PHARM 134: Biopharmaceutics and Pharmacokinetics 1st Semester PDF

PHARM 134: Biopharmaceutics and Pharmacokinetics 1st Semester Title UNIT I: INTRODUCTION TO BIOPHARMACEUTICS AND PHARMACOKINETICS Introduction This unit in...

PHARM 134: Biopharmaceutics and Pharmacokinetics 1st Semester Title UNIT I: INTRODUCTION TO BIOPHARMACEUTICS AND PHARMACOKINETICS Introduction This unit introduces Biopharmaceutics and Pharmacokinetics as pharmaceutical sciences to describe the relationship between dose and effectiveness, or dose–response, not only by the amount of drug administered and the pharmacologic effect of the drug but including many other factors that are responsible for the entrance of a drug into the body. It also describes the fate of drugs by the LADMER system showing that liberation, absorption, distribution, metabolism, and elimination are involved to elicit the response. It also describes the influence of the different drug products/drug delivery system and routes of drug administration on drug bioavailability and patient response. It also explains the advantages and disadvantages of these drug delivery systems and routes of administration. Learning At the end of the chapter, you must have: Outcomes 1. Described the different biopharmaceutics terms. 2. Described the difference between the biopharmaceutics and pharmacokinetics concepts. 3. Explained the basic concept of LADMER system. 4. Described the influence of the different drug products/drug delivery systems to drug bioavailability. 5. Explained the relationship between the route of administration and the response. Learning Inputs Lesson 1: Definition of Terms Pharmaceutics refers to the study that concerns itself with the physical, chemical and biological factors which influence the formulation, manufacture, stability, and effectiveness of pharmaceutical dosage forms (Ansel, Howard, 1995) Biopharmaceutics is the study of the relation of the physical and chemical properties of a drug to its pharmacodynamic, toxicologic or clinical effects after drug administration. A drug product is the finished dosage form (e.g., tablet, capsule, solution) that contains the active drug ingredient in association with nondrug (usually inactive) ingredients (excipients) that make up the vehicle or formulation matrix. The phrase drug delivery system is often used interchangeably with the terms drug product or dosage form. However, a drug delivery system is a more comprehensive concept, which includes the drug Page 1 of 13 formulation and the dynamic interactions among the drug, its formulation matrix, its container, and the patient. Bioavailability is a measurement of the rate and extent (amount) of systemic absorption of the therapeutically active drug. Pharmacokinetics is the study of the time course of drug movement in the body during absorption, distribution, and elimination (excretion and biotransformation). Pharmacodynamics is the study of the relation of the drug concentration or amount at the site of action (receptor) and its pharmacologic response as a function of time. In general, in order for a drug to exert its biologic effect, it must be.... causing alteration of function which is called “the action of the drug”. Application of Biopharmaceutics a. To predict in vivo performance of drug product using solubility and permeability measurements. b. Aid in earliest stages of drug discovery research. c. In designing a suitable drug delivery system for a particular drug d. or the regulation of bioequivalence of the drug product during scale up and post approval. Lesson 2: Overview of the LADMER System The LADMER system is a way of understanding what goes on in the body when any compound that has an effect on the body is administered or ingested. It describes the processes such as Liberation, Absorption, Distribution, Metabolism, Excretion and Response. Page 2 of 13  LADMER Processes from medicosite.com The LADMER system is the key to the following tasks: a. development of new active compounds, analogs, or derivatives; b. development of dosage forms with desired release characteristics; c. determination of pharmacokinetic parameters and pharmacokinetic drug product profiles; d. determination and evaluation of bioavailability; e. selection of the most appropriate route of administration; f. determination of effective dose sizes; and g. adjustment of dosage regimen to achieve a desired therapeutic concentration of drug in the body based on physiologic (body weight, age, sex, etc.) and pathologic factors (renal, hepatic or heart failure, obesity, malnutrition, etc.) Liberation refers to the release of active drug from the dosage form from the dosage form. It is the first step in which determines the onset of action, rate of absorption, and availability - controlled by the characteristics of the drug product. Disintegration is defined as the state in which any residue of the unit, except fragments of insoluble coating or capsule shell, remaining on the screen of the test apparatus is a soft mass having no palpably firm core. Dissolution is a process by which a chemical or drug becomes dissolved in a solvent. It is an important step prior to drug absorption into the systemic circulation. Lesson 3: Review of Drug Delivery System and Routes of Administration Page 3 of 13 Drugs are substances intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease. Drugs are given in a variety of dosage forms or drug products such as solids (tablets, capsules), semisolids (ointments, creams), liquids, suspensions, emulsions, etc, for systemic or local therapeutic activity. Dosage Forms refers to pharmaceutical preparations or formulations in which a specific mixture of drug substances (active pharmaceutical ingredients) and inactive components (excipients) are presented in a particular configuration to facilitate easy and accurate administration and delivery of active drug substances. Drug products can be considered to be drug delivery systems that release and deliver drug to the site of action such that they produce the desired therapeutic effect and are also designed specifically to meet the patient's needs including palatability, convenience, and safety. A. Oral Drug Products Oral administration of drug products is the most common, convenient, and economic route. The major advantages of oral drug products are the: convenience of administration, safety, and the elimination of discomforts involved with injections. hazard of rapid intravenous administration causing toxic high concentration of drug in the blood is also avoided. The main disadvantages of oral drug products are the potential issues of: reduced, erratic, or incomplete bioavailability due to solubility, permeability, and/or stability problems. altered contents and microbiologic flora of the gastrointestinal tract by unabsorbed drug. irritation of the gastrointestinal linings causing nausea or gastrointestinal discomfort by some drugs. altered bioavailability by some drugs and food interactions and any pathology of the GI tract such as ulcerative colitis. unpredictable nature of gastrointestinal drug absorption due to factors such as the presence of food that may alter the gastrointestinal tract pH, gastric motility, and emptying time, as well as the rate and extent of drug absorption. highly ionized drug molecules are not absorbed easily. drugs with large molecular weights may not be well absorbed when given orally. Some large molecules are absorbed when administered in solution with a surface-active agent. In developing oral protein delivery systems with high bioavailability, three practical approaches might be most helpful (Morishita and Peppas, 2006): Page 4 of 13  1. modification of the physicochemical properties of macromolecules; 2. addition of novel function to macromolecules; or 3. use of improved delivery carriers. B. Parenteral Drug Products The parenteral route of administration refers to all forms of drugs administered via a syringe, needle, or catheter into body tissues or fluids such as intravenous, intra-arterial, intraosseous, intramuscular, subcutaneous, and intrathecal routes. In general, intravenous (IV) bolus administration of a drug provides the most rapid onset of drug action. After IV bolus injection, the drug is distributed via the circulation to all parts of the body within a few minutes. After intramuscular (IM) injection, drug is absorbed from the injection site into the bloodstream. Plasma concentration of a drug after the same dose is administered by three different routes. Intramuscular injection may have faster or slower drug absorption than after oral drug administration. Intramuscular preparations are generally injected into a muscle mass such as in the buttocks (gluteus muscle) or in the deltoid muscle. Drug absorption occurs as the drug diffuses from the muscle into the surrounding tissue fluid and then into the blood. Different muscle tissues have different blood flow. For example, blood flow to the deltoid muscle is higher than blood flow to the gluteus muscle. Page 5 of 13  Intramuscular injections may be formulated to have a faster or slower drug release by changing the vehicle of the injection preparation. Aqueous solutions release drug more rapidly, and the drug is more rapidly absorbed from the injection site, whereas a viscous, oily, or suspension vehicle may result in a slow drug release and consequently slow and sustained drug absorption. Viscous vehicles generally slow down drug diffusion and distribution. A drug in an oily vehicle must partition into an aqueous phase before systemic absorption. A drug that is very soluble in oil and relatively insoluble in water may have a relatively long and sustained release from the absorption site because of slow partitioning. Modified-release parenteral dosage forms have been developed in which the drug is entrapped or encapsulated into inert polymeric or lipophilic matrices that slowly release the drug in vivo over a week or up to several years (Patil and Burgess, 2010). Drugs, including peptides and proteins, have also been formulated as emulsions, suspensions, liposomes, and nanoparticles for parenteral injection. A change in a parenteral drug product from a solution to an emulsion, liposome, etc will alter the drug’s distribution and pharmacokinetic profile. C. Nasal Drug Products The nasal route of administration has been used for the delivery of drug products for both topical and systemic actions. A variety of different drug products such as antihistamines, corticosteroids, anticholinergics, and vasoconstrictors are currently being marketed for the local treatment of congestion, rhinitis, sinusitis, and related allergic or chronic conditions. Recently, the nasal route of administration has gained increasing consideration for obtaining systemic absorption or brain uptake of drugs. The delivery of drugs to the CNS from the nasal route may occur via olfactory neuroepithelium. Drug delivery through nasal route into CNS has been reported for Alzheimer’s disease, brain tumors, epilepsy, pain, and sleep disorders (Pavan et al, 2008). Factors that affect the systemic bioavailability of drugs that are administered through the nasal route (Kumari et al, 2013). 1. Physiochemical properties of the drugs: lipophilic– hydrophilic balance, chemical form, polymorphism, enzymatic degradation in nasal cavity, molecular size, solubility, and dissolution rate. 2. Delivery effect: formulation (concentration, pH, osmolarity), droplet/particle size distribution, viscosity. Page 6 of 13  3. Nasal effect: mucociliary clearance, cold, rhinitis, membrane permeability, environmental pH, the anatomical and physiological. Nasal devices have progressively evolved from the pipettes and the droppers through to spraying devices such as squeeze bottles, toward, a nasal gel pump, pressurized metered dose inhalers (MDIs), and dry-powder inhalers (Djupesland, 2013). The concept of classical bioequivalence and bioavailability may not be applicable for all nasal drug products specially those for local action. In addition, the doses administered are typically so small that blood or serum concentrations may not be detectable by routine analytical procedures. Therefore, for locally acting drug product, major manufacturing changes may require the need for clinical trials. D. Buccal and Sublingual A tablet designed for release under the tongue is called a sublingual tablet. Nitroglycerin, isoproterenol, erythrityl tetranitrate, and isosorbide dinitrate A tablet designed for release and absorption of the drug in the buccal (cheek) pouch is called a buccal tablet. The buccal cavity is the space between the mandibular arch and the oral mucosa, an area well supplied with blood vessels for efficient drug absorption. Oral transmucosal absorption is generally rapid because of the rich vascular supply to the mucosa and the lack of a stratum corneum epidermis. A buccal tablet may be designed to release drug slowly for a prolonged effect. This form of drug product administration is very effective as it avoids first-pass metabolism by the liver before general distribution. Consequently, for a drug with significant first-pass effect, buccal/sublingual absorption may provide better bioavailability than oral administration and rapid unset of action as it may be absorbed in the blood stream in minutes. Sublingual and buccal medications are compounded in the form of small, quick-dissolving tablets, sprays, lozenges, or liquid suspensions. Recently developed approach: translingual nitroglycerin spray (Nitrolinqual Pumpspray) Fentanyl has been formulated as a transdermal drug product (Durapress®) and as an oral lozenge on a handle (Actiq®) containing fentanyl citrate for oral transmucosal delivery Page 7 of 13 E. Inhalation Drug Delivery Inhalation drug delivery may also be used for local or systemic drug effects. The lung has a much larger surface than the small intestine or nasal passages. If compounds such as aerosolized drug can reach the peripheral region of the lung, absorption can be very efficient. Particle (droplet) size and velocity of application control the extent to which inhaled substances penetrate into airway spaces. Optimum size for deep airway penetration of drug particles is 3–5 mm, large particles tend to deposit in upper airways, whereas very small molecules (