Dosage Form Design: Biopharmaceutical and Pharmacokinetic Considerations

Dosage Form Design: Biopharmaceutical and Pharmacokinetic Considerations

Learning Outcomes

  • Discuss the drug journey in the body system.
  • Discuss factors affecting the dissolution of drugs.
  • Discuss mechanisms by which drugs move across membranes.
  • Discuss factors affecting the absorption of drugs.
  • Discuss bioavailability and bioequivalence.
  • Discuss the effect of food on oral drug absorption.

Relationship of Dosage Form to Drug Response

  • Considering the properties of the drug and the dosage form in a physiological environment, what could be the expected therapeutic response after its administration to the patient?

The Drug Journey (LADMER)

  • Liberation: Drug delivery/liberating drug from dosage form (e.g., stomach).
  • Absorption: Getting drug from the outside to the inside of the body (e.g., cells of the GIT).
  • Distribution: Drug transport in the body (primarily in the blood).
  • Metabolism: Primarily in the liver.
  • Excretion: Primarily in the kidney.
  • Elimination: Removing drug from the body (ME).
  • Response: Drug action/pharmacology/therapeutics.

Biopharmaceutics

  • "Pharmaceutics" + "Bio" – interdependence of biological aspects of the living system and the physical-chemical properties that govern the preparation and behavior of the drug.
  • Interrelated with:
    • Physical pharmacy
    • Medicinal chemistry
    • Formulation
    • Physiology
    • Pharmacokinetics
  • Provides the scientific basis for drug product design and drug product development:
    • The design of the drug product
    • Stability of the drug within the drug product
    • The manufacture of the drug product
    • The release of the drug from the drug product
    • The rate of dissolution/release of the drug at the absorption site
    • Delivery of drug to the site of action

Drug Dissolution

  • Solid drugs must be dissolved before getting absorbed.
  • Dissolution is the first step in determining the rate of absorption, availability, and onset of action.
  • Rate of drug dissolution depends on:
    • Surface area of drug particles
    • Crystal or Amorphous Drug Form
    • Salt form

Surface Area

  • Particle size affects dissolution rate; smaller particles have a larger surface area and dissolve faster.

Crystal or Amorphous Drug Form

  • Crystalline: Lowest energy state and ordered; therefore, slower dissolution.
  • Amorphous: Metastable state and faster dissolution but can revert to crystalline state over time
  • Stable and unstable polymorphs

Salt Form

  • Salts are generally more soluble; therefore, dissolve faster (e.g., sodium and potassium salts of weak organic acids or hydrochloride salts of weak organic bases).

Drug Absorption

  • Drugs in the body must cross biological membranes (e.g., GI tract to blood for oral route, skin to blood for transdermal route).
  • Membranes are constructed from lipids and proteins.
    • The structure-forming matrix is a lipid double layer.
    • Proteins provide a pathway for selective transfer of certain polar molecules and charged ions through the lipid barrier.

Mechanisms by Which Drugs Cross Membranes

Passive Diffusion

  • Absorption process is driven by the concentration gradient of drug across the membrane (high to low).
  • Most drugs pass through membranes via this mechanism.
  • Follows Fick’s law: J= (P.SA/h) x (C1-C2)
    • J = Net rate of diffusion
    • P = Permeability
    • SA = Surface area
    • h = Membrane thickness
    • C1 - C2 = Concentration gradient
  • Net rate of diffusion:
    • Permeability
    • Concentration gradient
    • Membrane thickness
    • Surface area

Passive Diffusion - Rate

  • Permeability - measurement of ease at which molecules pass through membranes
  • Three main sources of variation in permeability are:
    • Molecular size (MW)
    • Lipophilicity of drug (characterized by the partition coefficient logP)
    • Charge on molecules
  • Small lipid soluble molecules that are unionized will penetrate easily
  • Larger and more polar molecules move much more slowly

Specialized Transport Mechanisms

  • Active transport
    • A process using a “carrier” to move drug across the membrane against a concentration gradient (from lower to higher).
    • Energy required.
    • Saturable mechanism - plateau in rate of absorption at higher concentration.
  • Facilitated diffusion
    • A specialized transport using the “carrier,” but the drug is not moved against a concentration gradient.
    • No energy expended.

Drug Absorption

  • Absorption is the rate and extent at which drugs reach the systemic circulation from the site of drug administration.
  • A drug has been “absorbed” if it has reached the systemic circulation.
  • Drugs directly administered into the bloodstream are assumed to be 100% absorbed.
  • Drugs administered extra-vascularly would not have 100% absorption.
  • Biopharmaceutics is concerned with the factors affecting drug absorption, as well as factors affecting drug liberation.
  • Two fundamental parameters that govern drug absorption: Solubility and Permeability.

Blood, Serum, or Plasma Drug Concentration–Time Profile

  • Characterization of the time course of a drug inside the body.
  • Administration of the same dose of different drugs to the same individual will produce different conc-time profiles. This is because different drugs have different absorption and disposition characteristics.
  • Administration of the same dose of a drug to different individuals will produce different conc-time profiles as well; the same drug can be absorbed, distributed, and eliminated at different rates in different individuals.

Bioavailability

  • Bioavailability (F): The fraction of drug dose of unchanged drug that reaches the systemic circulation.
  • Same drug in different dosage forms may have different bioavailability characteristics and different clinical effectiveness.

Fate of Drug After Absorption

  • Drug at the site of absorption.
  • Drug is absorbed.
  • Drug is distributed to different tissues.
  • Drug is metabolized.
  • Drug is excreted by the body by different means.
  • Pharmacokinetics: Kinetics of drug absorption, distribution, and elimination that deals with the time course of drug in the body (ADME).

Drug Metabolism or Biotransformation

  • Metabolism or biotransformation involves chemical changes to drugs within the body.
  • Results in one or more compounds that are:
    • More water-soluble
    • More ionized
    • Less capable of binding to proteins of the plasma and tissues
    • Less capable of being stored in fat tissue
    • Less able to penetrate cell membranes
  • Consequently, more easily excreted.
  • Also called detoxification or inactivation

Excretion of Drugs

  • Kidney (urine)
  • Feces
  • Lungs
  • Sweat
  • Saliva
  • Milk
  • Reabsorption of some drugs

Bioequivalence

  • Bioequivalence is a term in pharmacokinetics used to assess the expected in vivo biological equivalence of two different preparations of a drug.
  • "Two drug products (same API) are bioequivalent if, after drug administration of the same molar dose, their bioavailabilities are the same and provide similar effects with respect to safety and efficacy."
  • Should apply both in single or multiple administrations.
  • Results in vivo reflect the biopharmaceutics of the drug product.

Pharmacokinetic Basis of Bioequivalence

  • Based on these 3 parameters:
    1. Maximum drug concentration (Cpmax)
    2. Time to peak (tmax)
    3. Area under the drug concentration–time curve AUC (AUC{0→t(last)} and AUC{0→∞})

Physiological Factors

  • Physiological factors can affect the fate of drugs in the body and thereby have effects on their pharmacology and toxicology.

Factors Determining the Release and Absorption Kinetics of a Drug Following Oral Administration of a Solid Dosage Form

  • Release Characteristics of Dosage Form
    • Disintegration/deaggregation
    • Dissolution of drug from granules (also dependent on inactive ingredients and formulation variables)
  • Physicochemical Properties of Drug
    • Ionization (acid/base)
    • Partition coefficient (octanol/water)
    • Solubility in water
  • Physiology of Gastrointestinal Tract
    • Colonic retention
    • Gastric emptying
    • Intestinal motility
    • Perfusion of the gastrointestinal tract
    • Permeability of the gut wall
  • Gastrointestinal Tract Abnormalities and Diseases
    • Crohn's disease
    • Gastric resection (e.g., in obesity)
    • Diarrhea

Effect of Food

  • Delay gastric emptying
  • Stimulate bile flow
  • Change in pH of the GI tract
  • Increase splanchnic blood flow
  • Change in luminal metabolism of drug
  • Physical or chemical interaction of drug and meal