Improved Oral Bioavailability of Human Growth Hormone by a Combination of Liposomes Containing Bio-Enhancers and Tetraether Lipids and Omeprazole

• Published in: Journal of pharmaceutical sciences Vol. 103; no. 12; pp. 3985 - 3993
• Main Authors: Parmentier, Johannes, Hofhaus, Götz, Thomas, Silke, Cuesta, Laura Clusa, Gropp, Felix, Schröder, Rasmus, Hartmann, Klaus, Fricker, Gert
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.12.2014; Elsevier Limited
• Subjects: Administration, Oral; Animals; archae; Biological Availability; Chemistry, Pharmaceutical - methods; dual asymmetric centrifugation; Duodenum - metabolism; Human Growth Hormone - chemistry; Human Growth Hormone - metabolism; Humans; imaging methods; Intestinal Mucosa - metabolism; Jejunum - metabolism; Lipids - chemistry; lipogelosomes; liposomes; Liposomes - chemistry; Liposomes - metabolism; Male; Omeprazole - chemistry; Omeprazole - metabolism; oral absorption; permeation enhancers; proteins; Rats; Rats, Wistar; imaging methods; archae; liposomes; proteins; dual asymmetric centrifugation; permeation enhancers; lipogelosomes; oral absorption
• ISSN: 0022-3549; 1520-6017
• DOI: 10.1002/jps.24215

Liposomes for the oral delivery of human growth hormone (hGH) containing bio-enhancers and tetraether lipids were prepared by dual asymmetric centrifugation. Cetylpyridinium chloride (CpCl), d-α-tocopheryl polyethylene glycol 400 succinate, phenylpiperazine, sodium caprate or octadecanethiol were used as permeation enhancers. In vitro data showed that oligolamellar vesicles with average size in the range of 200–250nm were formed. Performance of the formulations was investigated both ex vivo by confocal microscopy scans of sections of rat small intestine and in vivo by comparing the area under the plasma curve of hGH after oral or subcutaneous (s.c.) application. The microscopic data reveal an interaction between the liposomal formulation and the intestinal mucus layer. Particularly one formulation, which was designed to be mucus penetrative by addition of a high quantity of TPGS 400 and a ζ-potential close to 0mV, showed a very strong mucus association in the duodenum and jejunum. Vesicles with CpCl 33% (mol/mol) led to a relative hGH bioavailability of 3.4% compared with s.c. control, whereas free hGH administered orally showed a bioavailability of only 0.01%. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association.