epidermal-growth-factor and decanoic-acid

Subcutaneous administration of human epidermal growth factor (hEGF) to rats gave a significantly smaller value of area under the curve (AUC) of concentration in plasma of immunoreactive hEGF versus time than intravenous administration, probably because the slow entry rate into the blood circulation and consequently the enzymic degradation of hEGF at the injection site. In the present study, absorption promoters such as sodium caprate, N-acylamino acids, disodium ethylenediamine-tetraacetate (EDTA), and sodium glycocholate were used because they were expected to inhibit the enzymic degradation of hEGF at the injection site and to facilitate the entry of hEGF into the blood circulation. Coadministration of an absorption promoter with hEGF significantly increased the entry rate and AUC value of immunoreactive hEGF compared with the case without the absorption promoter. The enzymic degradation of hEGF in the supernatant of the rat subcutaneous tissue homogenates and in the buffer solution containing leucine aminopeptidase or protease was markedly inhibited by the presence of the absorption promoters except EDTA. On the other hand, only EDTA increased the initial entry rate of FITC-dextran (M(r), 4000), which is not metabolized at the injection site, although all absorption promoters including EDTA markedly increased the extravasation of Evans blue. Thus, the increased subcutaneous bioavailability of hEGF in the presence of absorption promoters (except EDTA) was mainly attributed to the inhibitory effect of absorption promoters against the enzymic degradation of hEGF at the subcutaneous tissues.

Topics: Adjuvants, Pharmaceutic; Amino Acids; Animals; Decanoic Acids; Dextrans; Edetic Acid; Epidermal Growth Factor; Evans Blue; Extravasation of Diagnostic and Therapeutic Materials; Fluorescein-5-isothiocyanate; Glycocholic Acid; Humans; Injections, Intravenous; Injections, Subcutaneous; Male; Rats; Rats, Sprague-Dawley; Skin Absorption; Stimulation, Chemical

Previously, the presence of sodium carboxymethylcellulose (CMC Na) in addition to an absorption promoter, sodium caprate (C10 Na), in the dosing solution was found to be necessary for the enhancement of the rectal absorption of human epidermal growth factor (hEGF). In the present study, other synthetic polymers and absorption promoters were examined for their ability to enhance the rectal and nasal absorption of hEGF in rats. The effect of polymers in combined use with 100 mM C10 Na on the rectal absorption of hEGF was in the following order: 1% methylcellulose 1% hydroxypropylmethylcellulose 0.1% polyacrylic acid 1% CMC Na. Other absorption promoters such as N-lauroyl-alanine (C12-A) and dihydroxy-bile salts also enhanced the rectal absorption of hEGF in combined use with CMC Na. In order to confirm the increased rectal absorption of hEGF, the disappearance of hEGF from the rectal loop was examined. When hEGF in a 1% CMC Na solution (200 ug/kg) was administered in the rectal loop, the disappearance percent of hEGF during 60 min was 13.9% of the dose, although hEGF was not detected in the plasma. The presence of promoters such as 10 mM C10 Na or 15 mM C12-A in 1% CMC Na increased the disappearance percent to about 50% in a dosing range of hEGF from 100 to 500 ug/kg. On the other hand, a markedly enhanced nasal absorption of hEGF by 100 mM C10 Na was observed even in the absence of any polymer in a dising solution. However, addition of CMC Na into the dosing solution accelerated the rate of nasal absorption of hEGF in early phase.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Acrylic Resins; Administration, Intranasal; Administration, Rectal; Animals; Decanoic Acids; Epidermal Growth Factor; Excipients; Humans; Hypromellose Derivatives; Intestinal Absorption; Male; Methylcellulose; Nasal Mucosa; Polymers; Rats; Rats, Inbred Strains