SYSTEMIC ADMINISTRATION OF PEPTIDES AND PROTEINS THROUGH THE OCULAR ROUTE
V. SYSTEMIC ADMINISTRATION OF PEPTIDES AND PROTEINS THROUGH THE OCULAR ROUTE
Systemic absorption of polypeptides and proteins primarily occur through contact with the conjunctival and nasal mucosae. Table 5 lists some of the peptides that could be administered through the ocular route (93). Almost all the studies involving the absorption of peptides and proteins in animal models have been carried out using labeled peptide samples (94–96). Apart from monitoring the blood concentrations for pharmacokinetic evaluation, pharmacodynamic studies have also been extensively pursued. Some of the biological response parameters include reduction in blood sugar by insulin, increase in blood glucose by glucagon, analgesic effects by enkephalins, and increase in blood pressure by vasopressin.
Systemic peptide availability following ocular administration has been related to biological response. The study by Christie and Hanzal (97) showed that insulin instilled into the conjunctiva is absorbed rapidly, giving rise to a fairly constant and consistent lowering of blood sugar levels in rabbits. Another study with somatostatin and its analog revealed that there was an attenuation of the miotic response to noiceptive stimuli by these agents, whereas intracameral injection of 1–50 mg met-enkephalin had no effect on the miotic response (98).
Lee et al. (99) found that enkephalinamide and inulin are absorbed into the blood stream following topical ocular administration, the former to
a greater extent than the latter. The authors proposed that depending on the
Table 5 Therapeutically Useful Peptides that Could Be Administered Through the Ocular Route
Antiallergic, decongestant anti-inflammatory
-Endorphin Analgesic Calcitonin
Paget’s disease, hypercalcemia Glucagon
Hypoglycemic crisis Insulin
Diabetes mellitus Leu-enkephalin
Analgesic Met-enkephalin Immunostimulant Oxytocin
Induce uterine contractions Somatostatin
Attenuate miotic responses TRH
Diagnosis of thyroid cancer Vasopressin
Diabetes insipidus VIP
Secretion of insulin
506 Dey et al. molecular size, lipophilicity, and susceptibility to proteolysis, other peptides
and proteins may also be absorbed to varying extents. Similarly, Chiou and Chuang (94) demonstrated the feasibility of effective systemic delivery of topically instilled peptides in the eye. Their findings suggest that systemic delivery of peptide drugs is superior to the parenteral route, especially when the drug is potent and doses required are low. Enkephalin could effectively
be absorbed systemically through the eye with the use of an absorption enhancer (95). This ocular route was found to be superior to administering the peptide by an intravenous route. Similar results have been obtained with other peptides like thyrotropin-releasing hormone (TRH), luteinizing hor- mone–releasing hormone (LHRH), glucagon, and insulin (94). Spantide, a tachykinin antagonist, is readily taken up into the rabbit eye following topical application. Measurable concentrations of the peptide were observed in the aqueous humor as well as in the general circulation. Similarly, insulin could be absorbed effectively into the systemic circulation through ocular instillation (100). The systemic absorption of 1% insulin through the eyes can be enhanced at least sevenfold when 1% saponin, a surfactant, was added to the solution. This absorption enhancement was not affected by aminopeptidase inhibition. Recently, calcitonin, a polypeptide hormone, was found to be poorly absorbed into the systemic circulation through the ocular rote (101). Inclusion of permeation enhancers like Brij-78 and BL-9 markedly improved its systemic absorption.
In summary, small polypeptides such as TRH (MW 300), enkephalins
a significant extent through the eyes, almost to the extent of 99% (94). Polypeptides with larger molecular weight such as
-endorphin lesser extent. The absorption of such large molecular weight compounds
can, however, be improved by simultaneous use of absorption enhancers (78).