Preparation Of Clarithromycin Floating Beads And Research On Its Release Behavior In Vitro

Object:Clarithromycin(Cla),admitted internationally,is one of the high effective antibiotics to treat Helicobacter Pylori(HP),however,traditional Cla drug delivery formulations have some disadvantages in eliminate HP,including low availability and less target,and therapeutic action starts only after the drug was absorbed by enteric cavity.Objective of the research is to prepare a Cla floating beads,in which all Cla can be released within 5 hours at zero rate in stomach.Methods:Firstly the basic physico-chemical property of Cla were investigated, and then to prepare alginate floating beads with alginate sodium(Alg-Na) and liquid paraffin(LP),in which emulsification and Ca²⁺ crosslink were applied.Buoyancy, entrapment efficiency(EE),and drug release behavior in vitro were investigated with various amount of drug,floating agent and drying ways.Further more,the effect of chitosan(CTS) as a crosslink agent,PEG6000 and coating were investigated.The research of CTS floating beads was also doneResults:Cla has a week UV absorption,and a max absorption at 482nm was gained after H₂SO₄(75→100) adding,which can be used to determine content of Cla. Stability of Cla was affected by pH value:destructed at pH1.0,while very stable at pH5.0.Solubility in pH3.6 PBS under 37℃is 26mg/ml.Its dissolving is a endothermic process and the solvation enthalpy is 14.46KJ/mol.Beads can float on pH1 HCl for more than 12h at the ratio of 2%Alg-Na water solution:LP=10:2;Volume of beads grow with increase of LP ratio;Fixed release dose,lower drug ratio,faster drug release;The ratio of Cla:Alg=2:1 is a suitable factor to prepare floating beads;Release behavior in pH3.6 acetate buffer solution of beads dropped through 0.6,0.7,0.8mm inner diameter needles has little difference,and about 70%drug released after 30 min,all drug released after 90min;Floating beads at above-mentioned ratio has a EE of 90.2%and a drug loading rate of 15.6%.Beads without LP dried by lyophillization can not float,while beads with LP dried by lyophillization have a bigger volume than dried by vacuum drying,no difference in EE but a slight faster release rate.If CTS as crosslink agent,lower EE gained.When only CTS or firstly CTS then TPP(two steps crosslink),beads have a EE about 70%and a faster drug release rate(60min) than beads crosslinked only with Ca²⁺;When CTS and Ca²⁺ simultaneously(one step crosslink) or firstly CTS then(two steps crosslink),beads have the same drug release behavior,but at the other respect,one step crosslink-beads are more like beads crosslinked only by Ca²⁺,while two steps crosslink-beads have the same properties.When adding,more smooth and compact beads were gained,and more PEG6000,faster drug release rate(a little difference).However,the beads with PEG6000 have a lower EE about 86%.All the release behavior accord with Higuchi equation.After coated with 4%EC ethanol solution(contain caster oil and various amount of PEG6000),the release rate was slowed down remarkably.When EC:PEG6000=1:0.5 and 10%weight increased or EC:PEG6000=1:0.25 and 20% weight increased,the coating floating beads can release drug at zero order proximately for about 300min.Beads made through emulsification with CTS,crosslinked by TPP-methanal mixed solution,have a EE above 80%,and low wt CTS floating beads have slower release rate than high wt CTS because of high concentration,but still faster than alginate floating beads.Conclusion:Gastro-floating formulation has less dose and low incidence of ADR, and HP can be eliminated through repeated administration.Floating beads is a kind of multi-chamber formulation,which can reduce individual variation.Alg-Na is a cheap material and dropping method is simple,so it's a feasible method to prepare floating beads.