Biopharmaceutics

Introduction to Biopharmaceutics Physiological factors influencing oral drug absorption

Definition:

Biopharmaceutics is a branch of pharmaceutical sciences that concerns the interrelationship b/n the physicochemical properties of a drug, the dosage form in which the drug is given, and the route of administration on the rate and extent of systemic drug absorption

Pharmacologic, toxicologic or clinical response observed

The study of biopharmaceutics is based on fundamental scientific principles and experimental methodology - in vitro (test apparatus and equipment) and - in vivo (human subjects or laboratory animals) Knowledge of biopharmaceutics is essential for rational drug product design Inherent in design of suitable drug product are - Pharmacodynamics effect of drug on body onset, duration, intensity of action - Pharmacokinetics - effect of body on drug absorption, distribution, metabolism, excretion (ADME)

Factors that influence concentration of drug at its site(s) of action

Biopharmaceutics is concerned with getting drug from its route of administration to blood Pharmacokinetics is concerned with time course of drug absorption, distribution and elimination (ADME) Pharmacodynamics is concerned with relationship b/n concentration of drug at site of action and clinical response

Bioavailability If a drug is given i.v., it is administered directly into the blood 100 % bioavailable Extravascular routes dont guarantee that the whole dose will reach systemic circulation intact For orally administered drug to be 100% bioavailable
Completely released from DF Fully dissolved in GI fluids Stable in solution in GI fluids Pass through GI barrier into mesenteric circulation without metabolism Pass through liver into systemic circulation intact

Anything that adversely affect these will influence bioavailability Many factors affect bioavailability
Physicochemical properties of drug, Type of DF, Composition and method of manufacture of DF, Dose and frequency of administration, Route of administration, Food, Disease state, Age of patient, Site(s) of absorption of drug, Co-administration of other drugs,

Biopharmaceutical Factors - Biological / Physiological - Physico-chemical - Dosage Form

Emphasis on factors influencing oral absorption Oral route is most popular - Natural and convenient route - Relatively easy to manufacture need not be sterilized, compact, produced in bulk

Physiological Factors Influencing Oral Absorption GI tract is complex muscular tube ~ 6 m long mouth to anus 4 anatomical parts SI represent > 60% Luminal surface is very rough
CAECUM
APPENDIX

 GIT wall consists four principal histological layers

Lumen

(Muscularis externa)

Serosa: outer layer of epithelium, provides structural support to organs Muscularis externa: contains two layers of smooth muscle outer longitudinal layer thicker inner circular layer
circular muscle prevents food traveling backward longitudinal layer shortens tract mixing, propulsive movement of GI contents

Submucosa: layer of connective tissue supporting mucosa and joins it to underlying smooth muscles richly supplied with blood and lymphatic vessels network of nerve cells (k.a. submucous plexus)

 Mucosa: composed of three layers

Muscularis mucosa thin layer of smooth muscle alter local conformation of mucosa enhance contact b/n epithelium and contents of lumen lamina propria thin layer of connective tissue contains capillaries and lymph vessels contain glands with ducts opening to mucosal epithelium

secrete mucus
Epithelium selective absorption, secretion, protective functions

layer of mucus covers majority of GI epithelium - protective layer and mechanical barrier - constantly changing mix of secretions and exfoliated cells
components: mucin (large glycoproteins) + water (~95%) mucus layer: 5 m to 500 m, with 80 m average

Esophagus links oral cavity with stomach composed of thick muscular layer ~ 25 cm long and 2 cm diameter pH of lumen ~ 5 - 6 in upright position, transit of materials is assisted by gravity Esophageal transit of DFs is 10 - 14 s Limited biopharmaceutical importance Lodging of DFs

Stomach Two major functions: - temporary reservoir for ingested food

Capacity: ~ 1.5 l Fasting condition: not > 50 ml

- mix and reduce ingested components into slurry (k.a. chyme) Divided into four regions:
Fundus, Body, Antrum, Pylorus
Lesser curvature

Fundus and Body: little muscular tones (reservoir) Antrum and Pylorus: mix and pump (gastric emptying)

Pyloric sphincter

Greater curvature

Very little drug absorption occurs small SA High biopharmaceutical importance: Gastric emptying can dictate drug absorption from SI.

Small intestine Longest (4 - 5 m) and most convoluted part Extend from pyloric sphincter to ileocaecal junction 2 Main functions: - Digestion - Absorption 3 parts: Duodenum: 20 - 30 cm Jejunum: ~ 2 m Ileum ~ 3 m

SI wall has rich network of blood and lymphatic vessels

~ 1/3 cardiac output flows through GI viscera

SI receives blood from superior mesenteric artery Blood leaves SI via hepatic portal vein to liver and then to systemic circulation * Drugs susceptible to metabolism by liver are degraded hepatic presystemic clearance, first-pass metabolism SI has enormous SA ~ 200 m2 in adult Several adaptations!

 Folds of Kerckring: folds of SI mucous membrane that project within lumen Several mm in depth Well developed in duodenum and jejunum Villi: finger-like projections into lumen (~ 0.5 - 1.5 mm long & 0.1 mm wide) Well supplied with blood vessels Contain arterioles, venules and blind-ending lymphatic vessels (lacteal)

Microvilli: brush-like structures covering villi - ~ 1 m long & 0.1 m wide ~ 600 1000 per villus largest increase in SA Significant biopharmaceutical importance: Most nutrients and drugs absorbed from SI

10

Colon Final part - Ileocaecal junction to anus (~ 1.5 m long)

caecum ( ~ 8.5 cm) ascending colon ( ~ 20 cm) transverse colon ( > 45 cm) descending colon (~ 30 cm) sigmoid colon (~ 40 cm) rectum (~ 12 cm)

Rectum

2 Functions: absorption of Na+, Cl, water from lumen for K+, HCO3 significant homeostatic role store and compaction of faeces

No specialized villi but microvilli on absorptive epithelial cells SA ~ l/30th of SI Permanently colonized by extensive number ( ~ 1012 /g content) and variety of bacteria capable of several metabolic reactions Recent interest to exploit enzymes produced by these bacteria to targeted drug delivery to this region Some biopharmaceutical importance: Targeted drugs to colon (prodrug)

11