The British Transatlantic Slave Trade Vol 4

Kenneth Morgan, Robin Law, David Ryden, J R Oldfield

• Publisher: Routledge
• Year: 2021
• Print ISBN:
  9781138758001
• eBook ISBN:
  9781000559576
• Topic: History
• Subtopic: World History
• Index: History

Contains primary texts relating to the British slave trade in the 17th and 18th century. The first volume contains two 18th-century texts covering the slave trade in Africa. Volume two focuses on the work of the Royal African company, and volumes three and four focus on the abolitionists' struggle.

9Ocular Penetration Enhancers

Thomas Wai-Yip Lee and Joseph R. Robinson
School of Pharmacy, University of Wisconsin-Madison, Madison, Wisconsin, U.S.A.

DOI: 10.4324/9781003113423-9

I. INTRODUCTION

Drug delivery to the eye is not an easy assignment. The cornea, being a very important component in the visual pathway, is well protected by a number of very effective defense mechanisms, e.g., blinking, high tear secretion rate flushing its surface, induced lacrimation and tear protein production in response to foreign substances, etc. These protective mechanisms provide a challenge for pharmaceutical scientists to design drug delivery systems that can deliver therapeutic agents in sufficient concentrations to target sites.

After topical instillation of an eye drop, the drug is subject to a number of very efficient elimination mechanisms such as drainage, binding to proteins, normal tear turnover, induced tear production, and nonproductive absorption via the conjunctiva. Typically, drug absorption is virtually complete in 90 seconds due to the rapid removal of drug from the precorneal area. To make matters worse, the cornea is poorly permeable to both hydrophilic and hydrophobic compounds. As a result, only approximately 10% or less of the topically applied dose can be absorbed into the anterior segment of the eye.

Basically, the two major barriers encountered in ocular drug delivery are (a) short residence time in the precorneal area and (b) poor permeability of the cornea.

Various efforts have been made to prolong the drug solution residence time via vehicle modification (1,2), bioadhesives (3), inserts (4), etc. Another approach to improve ocular bioavailability, which is less well understood, is penetration enhancement. Penetration enhancement can be achieved via prodrugs, penetration enhancers, etc. Prodrugs will be covered elsewhere in this book. The main focus of this chapter will be on the use of penetration enhancers to improve ocular drug delivery. Fundamental aspects of ocular penetration enhancers will be covered, and recent advances will be presented as well.

II. KINETIC BASIS OF THE NEED FOR PENETRATION ENHANCEMENT

The simplest model for ocular pharmacokinetics is shown in Figure 1 (5). It is well known that for most drugs the true absorption rate constant is much smaller than the elimination rate constant. This will normally give rise to a flip-flop model. However, when the parallel elimination pathway is introduced (Fig. 2) (5), the apparent absorption rate constant is defined as:

Apparent k_abs = k_abs + k_loss,pp

Thus, the model is not a flip-flop model and drug concentration can be described as

where F is the fraction of dose absorbed, D is the dose, k and K are absorption and elimination rate constants, respectively, and V_d is the apparent volume of distribution. Obviously, K = k_elim, k = k_abs + k_loss,pp.

For many drugs, k_loss,pp is of the order of 0,5-0.7 min^-1, being several orders of magnitude larger than k_abs, which is typically of the order of 0.001 min^-1. As a result, the peak time, which is controlled by k_loss,pp and k_abs, is similar (20-40 min) for a wide range of compounds since k_{loss, pp}, which is mainly due to drainage, induced lacrimination, etc., predominates over k_abs in controlling the peak time.

In order to improve the bioavailability (F = k_abs/[k_abs + k_loss,pp]) significantly, it is essential to increase k_abs by one or two order of magnitudes or reduce k_loss,pp to a similar extent.

Figure 1 A one-compartment model for ocular absorption.

Several approaches have attempted to reduce the magnitude of k_loss,pp. However, it has its limit. Keister et al. (6) showed that reducing the dose volume from 25 μL to zero brings only a fourfold improvement in bioavailability for a poorly permeable compound. However, it is practically impossible to have zero dosing volume. Therefore, small dose volumes will give an improvement in bioavailability that is less than fourfold. Similarly, theoretical calculations showed that use of bioadhesives does not necessarily give any benefit if the cornea is poorly permeable to that compound (7). These calculations are as follows: steady-state, at which the rates of delivery and elimination are equal, is approached after about five drug half-lives, and the amount of the drug in a particular ocular compartment can be expressed as

Figure 2 A two-compartmental model for ocular absorption.

dA/dt = R — KA

where A is the amount of the drug (in mg), R is the rate of drug input, and K is the elimination rate constant. At steady state, dA/dt = 0, leading to

A_SS = R/K = M_pt_1/2/0.693T

where M_p is the mass penetrating and t_1/2 is the half-life of the drug. It is clearly shown that prolonging the contact time (T) via the use of bioadhesives will lower A_SS provided that M_p and t_1/2 are kept constant. For drugs where permeability is not a problem, the use of bioadhesives is beneficial since the therapeutic drug level can be sustained. On the contrary, for a poorly permeable compound, the use of adhesives may lower A_SS below the therapeutic level. In order to bring A_SS back to a therapeutic level, M_p has to be increased. This requires the use of penetration enhancers.

Methods of penetration enhancement such as prodrugs, ion pairing, etc. are beyond the scope of this chapter and will not be discussed. The main focus of this chapter will be ocular penetration enhancers.

III. TRANSPORT CHARACTERISTICS OF EPITHELIAL TISSUES

The normal expected mechanisms of corneal penetration is shown in Table 1 (8). Transport across epithelia occurs via two pathways: transcellular and paracellular. The former involves cell/tissue partitioning/diffusion, channel

Table 1 Expected Mechanisms of Corneal Penetration

Drug type	Apparent rate-limiting membrane	Mechanisms
Water soluble	Epithelium	Low o/w partition into epithelium
		Slow diffusion through epithelium
		High partition rate + rapid diffusion through stroma/endothelium
		Via leaky channels
		Solute movement may be intercellular and/or transcellular
Water and oil soluble	Epithelium-stroma	Both mechanisms operate
Oil soluble	Stroma	High o/w partition into epithelium Rapid diffusion through epithelium
Ionizable	Epithelium + stroma or leaky channel	Mechanism not solely dependent upon partition coefficient
Source: Adapted from Ref. 8.

diffusion, and carrier-mediated transport. In contrast, the latter represents diffusive and convective transport occurring through intercellular spaces and tight junctions. Due to its aqueous nature, hydrophilic solutes would preferably adopt the paracellular pathway. However, there are three forms of junctional complexes that form between cells which hinder transport of hydrophilic molecules, namely, tight junctions (zonula occludens), intermediate junctions (belt desmosome or zonula adherens), and spot desmosomes (macula adherens) (Fig. 3) (9). Among them, the tight junction is the uppermost and tightest, and it gives the greatest resistance for hydrophilic molecules to go between cells. The barrier property of the tight junction can be reflected by the transepithelial electrical resistance (TEER). The higher the TEER, the tighter the junctions that give a higher resistance for transport of molecules. Generally, epithelia with resistances in the range of 10-100 Ω cm² are considered leaky, whereas those with resistance ranging from 300 to 10,000 Ω cm² are "tight." The cornea is generally classified as a moderately tight or moderately leaky tissue (400-1000 Ω cm²). A comparison of the electrophysiology and permeability of the cornea with other tissues is show...

Table of contents

• Cover Page
• Half Title Page
• Series Page
• Title Page
• Copyright Page
• Foreword Page
• Preface Page
• Contents Page
• Contributors Page
• I. Fundamental Considerations
• II. Transport Models in Ocular Drug Delivery
• III. Drug Delivery Systems
• Index