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BIOPHARMACEUTICS

Adapted by : S. Campbell-Elliott M. Pharm. Sc.

Prepared by : A.S. Adebayo, Ph.D.&

M. A Williams. M.S.

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General Overview/Definitions

Biopharmaceutics - concerned with relationship between the physicochemical properties of a drug in a dosage form and observed therapeutic response after administration.

Biologic response Expressed as alteration of biologic process existing

before drug was administered Magnitude is related to drug concentration achieved at

receptor site. The observed effect of drug from a dosage form =

inherent pharmacological activity of the drug + its ability to reach the receptor site in appropriate concentration

Onset, intensity and duration of therapeutic effect drugs depend on biological + dosage form factors

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General Overview/Definitions

(Cont.) These factors are important for: attaining desired

drug conc. in the body + sustaining concentrations for desired length of time + drug removal after desired effect is attained.

Biopharmaceutics affords a basic understanding of the processes of drug absorption, distribution and elimination + potential effects of dosage form on these processes that can be applied to optimize therapeutic outcome of a patient.

Dosage form of a drug exerts its major influence on the absorption process

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Biopharmaceutics

Biopharmaceutics - “the effects of dosage form and route of administration on the biological effect of a drug”

-study of factors influencing the presence of drug at the site of absorption and the transfer of the dissolved drug across biomembrane(s) into the systemic circulation.

Biopharmaceutical methods: application of knowledge of drug release and transport across biomembranes to obtain/predict therapeutic effect from a product on administration to a patient.

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Factors Influencing the time course of a drug in plasma The physical/chemical properties of the drug Type of dosage form of the drug Composition and method of manufacture of the dosage

form The size of the dose and frequency of administration of the

dosage form Site of absorption of the administered drug Co-administration of other drugs Type of food taken by the patient The disease state of the patient that may affect drug

absorption, distribution and elimination of the drug The age of the patient. The genetic composition of the patient

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Bioavailability: rate & extent Bioavailability - transfer of drug from its

site of administration into the body system; manifested by appearance in general circulation.

Characterized by rate of transfer and the total amount (extent) transferred

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Factors Influencing Drug Absorption

Can be categorized into 3 factors: Physiological factors

- Nature of the cell membrane Semi-permeable: Permits only water, selected

small molecules and lipid-soluble molecules. Highly charged molecules and large molecules

e.g. proteins and protein-bound drug will not cross.

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Factors Influencing Drug Absorption

Physicochemical factors

Surface area of the drug Crystal or amorphous form Salt form State of hydration Solubility

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Factors Influencing Drug Absorption

Dosage form factors - The route of administration - The inert ingredients e.g. diluents, binders, disintegrants, suspending agents, coating agent, etc. -Type of dosage form e.g. tablet, capsule, solution,suspension, suppository, etc.

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STOMACH (Gastric content. pH 1-3)

SMALL INTESTINE (Intestinal cont. pH 5-7)

Tablet

Granules

Fine particles

Dissolution

Drug in solution

Tablet

Granules

Fine particles

Dissolution

Drug in solution

Absorption

Intact drug

Liver

Intact Drug in systemic Circulation

Pharmacologic effect

Intestinal metabolism

Metabolites

Urine

Hepatic Metabolism(1st Pass Effect)

Disintegration

Deaggregation

Schematic illustration of the steps involved in the appearance of intact drug in systemic circulation following oral administration of a tablet

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Rate Limiting Steps of AbsorptionNature of Drug Rate Limiting Step

Poor aqueous solubility

Rate of dissolution in gastrointestinal fluid

High aqueous solubility

Rate at which drug crosses membrane of the GIT

Dosage Design Rate of release from the dosage form

Other factors Rate of gastric emptying into small intestine

Rate at which drug is metabolized by the enzymes in the intestinal mucosal cells en route into mesenteric blood vessels

Rate of metabolism of drug during its initial passage through the liver (i.e. First-pass effect).

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Physiological Factors

Affecting Oral Absorption

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Fate of a Drug Product

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Simplified Model of Membrane

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Davson-Danielli Model

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Examples of Biomembranes

Blood-brain barrier Has effectively no pores to prevent many polar

materials (often toxic ) from entering the brain. Smaller lipid or lipid soluble materials, such as diethyl

ether, halothane (used as general anesthetics) can easily enter the brain.

Renal tubules Relatively non-porous; lipid compounds or non-ionized

species (dependent of pH and pKa) are reabsorbed.

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Examples of Biomembranes (cont’d)

Blood capillaries and renal glomerular membranes

Quite porous, allowing non-polar and polar molecules (up to a fairly large size, just below that of albumin, (M.Wt. 69,000) to pass through.

Especially useful in the kidneys as it allows for excretion of polar (drug and waste compounds) substances.

Placental barrier – Research!!!

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Structure of the Gastro-intestinal Tract

The GIT consists of 4 anatomical regions: Oesophagus Stomach Small intestine Large intestine (colon).

The luminal surface varies throughout the tract – suited for function

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Physiology of the G.I.T.

Hollow muscular tube composed of 4 concentric layers of tissues:

Mucosa (mucous membrane) Sub-mucosa Muscularis externa Serosa (outermost layer).

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Physiology of the GIT : Structure of the wall

Serosa – epithelium + connective tissue

Muscularis externa – moves GI contents

Submucosa Secretory tissue Rich supply of blood

and lymphatic vessels Network of nerve cells

Mucosa

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Physiology of the G.I.T. :The Mucosa

Mucosa is most important for drug absorption.- It contains the cellular membrane through which a drug

must pass in order to reach the blood (or lymph).

The mucosa is itself made of 3 layers: Lining epithelium Lamina propria Muscularis mucosa

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Physiology of the G.I.T.:The Mucous Layer

The gastrointestinal epithelium is covered by a layer of mucus.

Mucuous acts as a protective layer and a mechanical barrier.

It has a large water component (95%).

It also contains large glycoproteins (mucin)

The mucus layer ranges in thickness from 5 m to 500 m along the length of the gastrointestinal tract, with average valves of around 80 m.

The layer is thought to be continuous in the stomach and duodenum

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Physiology of the GIT:The Oesophagus

Links the oral cavity with the stomach. Composed of a thick muscular layer, approx.

250mm long and 20mm diameter. Epithelial cell function is mainly protective:

simple mucus glands secret mucus into the narrow lumen to lubricate food and protect the lower part of the oesophagus from gastric acid.

The pH of the oesophageal lumen is usually between 5 and 6.

The oesophageal transit of dosage form is approx. 10-14 seconds

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Physiology of the GIT:The Stomach

Most dilated part of the gastrointestinal tract.

Situated between the lower end of the oesophagus and the small intestine.

Opening to the duodenum is controlled by the pyloric sphincter.

Capacity of approx. 1.5L

Very little drug absorption occurs in the stomach due to relatively small surface area (compared to small intestines).

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Physiology of the GIT:The Stomach (cont’d)

Gastric secretions: Acid secreted by parietal cells - maintains the pH of the

stomach between 1 and 3.5 in fasted state.

Hormone gastrin - potent stimulator of gastric acid production.

Pepsin - secreted by peptic cells in the form of its precursor, pepsinogen; peptidase which break down proteins to peptides at low pH; above pH 5 pepsin is denatured.

Mucus - secreted by the surface mucosal cells and lines the gastric mucosa; protects gastric mucosa from auto digestion by the pepsin-acid combination.

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Physiology of the GIT: The Small Intestine

Longest (4-5m) and most convoluted part of the GIT, extending from the pyloric sphincter (of stomach) to the ileo-caecal junction where it joins the large intestines.

Main functions: Digestion: Process of enzymic degradation; begins in the stomach and completed in the small intestine. Absorption:

Small intestine is the region where most nutrients and other materials are absorbed.

Divided into the duodenum (200-300mm long), the jejunum (≈2m long) and the ileum (≈3m in length).

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Physiology of the GIT:The Small Intestine

(cont’d)The luminal pH of the small intestine increases to 6 -7.5 due to

: Brunner’s glands:

Located in the duodenum responsible for the secretion of bicarbonate which neutralizes

the acid emptied from the stomach.

Intestinal cells: present throughout the small intestine secrete mucus and enzymes, such as hydrolases and

proteases

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Physiology of the GIT:The Small Intestine

(cont’d)The following structures are responsible for the very large

surface area of the small intestine.

Folds of Kerckring: Submucosal folds extending circularly most of the way around the

intestine; well developed in the duodenum and jejunum

Villi: described as finger–like projections into the lumen (approx. 0.5 - 1.5mm in length and 0.1mm in diameter). Well perfused

Microvilli: approximately 600-1000 brush-like structures (1 m in length and 0.1

m in width) cover each villus, provides the largest increase in the surface area.

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Increase in Surface Surface AreaStructure (relative to cylinder) sq cm

simplecylinder

1 3,300

Folds ofKerckring

3 10,000

Villi 30 100,000

Microvilli 600 2,000,000

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Physiology of the GIT:The Colon

Terminal portion of GIT. Unlike the small intestine, has no specialized villi.

However, the surface area is increased by the following microvilli of the absorptive epithelial cells presence of crypts irregular folded mucosae serve to increase the surface area of the

colon by 10-15 times.

Main functions are: The absorption of sodium and chloride ions and water from the

lumen in exchange for bicarbonate and potassium ions. Significant homeostatic role in the body. Storage and compaction of faeces.

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Physiology of the GIT:The Colon (cont’d)

Colonized by a large number and variety of bacteria (about 1012 per gram of contents).

Bacterial mass is capable of several metabolic reaction, including hydrolysis of fatty acids, reduction of inactive conjugated drugs to their active form.

They degrade polysaccharide to produce short- chain fatty acids (acetic, proprionic butyric acids); generation of gases hydrogen, carbon dioxide and methane (lowers luminal pH to 6 - 6.5)

This increases to around 7-7.5. toward the distal parts of the colon.