Oral Controlled Release Formulation Design and Drug Delivery

Theory to Practice

Hong Wen, Kinam Park, Hong Wen, Kinam Park

• Publisher: Wiley
• Year: 2011
• Print ISBN: 9780470253175
• eBook ISBN: 9781118060322
• Edition: 1
• Topic: Physical Sciences
• Subtopic: Organic Chemistry

This book describes the theories, applications, and challenges for different oral controlled release formulations. This book differs from most in its focus on oral controlled release formulation design and process development. It also covers the related areas like preformulation, biopharmaceutics, in vitro-in vivo correlations (IVIVC), quality by design (QbD), and regulatory issues.

Chapter 1

Hong Wen

Pharmaceutical Development, Novartis Pharmaceuticals Corporation, East Hanover, NJ,xf USA

Kinam Park

Departments of Pharmaceutics & Biomedical Engineering, Purdue University School of Pharmacy, West Lafayette, IN, USA

1.1 Fundamentals of Oral Controlled Release Formulation Design and Drug Delivery

1.1.1 Overview

Due to the difficulty in developing new drugs, more and more emphasis has been given to developing new drug delivery systems for existing drugs as well as new chemical entities. Drugs can be delivered to patients by more than one route and by more than one type of dosage form. Even though “dosage form” and “drug delivery system” are used interchangeably, “drug delivery system” implies that a technology has been used to deliver a drug to the desired body site for drug release with a predetermined rate. Among various drug delivery systems, oral controlled release (CR) formulation is the most commonly used in pharmaceutical industry.

Delayed release, sustained release, and repeat action formulations are the three most common controlled release formulations [1, 2]. The most widely used example of delayed release form is enteric coated tablets [3, 4] or capsules, in which drug will not release in gastric fluid, that is, acidic environment, until it reaches the intestine, that is, neutral environment. In sustained release formulations, a portion of drug is released immediately, and the remaining drug is released slowly over an extended period of time, normally over 12–18 h. In fixed dosage combination (FDC), immediate release (IR) formulation for one drug and sustained release (SR) for another drug [5] or the same drug in both IR and SR formulation parts are popular approaches [6, 7]. For example, metoprolol succinate extended release and hydrochlorothiazide immediate release combination tablets have additive antihypertensive effects [8]. In Sanofi-Aventis' Ambien CR, there is a biphasic profile of dissolution, where the first phase is an IR phase and the second phase is a prolonged release phase [7].

For those drugs where prolonging blood levels of the drugs have no therapeutic advantages, there is no need to develop their controlled release formulations [9]. For example, drugs with a long half-life (t_1/2) (e.g., diazepam [10, 11] and amitriptyline [12]), drugs whose maintained effect is undesirable (e.g., β-lactamase antibiotic (amoxicillin) may induce emergence of resistant bacteria [13]), and drugs that require immediate effect (e.g., nitroglycerin for heart attack) [14] are not suitable in controlled release formulations.

1.1.2 Advantages and Disadvantages

In addition to extending the patent life of those drugs whose patent protection are expiring, there are many other benefits for patients by using an oral controlled release formulation [15–17]. They include maintenance of optimum drug concentration and increased duration of therapeutic effect [18], improved efficiency of treatment with less amount of drug [19], minimized side effects [20–23], less frequent administration [24], and increased patient convenience and compliance [18, 25]. The controlled release formulations are also beneficial for the study of pharmacokinetic (PK) and pharmacodynamic (PD) properties of the drug [26, 27].

Like any other formulation, there are some disadvantages of oral controlled release formulations. In most cases, the amount of drug contained in the dosage form is higher than a single dose of conventional dosage forms. If the drug reservoir of a controlled release formulation is damaged and release the drug all at once, the drug concentration may go above the toxic level. Therefore, the potential of dose dumping has to be taken into consideration in controlled release formulation design. Furthermore, once the drug release begins, it is difficult to stop the release even if it is necessary. In addition, the cost of producing the controlled release formulation is higher than that of the conventional dosage forms. The relative higher production cost can be compensated if the benefit of the controlled release formulations is immediate and obvious to the patients.

1.1.3 Fundamental Release Theories

Based on different drug release mechanisms, quite a few drug release theories have been developed, which will be elaborated in the corresponding chapters. For all different types of controlled release systems except osmosis-based systems, the drug concentration difference between formulation and dissolution medium plays a very important role in drug release rate. The drug concentration can be affected by its solubility, drug loading, and/or excipients used. Besides drug concentration difference, the dissolution rate of polymer carriers can affect drug release rate in dissolution-controlled systems, and the diffusion speeds of both drug and dissolution medium inside polymer(s) can affect drug release rate in diffusion-controlled systems. For osmosis-based and ion exchange-based systems, the drug release can be affected by other factors as well. Overall, for most CR formulations, drug release can be affected by one or more mechanisms. Here, a few fundamental theories will be briefly discussed.

Fick's first law of diffusion is used in steady-state diffusion, in which the concentration within the diffusion volume does not change with time. The drug release rate is determined by drug release surface area (S), thickness (h) of transport barrier (such as polymer membrane or stagnant water layer), and the concentration difference (

) between drug donor (C_d) and receptor (C_r), that is, between drug dosage surface and bulk medium.

Fick's first law states that

where M is the total amount of solute crossing surface area S in time t, J is the flux rate, and D is the diffusion coefficient of the drug molecule in the unit of cm²/s.

Fick's first law did not take into account the drug concentration changes with time in each diffusion volume, which have been taken into consideration by Fick's second law of diffusion. Based on Fick's second law, drug accumulation speed (dC/dt) is determined by drug diffusivity (D) and the curvature of drug concentration:

Most commonly seen drug release rate for oral controlled release formulation is first-order release and/or zero-order release. Most oral controlled release formulations based on matrix and coating approaches are close to first-order release. Alza's osmotic pump and Egalet's erosion tube can release drugs at zero order. Based on the shape of release profile, there are five major release profiles: zero-order release (constant release rate); first-order release (decreasing release rate); bimodal release (two release modes, which can be either two separate immediate release modes or one immediate release mode followed by one sustained release mode [28–30]); pulsatile release (multiple release modes and multiple peaks of release rate [31]); and delayed release (e.g., enteric coated tablets [32–34]).

The two important phenomena in controlled release formulations are the lag time effect and the burst effect. In diffusion control system, if fresh membrane is used, it takes time for drug molecules on the donor side to appear on the receptor side. Under the sink condition, drug molecules will be released at constant rate into the receptor side and the steady state is reached. The time to reach the steady state is known as the “lag time.” However, if the membrane saturated with a drug is used, a “burst effect” will be observed at the beginning of drug release. Gradually, the drug concentration inside the polymer membrane will decrease until the steady state is reached. Actually, for matrix approach controlled release formulation, because it takes time for polymer molecules to form hydrogel, “burst effect” is also a common phenomenon.

TIMERx™ is very versatile hydrogel-based controlled release technology, which can provide different release kinetics for a wide range of drugs by manipulating molecular interactions. The release profiles range from zero order to chronotherapeutic release. This technology does not need complex processing or novel excipients, but still achieves desired drug release profiles using a simple formulation development process. TIMERx™ is a pregranulated blend composed of synergistic heterodisperse polysaccharides (usually xanthan gum and locust bean gum) together with a saccharide component (generally dextrose). Different drug release kinetics can be achieved based on the synergism between the homo- and heteropolysaccharide components in the system. Finally, the drug release rate is controlled by the speed of water penetrating into the matrix [35, 36]. The material has good compressibility and can be mixed or granulated with drug and other necessary excipients to be compressed into tablets.

1.1.4 Limiting Factors for Oral CR Formulations

There are a few unique properties of the gastrointestinal (GI) tract that make development of oral CR formulations rather difficult. Figure 1.1 shows schematic description of the GI tract. Based on histology and function, the small intestine is divided into the duodenum, jejunum, and ileum, and the large intestine is divided into the cecum, colon, rectum, and anal canal. W. A. Ritschel reported the average length, diameter, and absorbing surface area of different segments of the GI t...

Table of contents

• Cover
• Title Page
• Copyright
• Preface
• Contributors
• Chapter 1: Introduction and Overview of Oral Controlled Release Formulation Design
• Chapter 2: Evolution of Oral Controlled Release Dosage Forms
• Chapter 3: Biopharmaceutic Consideration and Assessment for Oral Controlled Release Formulations
• Chapter 4: Preformulation Consideration for Drugs in Oral CR Formulation
• Chapter 5: Polymers in Oral Modified Release Systems
• Chapter 6: Oral Extended Release Hydrophilic Matrices: Formulation and Design
• Chapter 7: Coating Systems for Oral Controlled Release Formulations
• Chapter 8: Fluid Bed Coating and Granulation for CR Delivery
• Chapter 9: Controlled Release Using Bilayer Osmotic Tablet Technology: Reducing Theory to Practice
• Chapter 10: Fast Disintegrating Tablets
• Chapter 11: Buccal Drug Delivery Systems
• Chapter 12: Oral Targeted Drug Delivery Systems: Gastric Retention Devices
• Chapter 13: Oral Targeted Drug Delivery Systems: Enteric Coating
• Chapter 14: Orally Administered Drug Delivery Systems to the Colon
• Chapter 15: Dissolution Testing: In Vitro Characterization of Oral Controlled Release Dosage Forms
• Chapter 16: Challenges and New Technologies of Oral Controlled Release
• Chapter 17: Oral Controlled Drug Delivery: Quality by Design (QbD) Approach to Drug Development
• Chapter 18: Oral Controlled Release-Based Products for Life Cycle Management
• Chapter 19: Generic Oral Controlled Release Product Development: Formulation and Process Considerations
• Chapter 20: The Science and Regulatory Perspectives of Emerging Controlled Release Dosage Forms
• Index