Systemic Delivery of Polypeptides with Molecular Weights of Between 300 and 3500 Through the Eyes

ABSTRACT

Systemic absorption of polypeptides through eyes has been demonstrated in this study to provide an effective route of peptide administration as an alternate to parenteral administration. TRH at 0.0025% reached a plateau of blood concentration at 0.05 ng/ml in 60 min. and stayed high for at least 4 hrs, thereafter. In contrast, a therapeutic dose of TRH (15 μg/70kg i.v.) could maintain a blood concentration of 0.07 ng/ml. At 1%, TRH reached a plateau of 26 ng/ml in 2 hrs. and persisted in the plateau for 10 hrs. thereafter. At 5%, TRH peaked at 138 ng/ml in 60 min. and then fell gradually to a steady state of 60 ng/ml in 9 hrs from the peak. Addition of peptidase inhibitors (Leu-Leu, 4 mM; Bestatin, 60 μM; and DL-Thiorphan 0.6 μM) did not affect the uptake of TRH into systemic circulation. LHRH showed entirely different kinetic of systemic absorption through eyes. The blood concentration never reached peak or plateau during 12 hrs. of experimental period. The blood concentration of LHRH increased steadily during experiments. With 0.0025%, 1% and 5% of LHRH, they reached final highest blood concentrations of 0.13 ng/ml, 45 ng/ml and 95 ng/ml, respectively. The therapeutic dose of LHRH (15 μg/70 kg i.v.) could maintain a blood concentration at 0.25-0.3 ng/ml which was slightly higher than that reached with 0.0025% of LHRH instilled into the eye. Addition of peptidase inhibitor (Leu-Leu, 5 mM) enhanced the absorption of LHRH into systemic circulation slightly but significantly. Glucagon behaved similarly as TRH except that the blood concentration remained high without falling at 5% dose level. These results suggest that topical instillation of peptide drugs into eyes is a workable method for administration of these peptide drugs.