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Abstract

Long-acting Oral Formulation of Doxycycline: In vitro-in vivo Correlation Studies

Author(s): Sara Melisa Arciniegas Ruiz, María J. Bernad1, S. C. C. Valderrabano2, I. J. Rodríguaz3 and Dinorah Varges*
Physiology and Pharmacology department, Veterinary Medicine School, 1Pharmaceutical Technology, Chemistry Faculty, Universidad Nacional Autónoma de México. Universidad 3000, Circuito Exterior S/N Delegación Coyoacán, C.P. 04510. Ciudad Universitaria, 2National Institute of Medical Sciences and Nutrition Salvador Zubiran, Department of Animal Nutrition. 3Department of Preventive Medicine and Public Health, Veterinary Medicine School, Universidad Nacional Autónoma de México, CD.MX. México

Correspondence Address:
Physiology and Pharmacology department, Veterinary Medicine School, 1Pharmaceutical Technology, Chemistry Faculty, Universidad Nacional Autónoma de México. Universidad 3000, Circuito Exterior S/N Delegación Coyoacán, C.P. 04510. Ciudad Universitaria, E-mail: [email protected]

The aim of this study was to establish and validate an in vitro-in vivo correlation that could predict the bioavailability of 4 oral long-acting formulations of doxycycline hyclate, acrylic acid and polymethacrylate matrices prepared using various proportions of doxycycline:acrylic acid:polymethacrylate for formulation 1 (1:0.25:0.0035), formulation 2 (1:0.5:0.0075), formulation 3 (1:1:0.015) and formulation 4 (1:2:0.0225) and a sample of doxycycline without excipients. In vitro dissolution profiles were obtained in phosphate buffer and hydrochloric acid media, which were fitted to several mathematical models. Plasma concentrations were obtained from 48 healthy dogs to achieve in vivo profiles. Therapeutic concentrations were observed for 60 h for formulation 1 and 4, 48 h for formulation 2 and 3 and 24 h for the sample of doxycycline. None of the pharmacokinetic parameter differed significantly between formulation 1 and 2 or between formulation 3 and 4; however, doxycycline differed significantly in comparison. The in vivo-in vitro correlation coefficient obtained from point-to-point analysis >0.999 for formulation 3 and 4 and >0.9581 for the others. To validate the model, the absorbed fractions for all formulations were estimated to predict plasma concentration profiles. In conclusion, adequate in vitro-in vivo correlation was established for long-acting formulations of doxycycline indicating that in vitro dissolution tests could be used as a surrogate for bioavailability studies.