title: In situ gelling pectin formulations for oral drug delivery at high gastric pH.
abstract: The aim of the study was to compare the gelation and drug release characteristics of formulations of pectin with high (31%) and low (9%) degrees of methoxylation over a wide pH range (pH 1.2-5.0). Dilute solutions of pectin (1.5%, w/v) containing complexed calcium ions formed gels in vitro at low pH (pH<2.5) as a consequence of cross-linking of the galacturonic chains by calcium ions released from the complex, but the efficiency of gelation was significantly reduced with increase of pH because of incomplete release of complexed Ca(++). Gelation of formulations of pectin with a degree of esterification of 9% (DE9) was observed over the pH range 2.5-5.0 in the presence of 1.6mM Ca(++), but was incomplete in formulations of pectin with a degree of esterification of 31% (DE31). A sustained release of ambroxol was observed following oral administration of pectin DE9 formulations to gastric-acidity controlled rabbits at pH 5.5-5.7 and visual observation of the stomach contents of these rabbits confirmed in situ gelation of these formulations. There was no evidence of in situ gelation of pectin DE31 formulations under these conditions and a rapid initial drug release was observed. Differences in gelling characteristics in this pH range were attributed to the greater susceptibility of low methoxylated pectin to cross-linking by di- and tri-valent ions present in the gastric juice. It is concluded that formulations of pectin with a low degree of esterification have potential application as in situ gelling vehicles for the sustained delivery of drugs following oral administration under conditions of high gastric pH.
authors.affiliation: Faculty of Pharmaceutical Sciences, Health Science University of Hokkaido, Ishikari-Tohbetsu, Hokkaido 061-0293, Japan.
authors.forename: Kunihiko
authors.initials: K
authors.lastname: Itoh
authors.affiliation: Faculty of Pharmaceutical Sciences, Health Science University of Hokkaido, Ishikari-Tohbetsu, Hokkaido 061-0293, Japan.
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Hirayama
authors.affiliation: Faculty of Pharmaceutical Sciences, Health Science University of Hokkaido, Ishikari-Tohbetsu, Hokkaido 061-0293, Japan.
authors.forename: Akie
authors.initials: A
authors.lastname: Takahashi
authors.affiliation: Faculty of Pharmaceutical Sciences, Health Science University of Hokkaido, Ishikari-Tohbetsu, Hokkaido 061-0293, Japan.
authors.forename: Wataru
authors.initials: W
authors.lastname: Kubo
authors.affiliation: Faculty of Pharmaceutical Sciences, Health Science University of Hokkaido, Ishikari-Tohbetsu, Hokkaido 061-0293, Japan.
authors.forename: Shozo
authors.initials: S
authors.lastname: Miyazaki
authors.affiliation: Research Development, R&D Division, Teikoku Medix Co. Ltd., Saitama-Shi, Saitama 331-0056, Japan.
authors.forename: Masatake
authors.initials: M
authors.lastname: Dairaku
authors.affiliation: Research Development, R&D Division, Teikoku Medix Co. Ltd., Saitama-Shi, Saitama 331-0056, Japan.
authors.forename: Mitsuo
authors.initials: M
authors.lastname: Togashi
authors.affiliation: Research Development, R&D Division, Teikoku Medix Co. Ltd., Saitama-Shi, Saitama 331-0056, Japan.
authors.forename: Ryozo
authors.initials: R
authors.lastname: Mikami
authors.affiliation: School of Pharmacy and Pharmaceutical Sciences, University of Manchester, Manchester M13 9PL, UK. Electronic address: david.attwood@man.ac.uk.
authors.forename: David
authors.initials: D
authors.lastname: Attwood
mesh_terms: D000284:Administration, Oral; D000551:Ambroxol / Q000008:administration & dosage / Q000097:blood / Q000737:chemistry* / Q000493:pharmacokinetics; D000818:Animals; D002122:Calcium Chloride / Q000737:chemistry; D002626:Chemistry, Pharmaceutical; D003432:Cross-Linking Reagents / Q000737:chemistry; D003692:Delayed-Action Preparations; D004337:Drug Carriers; D004339:Drug Compounding; D004951:Esterification; D005744:Gastric Acid / Q000737:chemistry*; D005745:Gastric Acidity Determination; D005753:Gastric Mucosa / Q000378:metabolism; D005782:Gels; D006863:Hydrogen-Ion Concentration; D008297:Male; D008956:Models, Chemical; D010368:Pectins / Q000737:chemistry*; D011817:Rabbits; D012212:Rheology / Q000379:methods; D012995:Solubility; D014783:Viscosity
chemical_list: D003432:Cross-Linking Reagents; D003692:Delayed-Action Preparations; D004337:Drug Carriers; D005782:Gels; D000551:Ambroxol; D010368:Pectins; D002122:Calcium Chloride