blood glucose levels (p less than .01). No changes were seen in controls. Animals with active patches also had significant differences from control animals in mean insulin response and peak insulin response (p less than .05). No cutaneous toxicity was observed in any of the animals. The authors conclude that low levels of electrical current can induce changes in stratum corneum permeability that are sufficient to produce the transdermal absorption of physiologic doses of a protein such as human insulin.

Successful transdermal administration of therapeutic doses of a polypeptide to normal human volunteers.

The human stratum corneum constitutes a relatively impermeable barrier to the transdermal absorption of most substances, including polypeptides and proteins. This double-blind, randomized, crossover study in 13 normal men evaluated whether a low level of electrical current could induce changes in cutaneous permeability sufficient to produce absorption of a polypeptide. We compared cutaneous absorption of 5 mg of leuprolide (a 9 amino acid luteinizing hormone releasing hormone analogue) in transdermal patches containing 0.2 mA electrical current (active) and in patches containing no electrical current (passive). Serum luteinizing hormone (LH) concentration was measured 12 times during an 8-hour period as a measure of drug effect. Similar baseline LH levels were seen in each group: active = 11.3 +/- 3.1 mIU/ml and passive = 13.7 +/- 4.7 mIU/ml (p not significant). Significant elevations of LH were seen in active compared with passive patches (p = 0.0084). As predicted, passive patches produced no elevation of LH concentration (LH = 11.8 +/- 7.1 mIU/ml at 4 hours). However, active patches produced elevations comparable to those achieved with subcutaneous administration of the drug (LH = 56.4 +/- 49.6 mIU/ml at 4 hours and p = 0.003 compared with passive). The patches were well tolerated without significant cutaneous toxicity. It is concluded that the use of low levels of electrical current can induce changes in the permeability of the stratum corneum. These changes are sufficient to promote the transdermal absorption of therapeutically relevant amounts of a polypeptide. This has major importance for our understanding of skin permeability and for the development of new techniques for drug administration.