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Application of Chemical Engineering Principles to Drug Delivery Madeline Torres-Lugo, PhD Associate Professor Department of Chemical Engineering University of Puerto Rico Mayagüez Campus Transport in Biological Systems Principles of Drug Delivery Physiology and Anatomy Drug Delivery Principles of Controlled Release Design and Regulatory Issues 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 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 Implications of Physiology and Anatomy in Drug Delivery 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. Organization of the Human Body 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 Relevance of Cell Anatomy in Drug Delivery 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 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 Cytoplasmic Organelles 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 Other Organelles Peroxisomes Centrosomes Cilia Flagella Vesicles Microfilaments/Microtubules The Tight Junction Occludin Actin and Myosin Filaments Mechanism for the Opening of the Tight Junction -Ca+2 +Ca+2 +Ca The Gastrointestinal Tract esophagus stomach liver large intestine gallbladder duodenum jejunum ileum appendix colon Anatomical Factors Relevant to Drug Delivery pH Area Length Residence time Metabolic activities Segment Area (m2) Segment Length (m) Area/length Residence Ratio time pH Oral cavity 100 cm2 - - sec to min 6.5 Esophagus 200 cm2 23-25 cm 8 sec - Stomach 3.5 0.25 14 90 min 1-2 Duodenum 1.9 0.35 5 30-40 min 4-5.5 Jejunum 184 2.8 66 1.5-2 h 5.5-7 Ileum 276 4.2 66 5-7 h 7-7.5 Colon and Rectum 1.3 1.5 0.9 1-60 h 7-7.5 Systemic Circulation Tight Junction Polymeric Carrier Protein Proteolytic Proteolitic Enzymes Enzymes Mucosa Anatomical Factors Influenced by External Circumstances Residence time Gastric emptying pH Metabolic activities Transport Mechanisms 1 2 3 1 - Paracellular Route 2 - Transcellular Route 3 - Carrier-mediated Route 4 - Transcytosis Route 4 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 Transcellular Type of passive transport where hydrophobic molecules are soluble in the cell membrane The cell membrane occupies a significant area of the GI tract Carrier-mediated 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 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 Metabolic Activity in GI tract Segment Enzymes Oral cavity Esophagus Stomach polysaccharidases proteases; lipases Duodenum polysaccharidases; oligosaccharidases; proteases; peptidades; lipases Jejunum Ileum oligosaccharidases; peptidades; lipases oligosaccharidases; peptidades; lipases Colon and Rectum bacterial enzymes Circumstances Affecting the Gastrointestinal Tract Disease – Diarrhea – Constipation – cancer Psychological state Accident Age Circumstances Affecting the Gastrointestinal Tract Body position Type of drug Volume ingested Type of ingested food Fats Proteins Carbohydrates 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 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 First Pass Metabolism Factors influencing FPM – Age – Diet – Disease Different animal species possess different liver metabolism capabilities Drugs affected by FPM Drug Class Examples Analgesics Aspirin, meperidine (Demerol), pentazocine (Talwin), propoxyphene (Darvocet) Antianginal Nitroglycerin Antiarrhythmics Lidocane Beta-adrenergic blockers Labetolol, metoprolol (Toprol), propanolol (Inderal) Calcium channel blockers Verapamil (Calan) Sympathomimetic amines Isoproterenol (Isuprel) Tricyclic antidepressants Desipremine, imipramine (Tofranil), notriptyline The Circulatory System 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 Red blood cell Fibrin Steps in the formation of a Thrombus 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 Skin and the Integumentary System Function of the Skin Protective cover – microorganisms, harmful substances, prevents loss of water Regulates body temperature Host of immune system cells Excrete toxins Layers of the Skin Epidermis Dermis Subcutaneous layer 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 Immune Response Foreign Body Response Immune System Responsible for – Protection against foreign antigens (infection) – Wound healing Protection against exogenous materials (foreign body response) Detection of internal injury and/or changes in tissue due to accident or disease Steps in Body Response to Implantation Injury Acute inflammation Chronic inflammation Granulation tissue Foreign body reaction Fibrosis Inflammation Flow of fluids, proteins and red blood cells to the site of injury with the purpose of containing, neutralizing, diluting, walling off injury Characterized – Formation of clot – Swelling, redness, warming of site – Neutrophils –phagocyte microorganisms and foreign material Acute and Chronic Inflammation Acute – Short duration – minutes to days – Increased swelling – Migration of white blood cells, neutrophils, and macrophages Chronic – presence of more immune system cells and growth of new blood vessels and vascular tissue Granulation Tissue and Foreign Body Response Granulation Tissue – Body forms granulation tissue to isolate implant Foreign Body Response – Complete formation of a capsule around the implant – Presence of most of the immune system cells Fibrosis The end of the healing process where the capsule around the implant is finished Challenges – Infection inside the capsule cannot be treated, therefore implant must be removed – For a drug delivery device this could be disastrous Biocompatibility Biomaterials – Is the ability of a material to perform with an appropriate host response Medical Devices – Ability of a device to fulfill its intended function Respiratory System Responsible for – Air filtration – Transport of carbon dioxide Divided into: – Upper respiratory tract Organs above the thorax – Lower respiratory tract Organs within the thorax Lining of the bronchial tubes – Filled with cilia responsible for moving irritants and contaminants out of the system Respiratory Tubes Transport of Gases through the Respiratory System Factors Influencing Drug Delivery Particles over the size of >100 μm are trapped by the cilia expelled Factors influenced by external circumstances – Breathing rate (psychological state) – Permeability of gases (disease, age)