Stimuli Responsive Polymeric Nanocarriers for Drug Delivery Applications

Volume 1: Types and triggers

Abdel Salam Hamdy Makhlouf, Nedal Yusuf Abu-Thabit

• Publisher: Woodhead Publishing
• Year: 2018
• Print ISBN: 9780081019979
• eBook ISBN: 9780081019986
• Topic: Technology & Engineering
• Subtopic: Biomedical Science
• Index: Technology & Engineering

Stimuli Responsive Polymeric Nanocarriers for Drug Delivery Applications, Volume One: Types and Triggers discusses, in detail, the recent trends in designing biodegradable and biocompatible single-responsive polymers and nanoparticles for safe drug delivery. Focusing on the most advanced materials and technologies, evaluation methods, and advanced synthesis techniques stimuli-responsive polymers, the book is an essential reference for scientists with an interest in drug delivery vehicles. Sections focus on innovation, development and the increased global demand for biodegradable and biocompatible responsive polymers and nanoparticles for safe drug delivery.- Offers an in-depth look at the basic and fundamental aspects of alternative stimuli-responsive polymers, mechanisms, structure, synthesis and properties- Provides a well-defined categorization for stimuli-responsive polymers for drug delivery based on different triggering mechanisms- Discusses novel approaches and challenges for scaling up and commercialization of stimuli-responsive polymers

Part One

Introduction

1

Historical development of drug delivery systems: From conventional macroscale to controlled, targeted, and responsive nanoscale systems

Nedal Y. Abu-Thabit^⁎; Abdel Salam H. Makhlouf^{† ⁎} Department of Chemical and Process Engineering Technology, Jubail Industrial College, Jubail Industrial City, Saudi Arabia
^† Central Metallurgical Research and Development Institute, Cairo, Egypt

Abstract

This chapter overviews the historical progress and development in drug delivery systems (DDSs) that based on polymeric carriers over the last 50 years. It discusses the main drug release mechanisms from polymeric carriers via diffusion, chemical, solvent, and responsive (on-demand) control. The breakthrough steps for the development of DDSs from macroscale to microscale and nanoscasle are summarized. Selected examples from successful clinical translations, marketed drugs and the ongoing clinical trials are briefly presented. The general features and the structure-property relationship of the most important polymers for macro-micro and nano-DDSs are highlighted. The evolution of passive and targeted DDSs based on polymeric nanocarriers including liposomes, micelles, protein-drug conjugates, polymer-drug conjugates (polymer prodrugs), polymeric nanoparticles, and on-demand release responsive polymeric nanocarriers, was discussed in detail. The evolution of stimuli-responsive DDSs as an emerging tool for drug design and targeted drug delivery was also discussed. The main aspects of the endogenous triggers (temperature, pH, and redox) and exogenous stimulus (thermo, magnetic, and ultrasound) are introduced with highlighted potential applications as DDSs. The recent status of the clinical trials based on stimuli-responsive nanocarriers is summarized.

Keywords

Drug delivery; Stimuli-responsive; Nanocarriers; Clinical trials; Macroscale drug delivery; Microscale drug delivery; Nanoscale drug delivery; Triggered-release; History of drug delivery

1.1 Introduction

The field of drug delivery is a very hot research area as it affects the life of millions of patients every year. The current annual global pharmaceutical market is valued at $980 billion [1]. Although pharmaceutical agents can be administrated in different ways, the effectiveness of certain drug delivery system (DDS) is associated directly with the method by which they are administrated (Fig. 1.1). DDSs, in the form of formulations or devices, enhance therapeutic efficacy and safety of drugs by improving their absorption, distribution, metabolism, and excretion (ADME) profiles [2,3]. DDSs are designed to address the limitations of controlled drug delivery such as release rates, cell- and tissue-specific targeting, and drug stability [1].

Fig. 1.1 Different administration pathways for drug delivery with an overview of the main challenges that need to be addressed when designing controlled/targeted drug delivery systems (DDSs). Reproduced with permission from M.W. Tibbitt, J.E. Dahlman, R. Langer, Emerging frontiers in drug delivery, J. Am. Chem. Soc. 138(3) (2016) 704–717. © 2016 American Chemical Society.

Conventional drug delivery systems (CDDSs) are generally developed for oral delivery, where there will be an immediate release and rapid absorption of the drug. Beside the fact that CDDSs are usually designed for short periods of time and require repeated administration, these systems exhibit fluctuations outside the desired range as the drug release goes through the peaks and valleys reaching either higher toxic levels or insufficient drug uptake during the administration period (Fig. 1.2). During the past decades, this situation has been overcome by using sustained drug release systems, which allow for slightly longer release periods or “slower release rates” (e.g., 12–24 h), employing methods such as emulsions, suspensions, compressed tablets, polymer coating, and complexation (e.g., with salts or ion-exchange resins). Although sustained release systems minimize the peaks and valleys, they do not eliminate them [4] (Fig. 1.2). Both CDDSs and sustained release systems require repeated drug administrations and their release behavior is affected by the local environment conditions (e.g., the pH of the stomach) (Fig. 1.1).

Fig. 1.2 Change in plasma drug concentrations with time for conventional, sustained release, and controlled release DDSs.

Controlled release systems deliver a drug at a predetermined rate and for a definite period of time. Controlled drug release can last for days to years without being affected by environmental conditions (Fig. 1.2). Controlled release systems offer advantages such as improved efficacy, reduced toxicity, and improved patient compliance and convenience [5]. Ideal controlled release systems are expected to have the following features [1]: (1) maintain the drug concentration within the effective therapeutic window; (2) localize the therapeutic to the desired site of action to reduce the off-target side effects and increase potency; (3) improved adherence by reducing the number of required doses; and (4) ability to be cleared or degraded when administrated on their own.

1.2 Mechanisms of controlled drug delivery

There are several mechanisms to control the drug delivery. As illustrated in Fig. 1.3, polymer materials release drug by one of the following mechanisms [6].

Fig. 1.3 Mechanisms for drug release from polymeric carriers. (A) Reservoir system, (B) nonbioerodible matrix system, (C) bioerodible matrix system, (D) polymer with pendent chain, (E) swelling controlled matrix, (F) osmotic controlled device, and (G) stimuli-responsive (triggered-release) targeted drug delivery system.

1.2.1 Diffusion control

The first mechanism includes the diffusion of the drug from reservoir via permeable polymeric membrane, hollow fibers, capsules, or microcapsules (Fig. 1.3A). Nonbiodegradable polymers such as silicone rubber, poly(ethylene-co-vinyl acetate) (PEVA), and hydrogels can be employed as a reservoir. Drug release rate can be adjusted by controlling the thickness and/or permeability of the used membrane. Drug delivery devices (DDDs) based on reservoir systems release dug with fairly constant rate, but with the risk of immediate release of the entire drug upon rupture of the rate controlling membrane (RCM). In the second diffusion mechanism, drug is dispersed (molecularly or as solid drug particles) in a nonbioerodible polymer network which is called as matrix system (Fig. 1.3B). Diffusion occurs when the drug passes from the polymer matrix into the external environment. The main advantages include the ease of fabrication, ability to load drugs with high molecular weights, and the absence of severe problems in case of system leak as compared with the leakage from ruptured reservoir. The major...

Table of contents

• Cover image
• Title page
• Table of Contents
• Copyright
• Contents for Volume 2
• Contributors
• Preface
• Part One: Introduction
• Part Two: Endogenous and exogenous stimuli-responsive drug delivery systems
• Part Three: Polymeric nanocarriers for stimuli-responsive drug delivery systems
• Part Four: Biopolymer and biodegradable nanocarriers for stimuli-responsive drug delivery systems
• Index