Development and Formulation of Veterinary Dosage Forms

Gregory E. Hardee, J. Desmond Baggo, Gregory E Hardee, J D Baggot

• Publisher: CRC Press
• Year: 2021
• ISBN:
  9781000454178
• Edition: 2
• Topic: Medicina
• Subtopic: Farmacología

Although the United States (U.S.) and the more developed nations of the remainder of the world are blessed with a variety of pharmaceuticals, feed additives, and biological products to treat, prevent, and control animal diseases, there is a healthy desire among persons involved in animal health issues to increase our animal medicine chest. The interest stems from the desire to efficiently produce food that is safe and plentiful and from the desire to have more and better government-approved products available for the prevention and treatment of diseases of dogs, cats, and horses and for an increasing variety of minor animal species. For the animal health industry, increased drug availability means broader markets, increased revenues, and an opportunity to better serve their customers. For the veterinarian, more animal health products means that he or she is better able to treat the usual and the unusual conditions, and to prevent animal disease and suffering. No doubt, we are all winners when new technology and industrial and regulatory initiatives hasten the availability of safe and effective animal health products.

1

Basis for Selection of the Dosage Form

J. DESMOND BAGGOT

University of Zimbabwe, Harare, Zimbabwe

SCOTT A. BROWN

Pharmacia & Upjohn, Inc., Kalamazoo, Michigan

I. Introduction

Each species of domestic animal has certain distinguishing features, some of which contribute to variations in its handling of a drug. Dietary habit appears to provide the most satisfactory basis for grouping species in a general way. Herbivorous species consist of the horse and ruminant animals (cattle, sheep, and goats), omnivorous species (pig), and carnivorous species (dog and cat). In terms of physiological function, the digestive system is the principal distinguishing feature between herbivorous and carnivorous species. Other distinguishing features, which could be considered as allied to dietary habit, are the activity of the hepatic microsomal enzymes and the urinary pH reaction. In these respects, the pig resembles more closely the carnivorous species. Within each group the individual species are distinct, so extrapolation of pharmacological data from one species to another may not be valid. However, with an understanding of comparative pharmacology, information derived from studies in one species can be applied for predictive purposes to another species. The confidence of such predictions is largely determined by a knowledge of the physicochemical properties of the drug substance which, in turn, determine its pharmacokinetic behavior and fate in the body.

The translocation process for drugs is common to all mammalian species. Since passive diffusion is the mechanism by which drugs penetrate biological membranes, lipid solubility and degree of ionization are the main properties of a drug substance that goven its translocation—i.e., absorption, distribution, and mechanism of elimination. The blood plasma is the body fluid into which drugs are absorbed and by which they are conveyed throughout the body for distribution to other tissues. Drugs distribute nonselectively to tissues: only a small fraction of the dose administered reaches the site of action. The pattern of distribution is largely determined by the degree of perfusion of tissue, molecular structure, and, in a general way, lipid solubility of the drug substance. The liver and kidneys, which are highly perfused and represent the principal organs of elimination for the majority of therapeutic agents, continually receive a major fraction of the amount of drug in the plasma. Because of the central role of the plasma in translocation processes, the plasma concentration of a drug is usually directly related to the concentration in the immediate vicinity of the site action—i.e., the biophasic concentration. Consequently, the plasma concentration versus time profile for a drug reflects the temporal course of its action. Factors influencing the concentration of a drug in the plasma include the size of the dose, formulation of the drug preparation, route of administration, extent of distribution and plasma protein binding, and rate of elimination.

To ensure selection of the most efficient dosage form and that reasonable predictions can be made with regard to the performance of formulations and drugs the physicochemical, pharmacological, and physiological influences on drug response are discussed in this chapter.

A. Drug Classification

Drugs can be broadly classified according to the system of the body on which they exert their primary action. This is generally qualified by the principal effect produced. Further classification of a drug can be based on the type(s) of receptor with which the drug interacts (activates or inhibits) or on chemical structure. Because generalization is inherent in drug classification, several exceptions are inevitable.

Knowledge of the precise classification of a drug allows prediction to be made of the pharmacological effects that are likely to be produced and provides a basis for the selection of drugs for concurrent use. When combination therapy is considered desirable, drugs that have different though complementary mechanisms of action on the same body system should be selected. Although a drug acts primarily on one system of the body, the resultant effects may affect several systems.

Antimicrobial drugs act selectively on microorganisms, but their action is not confined to pathogenic microorganisms. They are classified on the basis of chemical structure and proposed mechanism of antimicrobial action. The usual dosing rate of an antimicrobial drug is based on the quantitative susceptibility, which is detremined in vitro, of pathogenic microorganisms and on the pharmacokinetic properties of the drug. Antimicrobial drugs do not normally produce pharmacological effects in that they do not interact with drug receptors. Some antimicrobial drugs may, however, alter the rate of elimination or increase the toxicity of pharmacological agents administered concurrently (drug interaction).

Anthelmintic drugs have a relatively selective action on helminth parasites in the host animal. With the notable exception of the organophosphorus compounds, which inactive cholinesterase enzymes, anthelmintic drugs do not normally produce pharmacologic effects. The recommended doses of anthelmintic drugs take cognizance of their margin of safety in the target animal species. Classification of anthelmintic drugs is based on their chemical structure.

II. Species Comparisons of Anatomy and Physiology

A. Digestive System

The anatomical arrangement of the gastrointestinal tract and dietary habit are features that can serve to distinguish between the domestic animal species. Since the urinary pH reaction is determined mainly by the composition of the diet, the usual pH range differs between herbivorous (horse, cattle, sheep, and goat—alkaline) and carnivorous (dog and cat—acid) species, while urinary pH can vary over a wide range in omnivorous (pig) species.

The pig, dog, and cat are monogastric (single-stomached) species. The physiology of digestion and drug absorption processes are, in general, similar in these species, and are not unlike those in the human. The stomachs of human beings and dogs are lined with three main types of mucosal tissue: cardiac, gastric (oxyntic), and pyloric. The pig stomach is lined with the same mucosal types but differs in that cardiac mucosa, the glands of which secrete mucus and bicarbonate ion (Holler, 1970), constitutes a much larger relative area of the stomach lining. The gastric mucosa proper contains the compound tubular glands which secrete hydrochloric acid (parietal or oxyntic cells) and pepsinogen (neck chief cells). The strongly acidic reaction of the gastric contents (usual pH range is 3 to 4) can inactivate certain drugs, such as penicillin G and erythromycin. This type of inactivation can usually be overcome by modifying the dosage form.

Gastric emptying is perhaps the most important physiological factor controlling the rate of drug absorption, since, in monogastric species, the small intestine is the principal site of absorption. A drug in solution can be expected to be well absorbed if it is stable (i.e., neither chemically nor enzymatically inactivated) in the stomach, lipid-soluble, and not completely ionized in the small intestine. An effective pH of 5.3 in the microenvironment of the mucosal surface of the small intestine, rather than the reaction of the intestinal contents (pH 6.6), is consistent with observations on the absorption of drugs that are organic electrolytes. In the normal intestine, weak acids with pK_a values above 3 and bases with pK_a less than 7.8 have been shown to be very well absorbed (Hogben et al., 1959). Changes in the intestinal blood flow can alter the rate of absorption of lipid-soluble drugs (Ther and Winne, 1971; Rowland et al., 1973).

The horse is also a monogastric species but is a herbivore and, under natural conditions of management, feeds continuously. Unlike other monogastric species, a major portion of the stomach of the horse is lined with stratified squamous epithelium. Although the mean pH of gastric contents (pH 5.5) is higher than that in the pig and dog, the pH reaction can vary widely (1.13 to 6.8) in horses (Schwarz et al., 1926). Furthermore, gastric contents may by their nature hinder accessibility of drug molecules to the mucosal lining for absorption. A major fraction of an oral dose of drug may be adsorbed onto the contents and conveyed to the large intestine for absorption. The primary site of protein digestion to amino acids is the small intestine (Kern et al., 1974). The pH reaction of ingesta in the ileum of the horse is 7.4. The metabolic, digestive, and secre...

Table of contents

• Cover
• Half Title
• Series Page
• Title Page
• Copyright Page
• Preface
• Table of Contents
• Contributors
• Introduction: Veterinary Drug Availability
• 1. Basis for Selection of the Dosage Form
• 2. Formulation of Veterinary Dosage Forms
• 3. Protein/Peptide Veterinary Formulations
• 4. Formulation of Vaccines
• 5. Administration Devices and Techniques
• 6. Specification Development and Stability Assessment
• 7. Bioavailability Bioequivalence Assessments
• 8. Design of Preclinical Studies
• Index