Section 2.7: Biopharmaceutics & Drug Delivery Systems

Section 2.7: Biopharmaceutics & Drug Delivery Systems

Introduction to Biopharmaceutics

Biopharmaceutics is the study of how the physical and chemical properties of a drug, its dosage form, and the route of administration affect the rate and extent of systemic drug absorption. It bridges formulation science and clinical pharmacokinetics. In this section, we examine the factors affecting bioavailability, the regulatory standards for establishing bioequivalence, the design of modified-release formulations, and advanced targeted drug delivery systems.

Factors Affecting Bioavailability

Bioavailability (F) is the fraction of an administered dose of unchanged drug that reaches the systemic circulation. For intravenous (IV) administration, bioavailability is 100% ($F = 1$). For oral administration, $F < 1$ (or 100%) due to incomplete absorption and first-pass metabolism. Bioavailability is calculated as: $F = \frac{[AUC]_{\text{oral}} \cdot \text{Dose}_{\text{IV}}}{[AUC]_{\text{IV}} \cdot \text{Dose}_{\text{oral}}}$

Bioavailability is influenced by several factors:

1. Physicochemical Factors:
   • Dissolution Rate: The rate-limiting step for absorption of poorly soluble drugs. Governed by the Noyes-Whitney Equation: $\frac{dC}{dt} = \frac{D \cdot A}{h} \cdot (C_s - C_b)$ where $dC/dt$ is the dissolution rate, $D$ is the diffusion coefficient, $A$ is the surface area of the drug particles, $C_s$ is the saturation solubility, $C_b$ is the concentration of drug in bulk solvent, and $h$ is the thickness of the stagnant diffusion layer. Reducing particle size (micronization) increases surface area ($A$), thereby accelerating dissolution and bioavailability.
   • Polymorphism: Drugs can exist in different crystalline forms (polymorphs) or amorphous states. Amorphous forms generally have higher solubility and dissolve faster than crystalline forms because they lack a rigid crystal lattice.
2. Physiological Factors:
   • First-Pass Hepatic Metabolism: Portal blood from the GI tract passes through the liver via the portal vein before entering the systemic circulation. Drugs with high hepatic extraction ratios (e.g., propranolol, nitroglycerin, morphine) are heavily metabolized during this first pass, resulting in low oral bioavailability.
   • Gastric Emptying and GI Motility: Rapid gastric emptying generally accelerates absorption because most drugs are absorbed in the small intestine. Food can delay gastric emptying, altering the $C_{\text{max}}$ and $T_{\text{max}}$ of drugs.

Bioequivalence Criteria and SFDA Standards

Two drug products are considered bioequivalent if they are pharmaceutical equivalents (contain the same active ingredient, strength, and dosage form) and show no significant difference in the rate and extent of absorption when administered at the same molar dose under similar experimental conditions.

Bioequivalence is determined by comparing three pharmacokinetic parameters in a crossover study in healthy human volunteers:

• Area Under the Curve (AUC): Represents the total extent of drug exposure.
• Maximum Concentration ($C_{\text{max}}$): Represents both the rate and extent of absorption.
• Time to Maximum Concentration ($T_{\text{max}}$): Represents the rate of absorption.

SFDA Regulatory Standard: For a generic drug to be approved by the Saudi Food and Drug Authority (SFDA), the manufacturer must demonstrate bioequivalence to the reference brand product. The 90% confidence interval (CI) of the ratio of the geometric means of the test (generic) to reference (brand) product for both AUC and $C_{\text{max}}$ must fall entirely within the range of 80.00% to 125.00%.

Modified-Release Formulations

Modified-release dosage forms alter the time or rate of drug release to achieve therapeutic goals, such as improving compliance or reducing adverse effects.

• Delayed-Release (Enteric Coating): Protects the drug from gastric acid or protects the stomach from drug-induced irritation (e.g., enteric-coated aspirin). Enteric coatings use pH-dependent polymers (e.g., Cellulose Acetate Phthalate [CAP], hydroxypropyl methylcellulose phthalate, or Eudragit). These polymers possess free carboxylic acid groups that are insoluble at acidic gastric pH (<5) but ionize and dissolve rapidly at pH >6 in the duodenum, releasing the drug.
• Extended-Release (ER/XR): Designed to release the drug slowly over an extended period, maintaining therapeutic blood levels and reducing dosing frequency.
  • Diffusion-Controlled Systems:
    • Reservoir: The drug core is surrounded by a water-insoluble polymeric membrane. Water diffuses in, dissolves the drug, and the drug diffuses out. Danger: Crushing or chewing these tablets destroys the membrane, leading to dose dumping.
    • Matrix: The drug is uniformly dispersed in an insoluble polymer or lipid matrix. The drug slowly diffuses out of the matrix channels.
  • Osmotic-Controlled Systems (OROS - Osmotic Release Oral System): The tablet consists of an osmotic core containing the drug and an osmotic agent (e.g., sodium chloride), surrounded by a semipermeable membrane. The membrane allows water to enter the tablet, creating osmotic pressure that pushes the drug suspension or solution out through a laser-drilled orifice at a constant, zero-order rate. The release rate is independent of GI pH and motility (e.g., nifedipine XL, Concerta).

Novel and Targeted Drug Delivery Systems (NDDS)

Advanced delivery systems target drug release to specific tissues, maximizing efficacy and minimizing off-target toxicities.

• Liposomes: Spherical vesicles composed of one or more lipid bilayers enclosing an aqueous core. Hydrophilic drugs are encapsulated in the aqueous core, while hydrophobic drugs are dissolved within the lipid bilayer.
  • Stealth Liposomes (PEGylated Liposomes): Traditional liposomes are quickly cleared from blood by the mononuclear phagocyte system (MPS) in the liver and spleen. Modifying the liposome surface with polyethylene glycol (PEG) chains creates a hydration barrier that prevents opsonization, allowing the liposomes to evade macrophage detection and circulate in the bloodstream for days (e.g., pegylated liposomal doxorubicin / Doxil).
• Targeting Mechanisms:
  • Passive Targeting: Relies on the physiological characteristics of the target tissue. Tumors have leaky vasculature and poor lymphatic drainage, allowing liposomes and nanoparticles to accumulate preferentially in tumor tissue. This is known as the Enhanced Permeability and Retention (EPR) effect.
  • Active Targeting: Attaching specific ligands (e.g., monoclonal antibodies, transferrin, folate) to the surface of nanoparticles or liposomes. These ligands bind to receptors overexpressed on target cancer cells, triggering receptor-mediated endocytosis of the delivery system.