Oral Drug Delivery for Modified Release Formulations

Edmund S. Kostewicz, Maria Vertzoni, Heather A. E. Benson, Michael S. Roberts, Edmund S. Kostewicz, Maria Vertzoni, Heather A. E. Benson, Michael S. Roberts

• Publisher: Wiley
• Year: 2022
• Print ISBN:
  9781119772699
• eBook ISBN:
  9781119772712
• Edition: 1
• Topic: Medicine
• Subtopic: Pharmacology

ORAL DRUG DELIVERY FOR MODIFIED RELEASE FORMULATIONS

Provides pharmaceutical development scientists with a detailed reference guide for the development of MR formulations

Oral Drug Delivery for Modified Release Formulations is an up-to-date review of the key aspects of oral absorption from modified-release (MR) dosage forms. This edited volume provides in-depth coverage of the physiological factors that influence drug release and of the design and evaluation of MR formulations.

Divided into three sections, the book begins by describing the gastrointestinal tract (GIT) and detailing the conditions and absorption processes occurring in the GIT that determine a formulation's oral bioavailability. The second section explores the design of modified release formulations, covering early drug substance testing, the biopharmaceutics classification system, an array of formulation technologies that can be used for MR dosage forms, and more. The final section focuses on in vitro, in silico, and in vivo evaluation and regulatory considerations for MR formulations. Topics include biorelevant dissolution testing, preclinical evaluation, and physiologically-based pharmacokinetic modelling (PBPK) of in vivo behaviour. Featuring contributions from leading researchers with expertise in the different aspects of MR formulations, this volume:

• Provides authoritative coverage of physiology, physicochemical determinants, and in-vitro in-vivo correlation (IVIVC)
• Explains the different types of MR formulations and defines the key terms used in the field
• Discusses the present status of MR technologies and identifies current gaps in research
• Includes a summary of regulatory guidelines from both the US and the EU
• Shares industrial experiences and perspectives on the evaluation of MR dosage formulations

Oral Drug Delivery for Modified Release Formulations is an invaluable reference and guide for researchers, industrial scientists, and graduate students in general areas of drug delivery including pharmaceutics, pharmaceutical sciences, biomedical engineering, polymer and materials science, and chemical and biochemical engineering.

Part I
Understanding of Physiology and Anatomy – Factors Influencing Drug Release and Absorption from MR Formulations

1a
Composition of Gastric Fluids Under Fasting and Fed Conditions

Jens Van Den Abeele and Patrick Augustijns

Drug Delivery and Disposition, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, Belgium

1a.1 Gastric Volume

Gastric fluids consist of numerous components either secreted by the stomach (gastric acid, enzymes, electrolytes, mucus), swallowed/ingested (saliva, food, liquids), or refluxed from the duodenum in the stomach (bile constituents). When discussing stomach volume, distinction is often made between gastric content volume (GCV) and total gastric volume (TGV). GCV can be described as the resultant volume in the stomach of ingested material (e.g. food, liquids), swallowed saliva, gastric secretions, and the emptying of gastric content in the small intestine, whereas TGV also takes into account parts of the stomach void of liquid or solid material (i.e. GCV + air volume). In fasted state, gastric secretion occurs at a rate of approximately 1 ml/min [1–3]. In 1977, Dubois et al. reported a mean resting GCV (±SEM) of 24 ± 5 ml in fasted subjects [3]. In more recent studies, magnetic resonance imaging (MRI) has been used to assess GCV. Using this technique, Goetze et al. [4] and Koziolek et al. [5] calculated mean baseline GCVs (± SD) of 35 ± 22 ml (N = 48) and 31.4 ± 19.7 ml (N = 12), respectively. Similar mean fasted GCV (35 ± 7 ml; N = 12) was reported by Mudie et al. [6]. In addition, the authors investigated gastric volume changes after administration of 240 ml of water, in agreement with the guidelines for bioavailability (BA)/bioequivalence (BE) testing under fasting conditions [7, 8]. Immediately after water administration, GCV increased to a mean volume (±SEM) of 242 ± 9 ml which returned to baseline levels within 45 minutes (t_{1/2, emptying} = 13 ± 1 min) [6].

After meal intake, the stomach is capable of significantly increasing its volume to accommodate ingested food [4, 5, 9, 10]. This expansion was visualized by Di Ciaula et al. [11] using functional ultrasonography. Mean antral surface area (±SEM) after a 200 ml liquid meal increased approximately four‐fold in adults (basal area = 3.5 ± 0.1 cm², postprandial area = 12.0 ± 0.3 cm²; N = 67). The extent to which the stomach expands depends on both meal volume and the interplay between (stimulated) gastric secretion, reported by Malagelada et al. [12] to increase to ~10 ml/min in the first hour after a solid‐liquid meal, and emptying in response to food ingestion. TGVs of 800–900 ml have been reported [13]. Kwiatek et al. [13] observed that TGV increased with increasing meal volume (200, 400, 600, and 800 ml combinations of Ensure^® TwoCal with iso‐osmolar saline). However, TGV/meal volume ratio decreased with increasing meal volume, which has been suggested by the authors to be due to the rapid emptying of larger portions in case of large meal volumes compared to smaller meal volumes. Depending on meal volume and caloric content of the meal, it may take several hours for GCV to return to fasted state levels [5, 13].

1a.2 Gastric Acid

Under normal fasted state conditions, gastric content is typically acidic due to the secretion of hydrochloric acid, commonly referred to as “gastric acid”. Gastric acidity is crucial for several of the stomach’s functions [14]. Multiple gastric enzymes, for instance, require acidity to display optimal activity [1, 15–17]. Furthermore, an unfavorable environment for the survival of micro‐organisms is created, preventing bacterial overgrowth [15, 18]. Secretion is mediated by parietal cells of the oxyntic gastric mucosa, mainly located in the corpus and fundus region of the stomach [14, 18, 19]. Intraluminal potassium ions are exchanged for intracellular protons, a process regulated by the K⁺/H⁺ ATPase or “proton pump,” while chloride ions are simultaneously transported to the gastric lumen to ensure isoelectricity. At rest, K⁺/H⁺ ATPases are stored in cytoplasmatic tubulovesicles [14, 19]. Upon stimulation, these proton pumps translocate from the cytoplasm to the apical membrane and gastric acid is subsequently secreted. Neural (acetylcholine) as well as endocrine (histamine, gastrin) stimuli promote acid secretion, whereas somatostatin, mainly secreted by D cells of the pyloric mucosa located in the antrum region of the stomach, is the main inhibitor of acid secretion [14, 18].

Gastric acid secretion rates ranging from 0.03 to 0.07 meq H⁺ min⁻¹ have been reported for fasted subjects [3, 20]. In a study by Lindahl et al. [21], a total of 36 gastric fluid samples were aspirated in 24 healthy human volunteers. Subjects were not allowed to consume water for the entire duration of the study. Measured pH values ranged from 1.4 to 7.5, with seven samples exceeding pH 5....

Table of contents

• Cover
• Table of Contents
• Title Page
• Copyright Page
• Preface
• List of Contributors
• Part I: Understanding of Physiology and Anatomy – Factors Influencing Drug Release and Absorption from MR Formulations
• Part II: Design of MR Formulations – Considerations, Mechanisms and Technologies
• Part III: Evaluation of MR Formulations
• Index
• End User License Agreement