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Principles of Drug Delivery

Principles of Drug Delivery. 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

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Principles of Drug Delivery

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  1. Principles of Drug Delivery

  2. 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

  3. Drug Delivery Conventional Controlled Enteral Sustained Extended Parenteral Site-specific Other Pulsatile

  4. Advantages Patient: Convenience, not invasive, higher compliance Manufacture: well established processes, available infrastructure Disadvantages Unconscious patients cannot take dose Low solubility Low permeability Degradation by GI enzymes or flora First pass metabolism Food interactions Irregular absorption Oral Administration

  5. Oral Administration • Traditional oral delivery systems • Tablets • Capsules • Soft gelatin capsules • Suspensions • Elixirs

  6. Advantages By-pass First pass metabolism Rapid absorption Low enzymatic activity Disadvantages Discomfort during dissolution Probability of swallowing- lost of effect Small doses Traditional delivery system/devices Tablets Chewing gum Buccal/Sublingual

  7. Example from Industry: Generex Biotechnology • Oral-Lyn: liquid formulation of human insulin administered to buccal mucosa by aerosolization • Drug carried in lipid micelles

  8. Advantages By-pass first pass metabolism Useful for children Disadvantages Absorption depends on disease state Degradation by bacterial flora Uncomfortable Traditional delivery system/devices Suppository Enema Rectal

  9. Example from Industry: Valeant Pharmaceuticals • Diastat AcuDial: diazepam rectal gel

  10. Advantages Drug 100% bioavailable Rapid response Total control of blood concentration Maximize incorporation of degradable drugs By-pass FPM Disadvantages Invasive Trained personnel Possible toxicity due to incorrect dosing sterility Traditional delivery system/devices Injection-bolus IV bag - infusion Intravenous (IV)

  11. Advantages Patient self-administration Slow, complete absorption By-pass FPM Disadvantages Invasive Irritation, inflammation Maximum dose volume - 2mL Subcutaneous

  12. Advantages Patient can administer the drug himself Larger volume than subcutaneous By-pass first pass metabolism Disadvantages Invasive – patient disconfort Irritation, inflamation May require some training Intramuscular

  13. Advantages By-pass FPM Gases are rapidly absorbed Disadvantages Solids and liquids can be absorbed if size is below 0.5um Inhalers

  14. aerosol particle lung cell capillary cell solubilized drug molecules Glass stabilizer insulin molecules Example from Industry: Nektar Therapeutics • Pulmonary delivery of Insulin • Amorphous aerosol particles with ~1μm diameters

  15. Advantages Local effect Ease of administration Disadvantages Low absorption for some drugs May cause allergic reactions Requirements Low dosage <10 mg/mL MW< 1,000 Transdermal

  16. Factors Influencing the Selection of the Delivery Route • Drug physico-chemical properties • Drug molecular size (molecular weight) • Half-life • Chemical stability • Loss of biological activity in aqueous solution • Proteins • Denaturation, degradation

  17. Example from Industry: 3M Company • Microstructured Transdermal System: MTS • Microneedle system • Drug-in-adhesive technology platform (a) 3M microneedle system and (b) histological section of microneedles in guinea pig skin

  18. Factors Influencing the Selection of the Delivery Route • Solubility in aqueous solution (hydrophobicity/hydrophilicity) • pH • pKa - ionization • Temperature • Concentration • Crystalinity • Particle size • State of hydration

  19. Factors Influencing the Selection of the Delivery Route • Drug biological interactions • Sensitive to FPM • Low membrane permeabiltiy • Efflux pumps (MRP, MDR) – cancer drugs • Hydrophilicity • High-density charge • Enzymatic degradation • Bacterial degradation • Half-life • Side effects • Irritation

  20. Factors Influencing the Selection of the Delivery Route • Desired pharmacological effect • Local • topical, vaginal • Systemic • oral, buccal, IV, SC, IM, rectal, nasal • Immediate response • IV, SC, IM, nasal • Dose size • Drug molecular size

  21. Manufacture of Classical Oral Delivery Systems • Formulation – combination of active ingredients with the appropriate excipients • Excipients – inactive ingredients employed for the purpose of dilution, protection, stability, controlled release, taste, fillers, coloring, disintegration, etc

  22. Manufacture Process for Tablets and Capsules Blending Wet Granulation Dry Milling Compression Coating Labeling Packing

  23. Pharmacokinetics and Pharmacodynamics Pharmacokinetics Pharmacodynamics • Design • of dosage regimen • Where? • How much? • How often? • How long? Effects Plasma refers to the clear supernatant fluid that results from blood after the cellular components have been removed Plasma Concentration

  24. Toxicity Plasma concentration (mg/mL) Therapeutic window No therapeutic effect Time (min) Plasma Concentration

  25. Unsuccessful therapy Plasma concentration (mg/mL) Successful therapy Time (min)

  26. Magnitude of Drug Response • Depends upon concentration achieved at the site of action • Dosage • Extent of absorption • Distribution to the site • Rate/extent of elimination

  27. From the Site of Delivery to Elimination…steps in drug delivery, absorption, distribution and elimination • Drug Delivery • Selection of drug delivery route • Knowledge of physicochemical properties • Design of dosing regimen • Absorption • Knowledge of PK and PD • First pass effect • MDR or MRP

  28. From the Site of Delivery to Elimination…steps in drug delivery, absorption, distribution and elimination • Distribution • Drugs must reach the site of action • Tissue • Plasma • Elimination • Metabolism • Liver, kidneys, cells • Excretion • Kidneys • Feces Depends upon drug binding capabilities

  29. Gastrointestinal Tract Oral Administration Circulatory System Intravenous Injection Excretion Intramuscular Injection Metabolic Sites Tissues Subcutaneous Injection

  30. Absorption of drugs could vary within different administration routes • 500 mg dose given • intramuscularly • orally **to the same subject on separate occasions • Biological barriers greatly affect the extent of drug absorption

  31. Absorption of drugs could vary within the same administration route

  32. Important Concepts • Volume of distribution • apparent volume into which a drug distributes in the body at equilibrium • direct measure of the extent of distribution • V = amount of drug in the body/Plasma drug concentration

  33. Mathematical Modeling of Drug Disposition • Single compartment • Single compartment with absorption • Two compartments • Two compartments with absorption • Physiological Models

  34. C/C0 absorption C, Vd elimination k, C t Single Compartment Model • Assumptions: • Body one compartment characterized by a volume of distribution (Vd) • Drug is confined to the plasma (small V)

  35. M/D0 M/D0 t t One-Compartment Model with Absorption • Low absorption occurs • Absorption is the rate-limiting step • Slow absorption may represent drug entry through GI tract or leakage into circulation after SC injection • Drugs require multiple doses to maintain drug concentration within therapeutic window

  36. C/C0 C/C0 Compartment 1 Compartment 1 Compartment 2 Compartment 2 t t • Concentration after ingestion Concentration with slow absorption Two-Compartment Model k1, C1 C1, V1 • Drug rapidly injected • Drug distributed instantaneously throughout one compartment and slowly throughout second compartment • Describes drug concentration in plasma injected IV k12 k21 k2, C2 C2, V2

  37. Physiological Models

  38. Determination of the Efficacy of the Delivery Route • Bioavailability (F) • Fraction of the drug that reached the systemic circulation • According to the FDA, Food, Drug, and Cosmetic Act • “The rate and extent to which an active ingredient or active moiety is absorbed from a drug product and becomes available at the site of action. For drugs that are not intended to be absorbed in the bloodstream, bioavailability may be assessed by measurements intended to reflect the rate and extent to which the active ingredient or active moiety becomes available at the site of action.”

  39. Factors Influencing Bioavailabilty • Delivery route • The site of measurement • Type of animal employed • Physiological state of the animal/human • Disease • Anesthesia

  40. Implications of PK and PD in Drug Delivery • The PK and PD of a drug may be affected when administered via different routes • Examples • Proteins – oral vs. intramuscular • Morphine – oral vs. intramuscular • The PK and PD of a drug delineates its therapeutic window • Degree of absorption • Degree of elimination and/or metabolism • Example • Tetracycline (infection) – given 6 to 8 hours • Digoxin (cardiac failure)– given daily

  41. Where to Find PD and PK Information • United States Pharmacopeia • www.usp.org • It is also paper published • Provides standards, chemical properties, and protocols to perform pharmacological experiments • Federal Drug Administration – if it has already being approved • www.fda.org

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