title: Mini-tablet combination for sustained release of clonidine hydrochloride and hydrochlorothiazide: Preparation and pharmacokinetics in beagle dogs.
abstract: Mini-tablets are increasingly gaining attention in solid dosage form design as multiple-unit systems combining different active compounds and providing a single or combined pattern of modified release for polypharmacy or combined treatments. A combination therapy of clonidine hydrochloride and hydrochlorothiazide achieves effective blood pressure control and reduction in adverse effects. However, the combination formulation of immediate release must be taken several times a day, which causes noticeable fluctuation of blood pressure and inconveniences to the patients. The present study was performed to develop a mini-tablet combination for sustained release of clonidine hydrochloride and hydrochlorothiazide independently, in which the two drugs and fraction doses were formulated into separate mini-tablets with different release patterns. The mini-tablets were prepared by a direct compression method followed by filling into capsules and the factors that affected drug release were addressed. Further, studies of the pharmacokinetics were performed in beagle dogs. Finally, in vivo-in vitro correlations of the sustained release systems and bioequivalence with conventional preparations were evaluated. The mini-tablet combination released the two drugs over 24h in vivo with a steady plasma concentration, a markedly lower Cmax, extended Tmax and better bioavailability. In conclusion, sustained releases of the two drugs were obtained with this mini-tablet combination, which offers a feasible formulation and promising development value for hypertensive patients who need long-term therapy.
authors.forename: Bohui
authors.initials: B
authors.lastname: Xu
authors.forename: Yubin
authors.initials: Y
authors.lastname: Wang
authors.forename: Hongyan
authors.initials: H
authors.lastname: Zhu
mesh_terms: D000179:Acrylates; D000465:Algorithms; D000818:Animals; D000959:Antihypertensive Agents / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics*; D001682:Biological Availability; D002626:Chemistry, Pharmaceutical; D003000:Clonidine / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics*; D003692:Delayed-Action Preparations; D004285:Dogs; D004338:Drug Combinations; D005079:Excipients; D006852:Hydrochlorothiazide / Q000008:administration & dosage* / Q000737:chemistry; D008297:Male; D013607:Tablets; D013810:Therapeutic Equivalency
chemical_list: D000179:Acrylates; D000959:Antihypertensive Agents; D003692:Delayed-Action Preparations; D004338:Drug Combinations; D005079:Excipients; D013607:Tablets; D006852:Hydrochlorothiazide; C453622:carbopol 934P; D003000:Clonidine