Application of Chemical Engineering Principles to Drug Delivery

1. Application of Chemical Engineering Principles to Drug Delivery Madeline Torres-Lugo, PhD Associate Professor Department of Chemical Engineering University of Puerto Rico Mayagüez Campus

2. Transport in Biological Systems Physiology and Anatomy Principles of Drug Delivery Principles of Controlled Release Drug Delivery Design and Regulatory Issues

3. Drug Delivery • Definition • The appropriate administration of drugs through various routes in the body for the purpose of improving health • It is highly interdisciplinary • It is not a young field • It has recently evolved to take into consideration • Drug physico-chemical properties • Body effects and interactions • Improvement of drug effect • Patient comfort and well being Controlled Drug Delivery

4. Drug Delivery – The Market • Fastest growing health sector • The U.S. market for drug delivery systems in 2002 was $38.8 billion, and is expected to rise at an average annual growth rate (AAGR) of 11.3% and reach $74.5 billion by 2008 • The sustained release (oral, injectable and topical) dosage form market is rising at an AAGR of 9.7% is expected to reach $34.1 billion by 2008 • The transmucosal market is expected to grow at an AAGR of 12.8% and reach $17.7 billion by 2008 • The market for targeted delivery systems was $7.3 billion in 2002 and will reach $15.5 billion by 2008 • Transdermal systems and implants and IUDs are expected to climb at AAGRs of 11.1% and 12.4%, respectively • Sales of drugs incorporating drug delivery devices (drug delivery + controlled release systems) increase 15% annually Advanced Drug Delivery Systems: New Developments, New Technologies by Shalini Shahani, 2003

5. Implications of Physiology and Anatomyin Drug Delivery

6. Anatomy vs. Physiology • Anatomy: deals with the structures (or morphology) of body parts, how they look and how they are organized. • Physiology: considers the functions of these body parts-what do the do and how.

7. Organization of the Human Body

9. Cells: smallest living units • Approximately 75 trillion cells in a human adult • Posses many characteristics in common, but many vary in size, shape, and function • Measured in micrometers • Red blood cell - about 7.5 m in diameter, • Human egg cell - about 140 m in diameter

10. Ultimate site of drug action Metabolize drug Interact with the cell to stimulate production of proteins or hormones Stimulate elimination or metabolism of products Eradicate drug Ultimate site of transport challenge Physicochemical properties of drugs Efflux pumps MDR MRP Relevance of Cell Anatomy in Drug Delivery

14. Cell Membrane, Nucleus, and Cytoplasm • Cell Membrane: outermost part of the cell • composed mainly of lipids and proteins • controls the entrance and exit of substances • Nucleus: directs the activity of the cell • Nuclear envelope: contains pores that allow certain dissolved substances (messenger RNA) to move between the nucleus and the cytoplasm • Cytoplasm: mass of fluid that surrounds nucleus, where most of the cell activity occurs

15. Endoplasmic reticulum: Transport materials within cell, attachment for ribosomes, lipid synthesis Ribosomes: Protein synthesis Vesicles: Store and transport newly synthesized molecules Golgi apparatus: Package and modify proteins for transport and secretion Mitochondria: Release energy from food molecules and transform energy into usable form Lysosomes: Digest worn cellular parts or substances that enter the cell Cytoplasmic Organelles

16. Other Organelles • Peroxisomes • Centrosomes • Cilia • Flagella • Vesicles • Microfilaments/Microtubules

17. The Tight Junction Occludin Actin and Myosin Filaments

18. +2 +2 -Ca +Ca Mechanism for the Opening of the Tight Junction

19. The Gastrointestinal Tract

20. esophagus stomach liver large intestine gallbladder duodenum jejunum ileum appendix colon

21. Anatomical Factors Relevant to Drug Delivery • pH • Area • Length • Residence time • Metabolic activities

25. Proteolytic Enzymes

26. Anatomical Factors Influenced by External Circumstances • Residence time • Gastric emptying • pH • Metabolic activities

27. 1 2 4 3 Transport Mechanisms 1 - Paracellular Route 2 - Transcellular Route 3 - Carrier-mediated Route 4 - Transcytosis Route

28. Paracellular • Type of passive transport where hydrophilic molecules are absorbed through the small openings between epithelial cells that are filled with aqueous solution • Comprises the 0.01% of the total surface area of the epithelium • Intercellular spaces vary according to their location in the GI tract • Duodenum – 0.8 nm • Colon – 0.3 nm

29. Type of passive transport where hydrophobic molecules are soluble in the cell membrane The cell membrane occupies a significant area of the GI tract Transcellular

30. Active or facilitated transport where the cell surface contains specific receptors These receptors recognize specific molecules and transport them across the cell membrane Can be saturated Example –vitamin B6 Carrier-mediated

31. Transcytosis • Active Transport • Mechanism: • Molecule is recognized in the surface of the cell • Membrane ruptures, forming a vesicle • Vesicle is transported into the other side of the cell • Membrane ruptures again and the content released • Example –vitamin B12

32. Metabolic Activity in GI tract

33. Circumstances Affecting the Gastrointestinal Tract • Disease • Diarrhea • Constipation • cancer • Psychological state • Accident • Age

34. Circumstances Affecting the Gastrointestinal Tract • Body position • Type of drug • Volume ingested • Type of ingested food • Fats • Proteins • Carbohydrates

35. First Pass Metabolism (FPM) • Portal System • Portal Vein • Mesenteric Vein • Superior • Inferior • Lienal • Nutrients collected from the GI tract are directly transported to the liver for further metabolism before entering the systemic circulation

37. First Pass Metabolism • Liver transforms non-polar drugs into polar compounds which can be readily eliminated • Metabolites can be toxic or active • Mechanisms • Oxidation • Reduction • Hydrolysis • Conjugation

38. First Pass Metabolism • Factors influencing FPM • Age • Diet • Disease • Different animal species possess different liver metabolism capabilities

39. Drugs affected by FPM

40. The Circulatory System

42. Relevance of the Circulatory System in Drug Delivery • Transport of drugs to the site of action • Main transport route for immune system response • Inflammation • Foreign body response • Clotting cascade • Critical factor for implants Greatest challenge for implantable systems

43. Red blood cell Fibrin

44. Steps in the formation of a Thrombus

45. Control Mechanisms • Blood flow to reduce the localized concentration of precursors • Rate of several clotting reactions is fast when catalyzed by a surface • Naturally occurring inhibitors of the enzymes • Some enzymes activate coagulation factors but degrade cofactors

46. Skin and the Integumentary System

48. Function of the Skin • Protective cover • microorganisms, harmful substances, prevents loss of water • Regulates body temperature • Host of immune system cells • Excrete toxins

49. Layers of the Skin • Epidermis • Dermis • Subcutaneous layer

50. Challenges of Transdermal Drug Delivery • Skin can only by penetrated by small hydrophobic molecules • Major resistance comes from stratus corneum • Factors Affecting Transdermal Drug Delivery • Site • Skin condition/disease • Age • Metabolism