Absorption of interferon alpha from patches in rats

Interferon alpha (IFN-α), patch preparations composed of three layers, water-insoluble backing layer, drug containing layer with absorption enhancer and surface layer containing pH-dependent polymer were prepared. As absorption enhancer, three surfactants, Gelucire44/14 (Lauroyl macrogol-32 glycerides), Labrasol (Caprylocaproyl macrogol-8 glycerides) and HCO-60 (polyoxyethylated hydrogenerated castor oil) were used in preparing IFN-α patch preparations. The intestinal absorption of IFN-α was studied after the administration of test patch preparations into the rat jejunum, 50,000 IU/kg. The serum IFN-α levels were measured by an ELISA method and both C max and AUC were determined as the index of absorption of IFN-α. Gelucire44/14 preparation including Pharmasol for the stable solidification showed the higher C max, 7.66 ± 0.82 IU/ml, and AUC, 12.85 ± 1.49 IU h/ml, than Labrasol (6.51 ± 0.89 and 8.30 ± 1.34 IU h/ml) and HCO-60 (6.02 ± 1.14, 7.53 ± 1.84 IU h/ml) preparations, respectively. By comparing to the AUC obtained after s.c. injection of the same dose of IFN-α to rats, bioavailability (BA) was estimated to be 7.8% in Gelucire44/14 preparation. In vitro release study showed that the T50%s, the time when half of the formulated IFN-α is released from the patches, were 3.4 ± 0.1 min for HCO-60, 7.8 ± 0.1 min for Gelucire44/14 and 11.4 ± 0.1 min for Labrasol preparations. To study the effect of absorption site, Gelucire44/14 preparation was administered into the rat duodenum and ileum. However, there were not significant differences on AUC among the three absorption sites. By reducing the IFN-α dose from 50,000 to 25,000 IU/kg, the serum IFN-α levels vs time profile showed a tendency of dose-dependency. When the histological examination of small intestinal mucosa was carried out in this study, the small intestinal mucosa after the Gelucire44/14 patches administered and before it was administered, could not recognize impaired. From these results, the usefulness of oral patch system for the oral delivery of IFN-α has been proved in rats.

[1]  N. Shibata,et al.  Liquid filled nanoparticles as a drug delivery tool for protein therapeutics. , 2005, Biomaterials.

[2]  Samir Mitragotri,et al.  Oral delivery of macromolecules using intestinal patches: applications for insulin delivery. , 2004, Journal of controlled release : official journal of the Controlled Release Society.

[3]  K. Takada,et al.  Studies on the intestinal absorption of low molecular weight heparin using saturated fatty acids and their derivatives as an absorption enhancer in rats. , 2004, Biological & pharmaceutical bulletin.

[4]  Kanji Takada,et al.  In situ intestinal absorption studies on low molecular weight heparin in rats using labrasol as absorption enhancer. , 2004, International journal of pharmaceutics.

[5]  P. Artursson,et al.  Sodium Caprate Elicits Dilatations in Human Intestinal Tight Junctions and Enhances Drug Absorption by the Paracellular Route , 1993, Pharmaceutical Research.

[6]  P. Sinko,et al.  Regional Differences in Intestinal Spreading and pH Recovery and the Impact on Salmon Calcitonin Absorption in Dogs , 2004, Pharmaceutical Research.

[7]  Patrick J. Sinko,et al.  Biopharmaceutical Approaches for Developing and Assessing Oral Peptide Delivery Strategies and Systems: In Vitro Permeability and In Vivo Oral Absorption of Salmon Calcitonin , 2004, Pharmaceutical Research.

[8]  S. Sone,et al.  A peptide mimetic of human interferon (IFN)-beta. , 2003, The Biochemical journal.

[9]  N. Shibata,et al.  Possibility of a patch system as a new oral delivery system. , 2003, International journal of pharmaceutics.

[10]  S. Kawashima,et al.  In vitro and in situ evidence for the contribution of Labrasol and Gelucire 44/14 on transport of cephalexin and cefoperazone by rat intestine. , 2002, European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V.

[11]  N. Shibata,et al.  Gastrointestinal mucoadhesive patch system (GI-MAPS) for oral administration of G-CSF, a model protein. , 2002, Biomaterials.

[12]  N. Shibata,et al.  Evaluation of gastrointestinal transit characteristics of oral patch preparation using caffeine as a model drug in human volunteers. , 2002, Drug metabolism and pharmacokinetics.

[13]  H. Porst.  [Therapy of viral hepatitis]. , 2002, Zeitschrift fur Gastroenterologie.

[14]  K Takada,et al.  Retention and transit of intestinal mucoadhesive films in rat small intestine. , 2001, International journal of pharmaceutics.

[15]  J. McHutchison,et al.  Peginterferon alpha-2b: a new approach to improving response in hepatitis C patients , 2001, Expert opinion on pharmacotherapy.

[16]  M. Ikeda,et al.  Effects of oral administration of interferon-alpha on antibody production in mice with induced tolerance. , 1999, Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research.

[17]  P. Marcellin,et al.  Randomised trial of interferon α2b plus ribavirin for 48 weeks or for 24 weeks versus interferon α2b plus placebo for 48 weeks for treatment of chronic infection with hepatitis C virus , 1998, The Lancet.

[18]  J. Hoofnagle.  Therapy of Viral Hepatitis , 1998, Digestion.

[19]  Kanji Takada,et al.  Development and Evaluation of Noncompartmental Pharmacokinetic Analysis Program “WinHARMONY” Using Visual BASIC Language Having a Function of an Automatic Recognition of Terminal Elimination Phase of Plasma Drug Concentration vs. Time Profile , 1998 .

[20]  A. Sangchan.  Interferon Alfa-2b Alone or in Combination with Ribavin as Intial Treatment for Chronic Hepatitis C , 1998 .

[21]  J. Eyles,et al.  Oral Delivery and Fate of Poly(lactic acid) Microsphere‐encapsulated Interferon in Rats , 1997, The Journal of pharmacy and pharmacology.

[22]  W. Streit,et al.  Oral feeding of interferon τ can prevent the acute and chronic relapsing forms of experimental allergic encephalomyelitis , 1997, Journal of Neuroimmunology.

[23]  S. Tyring.  Interferons: biochemistry and mechanisms of action. , 1995, American journal of obstetrics and gynecology.

[24]  Alexander T. Florence,et al.  Titanium dioxide (rutile) particle uptake from the rat GI tract and translocation to systemic organs after oral administration , 1994 .

[25]  S. Davis,et al.  The quantitation of the absorption of microparticles into the intestinal lymph of Wistar rats , 1994 .

[26]  N. G. Popovich,et al.  Pharmaceutical Dosage Forms and Drug Delivery Systems , 1990 .