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Drug Delivery and Mass Balance

Drug Delivery and Mass Balance. BIOE201-B. Drug Delivery and Mass Balance. T he concentration of the drug at the site of action, over time. Drug delivery is about the complex mechanisms to getting that concentration profile to happen.

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Drug Delivery and Mass Balance

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  1. Drug Delivery and Mass Balance BIOE201-B

  2. Drug Delivery and Mass Balance • The concentration of the drug at the site of action, over time. • Drugdelivery is about the complex mechanisms to getting that concentration profile to happen. • Delivery methods can be classified by the anatomical site they target (oral, injection, topical, transdermal, pulmonary, ophthalmic, rectal/vaginal, implantable depot device, etc.).

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

  4. Even with controlled delivery side effects cannot be avoided Might cause severe side effects- spread over body Site specific delivery- active or passive targeting

  5. Site Specific Delivery RES Lungs Spleen Liver Site specific delivery- active or passive targeting Reticuloendothelial System (RES)

  6. Passive Targeting of Particulate by EPR Mechanism • Enhanced permeability and retention (EPR) effect • Disorganization of tumor vasculature • Poor lymphatic drainage

  7. Active Targeting Ringsdorf’s Model

  8. Various Drug Delivery System

  9. Chemically-Controlled DDS

  10. Major Classes of Matrix in DDS

  11. Environmentally Responsive System

  12. pH Responsive System

  13. 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

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

  15. Drug Delivery System (DDS) Toxicity Therapeutic Window No Therapeutic Effect • Controlled delivery system • Site specific delivery of drugs

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

  17. All drugs must diffuse through various barriers when administered to the body. • Some drugs must diffuse through the skin, gastric mucosa, or some other barrier to gain access to the interior of the body. • Parenteral drugs must diffuse through muscle, connective tissue, and so on, to get to the site of action. • Intravenous drugs must diffuse from the blood to the site of action. • Drugs must also diffuse through various barriers for metabolism and excretion. Laws governing diffusion are important to drug delivery systems

  18. Fick’s law for diffusion, compartmental analysis, and the general use of mass conservation equations . The mass conservation equation: In – out + Generation - Consumption = Accumulation This equation, when properly replaced with mathematical terms, is used to describe transport everywhere. We can use simplified experiments and model fitting to calculate the value of drug diffusion constants, which can then be used to predict concentration profiles in relevant drug delivery scenarios.

  19. Bioavailability and Area Under the Curve • Bioavailability is defined as a ratio of the areas under the curves (AUCs) of plasma concentration versus time. • The AUC for intravenous injection is the standard, and any other delivery method is compared against that.

  20. 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

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

  22. Compartmental analysis These compartments don't usually correspond to actual bodily compartments, but they're still useful. The simplest case is the single‐compartment model. All the compartments are considered to be uniform and well‐mixed. In cases where the drug doesn't readily distribute to the whole body immediately, it's better to model things with more than one model. For example, using two of them:

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

  24. 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

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

  26. Diffusion occurs when individual molecules move within a substance, as the result of a concentration gradient or by random molecular motion. Fick’s Law Molecular diffusion from a microscopic and macroscopic point of view. Initially, there are solute molecules on the left side of a barrier (purple line) and none on the right. The barrier is removed, and the solute diffuses to fill the whole container. Top: A single molecule moves around randomly. Middle: With more molecules, there is a clear trend where the solute fills the container more and more uniformly. Bottom: With an enormous number of solute molecules, randomness becomes undetectable: The solute appears to move smoothly and systematically from high-concentration areas to low-concentration areas. This smooth flow is described by Fick's laws.

  27. Fick’s first law relates to a steady-state flow • J = dM/(S dt)= -DdC/dX • J = Flux (in g/cm2 s) • M = material (in g) • S = surface area (in cm2) • t = time (in s) • D = diffusion coefficient (in cm2/s) • C = concentration (in g/cm3) • X = distance of movement (in cm) • units: g/cm^2*s • Steady State Diffusion • Fick’s second law relates to a change in concentration of drug with time, at any distance, or an unsteady state of flow. • J= -D*(C1-C2)/h • D = diffusion coefficient (in cm2/s) • C = concentration (in g/cm3) • h = thickness of membrane (in cm) • Non-Steady State Diffusion Partition Coefficient K=C1/Cd=C2/CrK=[Drug]oil/[Drug]waterdetermines concentration of drug in the membrane

  28. A Versatile “Prodrug” Platform API= ACTIVE PHARMACEUTICS INGREDIENT SN-2 Pan, D. et al. Nanomedicine (Lond). 2012 Oct;7(10):1507-19.

  29. AntiAngiogenic Therapy THERAPY Treated 30µg/kg x 3 times (3, 6, 9 days) NO THERAPY Comparison of MR Contrast Enhanced Images presented as 2D Slice and 3D Volume Un-treated Pan et. al. Nanomedicine (UK), 2012 Pan et. al. Circulation. 2009, 120, S322. Biomaterials, 2012, 33 (33), 8632–8640

  30. Theranostic 2014

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