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Date of Award

2013

Document Type

Dissertation - Pacific Access Restricted

Degree Name

Doctor of Philosophy (Ph.D.)

Department

Pharmaceutical and Chemical Sciences

First Advisor

Xiaoling Li

Second Advisor

Bhaskara Jasti

First Committee Member

Silvio Rodriguez

Second Committee Member

Xin Guo

Third Committee Member

Krishna Devarakonda

Abstract

Administration of drugs sublingually allows direct absorption into the systemic circulation which results in quick onset of action and a higher bioavailability as a consequence of by-passing first pass metabolism. Absorption of drugs across sublingual mucosa is typically determined by means of in vitro permeation studies using excised sublingual tissue during early phases of drug development. Although in vitro set up has been designed to mimic in vivo system yet the results of in vitro studies often deviate from in vivo results. Therefore, it is not known if the in vitro studies can be used as surrogate for in vivo studies in a predictable manner. To understand the relationship between in vitro and in vivo system for sublingual drug delivery, the first objective of this dissertation research was to investigate difference/similarities between in vitro and in vivo system by performing parallel in vitro and in vivo studies and establish a correlation. Five model drugs possessing diverse physicochemical properties and New Zealand White rabbits were used for these studies. Comparison of time course of absorption revealed a significant difference in time lag between in vivo (less than 5 min) and in vitro (30-120 min) systems. However, the derived absorption parameter permeability coefficient was similar in in vitro and in vivo system for caffeine: (2.10±0.22)×10 –5 , (2.06±0.47)×10 –5 ; Naproxen: (1.91±0.44)×10 –5 , (2.34±0.26)×10 –5 ; Propranolol: (2.93±0.52)×10 –5 , (3.51±0.75)×10 –5 ; Verapamil: (3.95±0.29)×10 –5 , (4.75±0.81)×10 –5 and Atenolol: (2.01±0.68)×10 –6 , (2.95±0.32)×10 –6 cm/s, respectively (p>0.05). The discrepancy between in vitro and in vivo system was hypothesized in this study to be due to the difference in thickness and role of extensive microcirculation in the two systems. Histological evaluation revealed the presence of rich vasculature 10-20 μm below the epithelium which is responsible for quick removal of drug permeating the epithelium (100-150 μm) of sublingual mucosa and reaching systemic circulation in an in vivo system. In contrast, in in vitro system the permeated drug can only be detected after crossing the excised sublingual tissue of 250±50 μm thickness. A mathematical model based on the monolayer (epithelium) and bilayer (epithelium+connective tissue) nature of the membrane representing in vivo and in vitro system, respectively demonstrated the nature of membrane to be responsible for difference in time lag but similar permeability coefficient. To be able to predict in vivo result using in vitro data, the second objective of this dissertation research was to develop a predictive pharmacokinetic model based on the established in vitro in vivo correlation (IVIVC) of sublingual absorption parameters across two systems. Predicted plasma concentration-time profiles of propranolol, verapamil, naproxen, atenolol and caffeine were found to be in good agreement with the experimental profile with the coefficient of determination of 0.85, 0.80, 0.97, 0.98 and 0.88, respectively. The applicability of the model was further evaluated by predicting in vivo performance of Zolpidem and Propranolol following sublingual administration in human beings and comparing area under the plasma concentration-time curve. Percent prediction error was 12.02% and less than 10% (4.69, 6.69, 5.02 for 1, 1.75 and 3 mg dose, respectively) for Propranolol and Zolpidem, respectively. The final objective of this dissertation was to extend the established IVIVC to other suitable animal models such as pig for assessing sublingual absorption. Histological evaluation revealed the similarity in the structure of sublingual mucosa of pig and New Zealand White rabbit. Similar transport characteristics (p>0.05) of model drugs across sublingual mucosae of two species were observed indicating the possibility of using them interchangeably. In conclusion, a rational attempt was made in this dissertation research to identify the root cause of the discrepancy between in vitro and in vivo system and establish a correlation correcting the discrepancies. The established IVIVC and predictive pharmacokinetic model will help in rationale design and development of new sublingual formulations and will be a valuable tool in the preclinical phase of early drug development stage.

Pages

242

ISBN

9781303319969

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