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Date of Award

2008

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

Rajul Patel

Second Committee Member

Miki Park

Third Committee Member

Sanjay Goskonda

Abstract

Sublingual administration of drugs offers advantages including avoidance of first pass metabolism and quick absorption into the systemic circulation. In spite of being one of the oldest routes of drug delivery, there is dearth of literature on characterization of the barrier properties of the sublingual mucosa. Therefore, the aim of this research was to gain an insight into the barrier properties of the porcine sublingual mucosa. The studies conducted in this dissertation research focused on an important aspect of sublingual permeation, the dependence of permeability on different physicochemical properties of the permeant such as the degree of ionization, distribution coefficient and molecular weight/size on drug transport across sublingual mucosa. Further the data from the sublingual permeation of model compounds was used in development of a predictive model which provided us with some understanding regarding the important descriptors required for sublingual drug delivery. A series of β-blockers were employed as the model drugs to study the dependence of permeability on lipophilicity across the sublingual mucosa. Eighth different β-blockers with log D (distribution coefficient) values ranging from -1.30 to 1.37 were used in this study. The most hydrophilic drug atenolol showed the lowest permeability (0.19 ± 0.04 x 10 -6 ) cm/sec and the most lipophilic drug propranolol showed the highest permeability (38.25 ± 4.30 x 10 -6 ) cm/sec. The log-log plot of permeability coefficient and the distribution coefficient showed a linear relationship. It was concluded that the increase in lipophilicity results in improved partitioning across the lipid bilayers of sublingual mucosa which results in increased permeation for the drugs. As the sublingual mucosa contains a significant amount of the polar lipids bonded with water molecules, therefore, it was hypothesized that the hydrophilic or ionized permeants will have significant permeation across the sublingual mucosa. The objective of this research was to study the effect of ionization on permeation across sublingual mucosa using a model drug nimesulide. Based on the relationship between the permeability coefficient and distribution coefficient of nimesulide at different pH, the lipoidal route was suggested as the dominant transport route for nimesulide across the sublingual mucosa. The contribution of individual ionic species of nimesulide to the total drug flux was quantitatively delineated. It was observed that the ionized species of nimesulide contributes significantly to the total flux across the sublingual mucosa. The contribution of the ionized species to total flux was almost (90%) at a pH where the drug was almost completely ionized. Polyethylene glycols (PEGs) were used as the model permeants to study the dependence of permeability on molecular weight. An inverse relationship between molecular weight and permeability coefficients was observed. This relationship was used to estimate the molecular weight cut off for the sublingual mucosa. The molecular weight cut off was estimated to be around 1675 daltons. Further, the Renkin function was used to estimate the theoretical pore size of the sublingual mucosa and the pore size of the sublingual mucosa was estimated to be around 30–53 Å based on two separate calculations using the radius of gyration and Stokes-Einstein radius for PEG molecules, respectively. No specific model is present in literature to predict the in vitro sublingual drug permeability. In this dissertation a specific model was developed and validated by performing permeation studies of 14 small molecules across the porcine sublingual mucosa. It was shown that the lipophilicity (logD 6.8 ) and the number of hydrogen bond donors (HBD) were the most significant descriptors affecting sublingual permeability. Research conducted in this dissertation provided an in-depth understanding about the barrier properties of the porcine sublingual mucosa and role of different physicochemical properties on sublingual transport. Such an understanding will hopefully expand the suitable lead candidates for sublingual delivery.

Pages

191

ISBN

9780549552864

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