Study On Famotidine Gastric Bioadhesive Microspheres

Famotidine (Fam) is one of the3rd-generation H2-receptor antagonists, which is a feature of high selectivity to H2receptors and strong binding activity. Hence, it is often clinically used to treat peptic ulcers with high therapeutic effectiveness that is20-fold of cimetidine and7.5-fold of ranitidine, respectively. Although, these are many dosage forms to select such as tablets, orally disintegrating, tablets, oral suspensions, injections and powder, as well as fixed formulation of ibuprofen and Fam nowadays, some problems have been existing in clinical application like short retentive time in the stomach, low concentration in parietal cell, short half-life and strong fluctuations of plasma concentration, so Fam is fully able to no utilization and is urgent to manufacture a novel formulation in order to meet the challenge from treatment of stomach diseases through gastric retention technology. In this thesis, a new Fam gastric bioadhesive microspheres has been fabricated to solve the clinical problem and is significant to be convenient to patients, reduce side effects, and enhance value of the old drug.The main task in this thesis is:(1) to measure physicochemical properties of Fam, and to establish a quality evaluation system of the preparation;(2) to prepare the formulation by emulsion-solvent evaporation method;(3) to study bioahension properties of bioadhesive microspheres;(4) to obtain pharmacokinetic parameters, relative bioavailability and correlation in vitro and in vivo.A lot of methods have been used including:(1) Measurement of solubility and octanol-water partition coefficients to explore physicochemical properties;(2) Method establishment of content determination and release by linear relation, precision, stability, recovery test;(3) The optimal process and formulation by single factor test, orthogonal experimental design and document retrieval.(4) Characteristics of release by various equation fitting like zero level equation, first level equation, Higuchi equation, Peppas equation;(5) Apparent characteristics of microspheres by microscope and measurement of particle size, particle size distribution, bulk density, roundness, angle of repose and so on.(6) Bioahension properties through four experiments, namely retentive time test in vitro, shear stress test, detachment force and bioadhension test in vivo.(7) Establishment of method of drug concentration in plasma by solid-phase extraction, external standard method and high-performance liquid chromatography (HPLC); pharmacokinetic experiments by randomized crossover design and main parameters by DAS2.0software; bioequivalence, relative bioavailability and correlation in vitro and in vivo through calculation of equation and analysis of variance;The primary results from this thesis including:(1) The higher pH of solution is, the lower solubility of Fam is and the higher octanol-water partition coefficient is.(2) Fam maximally absorbs UV at266nm, and the established method is suitable in range of2～20μg/mL for content assay in pH4.5phosphate buffer with good precision, linear relationship and recovery, as well as in range of4～40μg/mL for release test in pH1.0hydrochloric acid solution.(3) An excellent formulation and process with strong mucoadhesive performance was obtained by using ethyl cellulose as matrix material, carbopol934P as bioadhensive agent, PEG6000as pore-foaming agent, polysorbate80as emulsifiers, liquid paraffin as continuous phase and through emulsion-solvent evaporation method;(4) Release in pH1.0solution fits zero-order equation;(5) Carbomer showed obvious adhesion properties in four experiments in vivo or in vitro.(6) Pharmacokinetic studies showed gastric bioadhensive microspheres with sustained release, relatively lower plasma concentration in vivo, no bioequivalence compared with conventional tablets, a significant correlation feature between in vivo and in vitro, higher relative bioavailability of approximate130%for test formulation. The formulation showed highly gastric targeting.The conclusion was drawn from the context:a novel Fam gastric bioadhesive microspheres met the challenge from clinical requirements and achieved aim of design due to sustained release, strong bioadhesion in stomach, slow absorption in vivo, flat fluctuation of plasma concentration and high bioavailability.