title: In vivo proof of concept of oral insulin delivery based on a co-administration strategy with the cell-penetrating peptide penetratin.
abstract: Oral delivery of insulin is blocked by low intestinal absorption caused by the poor permeability of insulin across cellular membranes and the susceptibility to enzymatic degradation in the gastrointestinal tract. Cell-penetrating peptides (CPPs) have been investigated for a number of years as oral absorption enhancers for hydrophilic macromolecules. Penetratin, a cationic and amphipathic CPP, effectively enhances insulin absorption and we were able to alleviate the enzymatic barrier by using the enzymatic resistant D-form of penetratin. In this study, mice were dosed orally with a physical mixture of insulin and penetratin. Blood glucose concentrations were measured and a pharmacological availability (PA) of 18.2% was achieved in mice dosed with insulin and D-penetratin. Following the promising data, we investigated the degradation parameters of insulin and penetratin in rat intestinal fluid. As expected, L-penetratin was degraded rapidly whereas D-penetratin had a halflife of 67±7min in 10-fold diluted gastrointestinal fluid. Insulin degradation was slowed by the presence of penetratin in intestinal fluid. The half-life of insulin increased from 24.9±4.5min to 55.6±14min and 90.5±11.8min in the presence of L- and D-penetratin respectively. In conclusion, both Land D-penetratin acted as oral absorption enhancers at select CPP concentrations for insulin and the current study is the first solid evidence of pharmacological activity of oral insulin delivery systems based on non-covalent intermolecular interactions with penetratin.
authors: Laboratory of Drug Delivery Systems, Faculty of Pharmaceutical Sciences, Kobe Gakuin University, 1-1-3 Minatojima, Chuo-ku, Kobe, Hyogo 650-8586, Japan; Novo Nordisk A/S, Novo Nordisk Park, DK-2760, Måløv, Denmark.
authors: Ebbe Juel Bech
authors: EJ
authors: Nielsen
authors: Department of Pharmaceutics, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo 142-8501, Japan.
authors: Shinya
authors: S
authors: Yoshida
authors: Laboratory of Drug Delivery Systems, Faculty of Pharmaceutical Sciences, Kobe Gakuin University, 1-1-3 Minatojima, Chuo-ku, Kobe, Hyogo 650-8586, Japan.
authors: Noriyasu
authors: N
authors: Kamei
authors: Laboratory of Drug Delivery Systems, Faculty of Pharmaceutical Sciences, Kobe Gakuin University, 1-1-3 Minatojima, Chuo-ku, Kobe, Hyogo 650-8586, Japan.
authors: Ruisha
authors: R
authors: Iwamae
authors: Laboratory of Drug Delivery Systems, Faculty of Pharmaceutical Sciences, Kobe Gakuin University, 1-1-3 Minatojima, Chuo-ku, Kobe, Hyogo 650-8586, Japan; Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Suez Canal University, Ismailia 415-22, Egypt.
authors: El-Sayed
authors: el-S
authors: Khafagy
authors: Novo Nordisk A/S, Novo Nordisk Park, DK-2760, Måløv, Denmark.
authors: Jørgen
authors: J
authors: Olsen
authors: Novo Nordisk A/S, Novo Nordisk Park, DK-2760, Måløv, Denmark.
authors: Ulrik Lytt
authors: UL
authors: Rahbek
authors: Novo Nordisk A/S, Novo Nordisk Park, DK-2760, Måløv, Denmark.
authors: Betty Lomstein
authors: BL
authors: Pedersen
authors: Department of Pharmaceutics, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo 142-8501, Japan.
authors: Kozo
authors: K
authors: Takayama
authors: Laboratory of Drug Delivery Systems, Faculty of Pharmaceutical Sciences, Kobe Gakuin University, 1-1-3 Minatojima, Chuo-ku, Kobe, Hyogo 650-8586, Japan. Electronic address: mmtakeda@pharm.kobegakuin.ac.jp.
authors: Mariko
authors: M
authors: Takeda-Morishita
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D002352:Carrier Proteins / Q000008:administration & dosage* / Q000737:chemistry; D057846:Cell-Penetrating Peptides / Q000008:administration & dosage* / Q000737:chemistry; D016503:Drug Delivery Systems; D007004:Hypoglycemic Agents / Q000008:administration & dosage* / Q000737:chemistry; D007328:Insulin / Q000008:administration & dosage* / Q000737:chemistry; D007419:Intestinal Secretions / Q000737:chemistry; D008297:Male; D051379:Mice; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D001786:Blood Glucose; D002352:Carrier Proteins; D057846:Cell-Penetrating Peptides; D007004:Hypoglycemic Agents; D007328:Insulin; C414409:penetratin
keywords: Cell-penetrating peptides; Insulin; Oral absorption; Penetratin; Pharmacological availability