title: Self-Stabilizing Ampholytic Starch Excipients for Sustained Release of Highly Soluble Drugs: the Case Study of Metformin.
abstract: A new class of starch derivatives carrying cationic and anionic functional groups was developed aiming to provide an alternative for the formulation of highly soluble drugs. The new ampholytic starch derivatives were synthesized in two steps; first the CarboxyMethyl (CM) groups were grafted on starch chains followed by introduction of AminoEthyl (AE) groups. The final product, CarboxyMethyl-AminoEthyl-Starch (CM-AE-St), could be obtained in different degrees of substitution by varying the number of CM and AE groups. It was hypothesized that the simultaneous presence of anionic and cationic groups will generate a stronger self-stabilization of starch matrices and an improved control of drug release. Metformin (biopharmaceutical classification system-BCS, class I) was selected as model drug and monolithic tablets with 50 and 60% loading were prepared by direct compression of the active molecule with various CM-AE-St derivatives. The in vitro drug dissolution tests have shown that higher degrees of substitution for both CM and AE groups favor the ability of ampholytic CM-AE-St to control the drug release in simulated gastric fluid and in simulated intestinal fluid. Tablets based on CM-AE-St derivatives were compared to the commercial Glumetza® (50% loading). The drug release was controlled for 12 h exhibiting a similar Higuchi's model dissolution profile for the two dosage forms. Structural studies (FT-IR,1H NMR, SEM, TG, X-ray diffraction) run on CM-AE-St derivatives put in evidence derivatization and self-stabilization phenomena. These new ampholytic starch derivatives offer a simple and convenient alternative to formulate and manufacture highly soluble drugs in a single step process.
authors.affiliation: Department of Chemistry and Pharmaqam Center, Université du Québec à Montréal, C. P. 8888, Branch A, Montréal, Québec, H3C 3P8, Canada.
authors.forename: Khalil
authors.initials: K
authors.lastname: Sakeer
authors.affiliation: Department of Chemistry and Pharmaqam Center, Université du Québec à Montréal, C. P. 8888, Branch A, Montréal, Québec, H3C 3P8, Canada.
authors.forename: Pompilia
authors.initials: P
authors.lastname: Ispas-Szabo
authors.affiliation: Department of Chemistry and Pharmaqam Center, Université du Québec à Montréal, C. P. 8888, Branch A, Montréal, Québec, H3C 3P8, Canada. mateescu.m-alexandru@uqam.ca.
authors.forename: Mircea Alexandru
authors.initials: MA
authors.lastname: Mateescu
mesh_terms: D003692:Delayed-Action Preparations; D004355:Drug Stability; D005079:Excipients / Q000737:chemistry; D008687:Metformin / Q000737:chemistry*; D012995:Solubility; D013213:Starch / Q000737:chemistry*; D013607:Tablets
chemical_list: D003692:Delayed-Action Preparations; D005079:Excipients; D013607:Tablets; D013213:Starch; D008687:Metformin
keywords: CarboxyMethyl-AminoEthyl-Starch; ampholytic starch; controlled release; metformin; monolithic tablet