Lecture 16 ABSORPTION FROM ORAL DOSAGE FORMS Factors

Lecture #16 ABSORPTION FROM ORAL DOSAGE FORMS

Factors Determining Absorption of Oral Dosage Forms • Dosage Form Characteristics • Active Pharmaceutical Ingredient (API) Properties • GI Tract Physiology • GI Tract Abnormalities/Disease

Dosage Form Characteristics • Disintegration/Deaggregation • Dissolution

Oral Dosage Form Characteristics: Key Excipient Types • • • Diluents (Fillers) Disintegrants Binders Lubricants Glidants Other

Diluents (Fillers) • Bulking Agent – Practical weight for patient to hold (min. 50 mg) • Compression Aid – Facilitate bonding deformation and fragmentation • Good bulk powder flow

Disintegrants • De-aggregation water – Water uptake – Swelling

Binders • Adhesive • Mechanical Strength

Lubricants • Compression Lubricants – Promote smooth ejection – Hydrophobic (0. 2 -3%) – Magnesium Stearate • Non-compression Lubricants – Prevent adherence to equipment surfaces

Glidants • Flowability High speed processing • Only added if needed <0. 2%

Other • • • Coloring Sweetening/Flavoring Agents Preservatives (Anti-oxidants) Solubilizing agents Perfumes

Active Pharmaceutical Ingredient (API) Properties • Ionization (acid/base) • Hydrophobicity log P (Partition Coefficient) • Water solubility – Paradox: Often higher water solubility, lower absorption

API: Potential Problems • API degraded at site of administration – low stomach p. H • API causes irritation, immune response or injury at the site of administration • API possesses undesirable organoleptic properties – taste and smell • API has undesirable PK properties

GI Tract Physiology • Colonic retention – colon absorbs too much water. • Gastric emptying (Pyloric sphincter) • Intestinal motility – spasms and paralysis • Blood flow (Perfusion) GI Tract • Permeability of the GI system

GI Tract Abnormalities and Disease Healthy • Crohn’s Disease Crohn’s disease – inflammatory bowel disease – developed world – cause unknown (smokers) – (ulcerative colitis? ) • Gastric resection – Cancer – Obesity – Intractable Peptic Ulcer • Diarrhea – – – Secretory (cholera) Osmotic (high salt/sugar) Exudative (Crohn’s) Inflammation (infections) Dysentery (Infections) Cancer Obesity

Oral Dosage Forms • • • Tablets Capsule Lozenge Pastilles Dental Cones Pills Granules Powder Liquid

Oral Dosage Forms: Tablets • round, oval or square • excipients – binders, gliders, lubricants – disintegrants – sweetners – color (more attractive) – coating

Oral Dosage Forms: Orally Disintegrating Tablet (ODT) • Not swallowed dissolved on the tongue • for patients with dysphagia (35%) or compliance issues • Limited range of drugs available Clonazepam (Klonopin) • seizures and panic disorder

Oral Dosage Forms: Tablet Coating • • hide taste make easier to swallow resistant to the environment (e. g. low p. H) extend shelf life

Oral Dosage Forms: Buccal/Sublingual Tablet sublingual buccal • Dissolve rapidly absorbed through mucous membranes • Avoid acid and enzymatic environment of the stomach • Bypasses first pass metabolism (venous circulation heart) • sublingual: lingual vein jugular vein heart • Often, faster absorption

Oral Dosage Forms: Effervescent Tablet • Uncoated – citric/tartaric acids carbonates and bicarbonates • Very rapid dispersion and dissolution • Pleasant tasting carbonated drink

Oral Dosage Forms: Chewable Tablet • Chewed Prior to Swallowing • Flavored/Scented/Colored • Children – Vitamins

Oral Dosage Forms: Capsule • Advantage: mask the unpleasant taste of its contents • hard-shelled – dry, powdered ingredients • soft-shelled – oils

Oral Dosage Forms: Lozenges and Pastilles • Lozenges – Solid (sugar and gum) – Gum used to facilitate slow release of API – Coloring/Flavoring/Scent • Pastilles – Solid, but softer than lozenges • glycerol, gelatin, acacia and sugar – Slow release of API cannabis oil

Oral Dosage Forms: Dental Cones • Tablet empty socket tooth extraction – antibiotic and antiseptic

Oral Dosage Forms: Pills • round ball (vs. tablets flat) • designed to go down easily • currently rarely used Benzonatate B (Cough Suppressant) Dronabinol (THC)

Oral Dosage Forms: Granules • solid, dry aggregates powder particles – single dose sachets • swallowed with water • dissolved water first • effervescent

Oral Dosage Forms: Powder • Bulk and Divided – degrees of fineness – coloring/flavoring – broad therapeutic window (OTC) – with water, dissolved in water – effervescent sapropterin (phenylketonuria) • Mixtures powder tablet

Oral Dosage Forms: Liquids • • • Solution Emulsion – oil-in-water dispersions Suspensions (cloudy) – sediment Syrup – aqueous solution of sucrose Elixir – flavored clear liquid – more ethanol/sucrose – preservatives Elixir Fluoxetine (antidepressant) Emulsion Solution Acetaminophen Suspension Syrup

Oral Dosage Forms: Liquids • Linctuses – cough relief – syrup (aqueous sucrose) and glycerol – contains demulcent • relieves irritation of the mucous membranes of throat • Drops – small volumes – solutions, suspensions and emulsions

Oral Dosage Forms: Liquids • Gargles – Aqueous solutions – Dilute with warm water – Throat infections • Mouthwashes – Oral hygiene/Infections of the mouth

Rate Limitations Intestinal Wall Dissolved Drug absorption rate (ka) dissolution rate (kdissolve) Absorption Rate Limiting • • dissolution rate = 0. 5 /hr absorption rate = 0. 1 /hr Systemic Circulation Dissolution Rate Limiting • • dissolution rate = 0. 1 /hr absorption rate = 0. 5 /hr

Control Absorption with Dissolution • dissolution rate = 0. 1 /hr • absorption rate = 0. 5 /hr • dissolution rate = 0. 05 /hr • absorption rate = 0. 5 /hr Modified Release Products

Gastric Emptying • Food (Fat)

Situation Solution Drugs Increase absorption of a drug that rapidly dissolves in the stomach Increase gastric emptying by taking the drug without food. Ibuprofen acetaminophen Increase absorption of a drug that rapidly dissolves in the small intestines Increase gastric emptying by taking a drug without food Drugs with an enteric coating to prevent dissolution in the stomach Drug has poor dissolution properties Slow gastric emptying by taking the drug with a fatty meal. Albendazole Drug is a a gastric irritant (stomach and esophagus) Use an acid resistant coat to prevent dissolution in the stomach (enteric coating) Aspirin Sulfasalazine Bisacodyl Drug is inactivated by acid Use an acid resistant coat to prevent hydrolysis in the stomach (enteric coating) Omeprazole Lansoprazole Pantoprazole Didanosine

Biopharmaceutics Classification System (BCS) Table 7 -8 Class III Class II Note: This Table in the book is incorrect. I checked against the FDA. gov website. The corrections are shown in blue.

Absorption and PK Parameters • • • Absorption Rate Constant (ka) Bioavailability (F) Hepatic Clearance (CLH) Renal Clearance (CLR) Volume Distribution (V)

Absorption Rate Constant (ka) • • • Blood flow (Q) at the absorption site Rubbing (IM, SC, ID) Exercise (IM, SC) Gastric Emptying (Oral) Intestinal Motility (Oral)

Oral Bioavailability (F) • • Gastric emptying rate Gastric acid secretion Biliary excretion Intestinal motility Permeability of the gut wall Drug transporters Drug metabolizing enzymes