Unit 2: Sustained & Controlled Release Dosage Forms

Sustained and controlled release systems are engineered to release an active pharmaceutical ingredient (API) at predefined rates over extended periods, thereby maintaining therapeutic drug levels and improving patient compliance.

1. Definitions

• Sustained Release (SR):
  Formulations that prolong drug release beyond that of an immediate‑release dosage form, typically reducing dosing frequency but exhibiting a gradually declining release rate.

• Controlled Release (CR):
  Systems designed to deliver drug at a constant, predictable rate (often zero‑order kinetics), maintaining plasma concentrations within the therapeutic window for the designated period.

2. Design Principles

1. Rate‑Controlling Membranes (Reservoir Systems)

   • Structure: Core containing API surrounded by a polymer membrane.

   • Mechanism: Drug diffuses through membrane pores; polymer thickness and pore size govern release rate.

2. Matrix Systems

   • Hydrophilic Matrices: Hydrate upon contact with gastrointestinal fluids; gel layer controls diffusion and erosion (e.g., HPMC-based tablets).

   • Hydrophobic Matrices: API dispersed in insoluble polymer (e.g., ethylcellulose); drug release via diffusion through polymer channels.

3. Osmotic Pumps

   • Design: Semi‑permeable membrane encloses core with API and osmogen.

   • Mechanism: Water influx generates osmotic pressure, forcing drug solution out through a delivery orifice at near zero‑order rate (e.g., OROS® systems).

4. Multiparticulate Systems (Pellets, Beads)

   • Structure: Small coated units each functioning as a micro‑reservoir or matrix.

   • Advantage: Uniform GI transit, reduced risk of dose dumping, flexible release profiles via varying coat thickness.

3. Examples & Applications

4. Advantages & Limitations

• Advantages:

  • Reduced dosing frequency enhances adherence.

  • Stable plasma levels minimize peaks and troughs, reducing side‑effects.

  • Flexibility in tailoring release profiles via polymer selection and coat thickness.

• Limitations:

  • Complex manufacturing with stringent quality controls.

  • Risk of dose dumping if membrane ruptures or coating defects occur.

  • Higher cost relative to immediate‑release forms.

  • Inappropriate for drugs with very short half‑lives (<2 h), narrow therapeutic indices, or those requiring rapid onset.

5. Evaluation Methods

• In Vitro Release Testing:

  • USP apparatus I/II (basket or paddle) under simulated GI conditions; sampling over time to generate release profiles.

• Kinetic Modeling:

  • Fit data to zero‑order, first‑order, Higuchi, or Korsmeyer–Peppas models to elucidate release mechanisms.

• In Vivo Correlation:

  • Establish IVIVC (in vitro–in vivo correlation) to predict clinical performance.

6. Key Exam Tips

• Differentiate zero‑order vs. first‑order release kinetics and name a system for each.

• Diagram a reservoir tablet, labeling core, rate‑controlling membrane, and delivery orifice.

• List three physicochemical properties of APIs that influence suitability for SR/CR (e.g., solubility, dose size, half‑life).

• Explain IVOS (in vitro–in vivo) Level A correlation and its regulatory importance.

Shall we move on to Unit 4.3: Targeted Drug Delivery Systems, or would you like any clarifications here?

Unit 3: Targeted Drug Delivery Systems

Targeted Drug Delivery Systems (TDDS) are designed to concentrate a therapeutic agent at its site of action while minimizing systemic exposure, thereby improving efficacy and reducing off‑target side effects.

1. Definition & Rationale

• Definition:
  A drug delivery approach that employs carrier systems or molecular modifications to direct drugs specifically to targeted tissues, cells, or organelles.

• Rationale:

  • Enhance therapeutic index by raising local drug concentration at disease sites (e.g., tumors).

  • Reduce systemic toxicity by preventing widespread distribution of potent agents.

  • Overcome biological barriers (e.g., blood–brain barrier, cellular membranes) via specialized carriers or ligands.

2. Mechanisms of Targeting

1. Passive Targeting

   • Enhanced Permeability and Retention (EPR) Effect: Leaky tumor vasculature and poor lymphatic drainage allow nanoparticles (100–200 nm) to accumulate preferentially in tumor tissue.

   • Macrophage Uptake: Liposomes and particulates are naturally taken up by the reticuloendothelial system (useful for targeting liver or spleen).

2. Active Targeting

   • Ligand–Receptor Interactions: Surface functionalization of carriers with ligands (antibodies, peptides, vitamins) that bind receptors overexpressed on target cells.

   • Examples of Ligands:

     • Folate for folate‑receptor–positive cancers.

     • Transferrin for brain delivery via transferrin receptor–mediated transcytosis.

     • Antibodies (e.g., trastuzumab) on liposomes or nanoparticles.

3. Physical Targeting

   • Magnetic Targeting: Magnetic nanoparticles guided by external magnetic fields to localize at a specific site.

   • Ultrasound‑Triggered Release: Microbubbles or echogenic liposomes burst upon ultrasound exposure, releasing their payload at the target.

3. Carrier Systems

4. Design Considerations

• Particle Size & Surface Properties:

  • 50–200 nm diameter for optimal EPR.

  • Surface charge: neutral or slightly negative to minimize opsonization.

• Stability & Stealth:

  • PEGylation to evade immune recognition and prolong circulation half‑life.

  • Surface coatings to resist protein adsorption (“protein corona”).

• Ligand Density & Binding Affinity:

  • Balance between multivalent binding and off‑target interactions.

  • Control ligand density to optimize targeting without compromising pharmacokinetics.

5. Evaluation of Targeting Efficiency

1. In Vitro

   • Binding assays: Measure ligand–receptor interactions (e.g., ELISA, flow cytometry).

   • Cellular Uptake Studies: Quantify internalization in target vs. non‑target cells (fluorescence microscopy, quantitative assays).

2. In Vivo

   • Biodistribution Studies: Radiolabel or fluorescently label carriers and track organ/tumor accumulation in animal models.

   • Therapeutic Efficacy: Compare tumor growth inhibition or survival in treated vs. control groups.

   • Toxicity Assessment: Monitor off‑target organ toxicity (histopathology, serum biomarkers).

6. Advantages & Limitations

• Advantages:

  • Enhanced drug accumulation at disease sites leading to improved outcomes.

  • Reduced systemic side effects and lower required doses.

  • Potential for combinatorial therapies (e.g., co‑delivery of drugs and imaging agents).

• Limitations:

  • Heterogeneous tumor vasculature can limit EPR-based accumulation.

  • Immunogenicity or hypersensitivity reactions to carrier materials.

  • Complex manufacturing and scale‑up challenges.

  • High development and regulatory costs.

7. Key Exam Tips

• Differentiate passive vs. active vs. physical targeting with one example each.

• List four carrier systems used in TDDS and a key feature of each.

• Explain why PEGylation enhances circulation time and how it is achieved.

• Outline an in vivo study design to assess biodistribution of a targeted nanoparticle.

Unit 4: Vesicular Systems – Liposomes & Niosomes

Vesicular systems are spherical carriers with one or more bilayer membranes that encapsulate drugs, enabling both hydrophilic and lipophilic compounds to be delivered effectively. Two principal types—liposomes and niosomes—offer customizable properties for targeted and controlled release applications.

1. Definitions & Structure

• Liposomes:

  • Definition: Self‑assembling vesicles comprised of phospholipid bilayers enclosing an aqueous core.

  • Structure:

    • Inner Aqueous Core: Encapsulates water‑soluble drugs.

    • Lipid Bilayer(s): Phosphatidylcholine, phosphatidylethanolamine, cholesterol stabilize the membrane; can form uni‑ or multilamellar vesicles.

• Niosomes:

  • Definition: Non‑ionic surfactant vesicles analogous to liposomes, where the bilayer is formed from surfactants (e.g., Span, Tween) and cholesterol.

  • Structure:

    • Surfactant Bilayer: Hydrophilic head groups face aqueous phases; hydrophobic tails form the membrane core.

    • Cholesterol: Incorporated to enhance membrane rigidity and stability.

2. Preparation Methods

1. Thin Film Hydration (Bangham Method):

   • Dissolve lipids or surfactants in organic solvent; evaporate to form thin film; hydrate with aqueous drug solution to yield multilamellar vesicles.

2. Reverse‑Phase Evaporation:

   • Emulsify aqueous drug solution in organic phase containing lipids; remove solvent under reduced pressure to form large unilamellar vesicles with high encapsulation efficiency.

3. Ether Injection:

   • Rapid injection of lipid‑containing ether solution into heated aqueous medium; vesicles form upon ether evaporation.

4. Microfluidization & Sonication:

   • Apply energy to reduce vesicle size and polydispersity, yielding small unilamellar vesicles (<100 nm).

3. Drug Encapsulation & Release Mechanisms

• Hydrophilic Drugs: Localize in the aqueous core; release via diffusion through the bilayer.

• Lipophilic Drugs: Partition into the lipid bilayer; release as bilayer degrades or through partitioning into biological membranes.

• Release Control: Adjust lipid composition, cholesterol content, and vesicle size to modulate membrane permeability and circulation half‑life.

4. Surface Modification & Targeting

• PEGylation (Stealth Liposomes/Niosomes):

  • Graft polyethylene glycol chains onto vesicle surface to evade recognition by the mononuclear phagocyte system, extending blood circulation time.

• Ligand Conjugation:

  • Attach antibodies, peptides, or small molecules to vesicle surface for active targeting to specific cell receptors.

5. Applications

6. Advantages & Limitations

• Advantages:

  • Encapsulation of both hydrophilic and lipophilic drugs.

  • Biocompatible and biodegradable (liposomes).

  • Reduced systemic toxicity through targeted delivery.

  • Surface modification enables “stealth” behavior and active targeting.

• Limitations:

  • Physical/chemical stability issues: vesicle aggregation, drug leakage.

  • High production costs and complex scalability.

  • Potential for rapid clearance by the reticuloendothelial system if not PEGylated.

  • Limited loading capacity for certain drugs.

7. Evaluation & Characterization

• Vesicle Size & Distribution: Dynamic light scattering (DLS) for mean diameter and polydispersity index.

• Zeta Potential: Surface charge measurement indicates colloidal stability.

• Encapsulation Efficiency: Quantify the percentage of drug entrapped vs. total drug added.

• In Vitro Release: Dialysis or Franz diffusion cells to monitor release kinetics under physiological conditions.

• Morphology: Transmission electron microscopy (TEM) or cryo‑TEM to visualize vesicle structure.

8. Key Exam Tips

• Compare liposomes vs. niosomes in terms of components, stability, and cost.

• Outline one preparation method (e.g., thin film hydration) step by step.

• List three factors affecting encapsulation efficiency.

• Explain how PEGylation prolongs circulation and prevents opsonization.

Unit 4.5: Micro‑ & Nanoparticulate Systems

Micro‑ and nanoparticulate systems encompass solid particles sized from nanometers (1–1,000 nm) to micrometers (1–100 µm), designed to control release, enhance bioavailability, and target drugs to specific tissues.

1. Definitions

• Microspheres / Microcapsules:
  Spherical particles (1–100 µm) in which the drug is either dispersed within a polymer matrix (microsphere) or enclosed within a polymer shell (microcapsule).

• Nanoparticles:
  Particles <1,000 nm, including polymeric nanoparticles, solid lipid nanoparticles (SLNs), and nanocrystals, engineered for enhanced cellular uptake, lymphatic transport, or CNS delivery.

2. Materials & Composition

• Polymers:

  • Biodegradable: PLA, PLGA, PCL—degrade into non‑toxic monomers.

  • Non‑biodegradable: Ethylcellulose—requires removal or remains as depot.

• Lipids:

  • SLNs: Solid lipid cores (e.g., glyceryl behenate) stabilized by surfactants.

  • Nanostructured Lipid Carriers (NLCs): Blend of solid and liquid lipids to improve drug loading.

• Inorganic:

  • Mesoporous silica nanoparticles (MSNs): High surface area, tunable pore sizes.

  • Gold & Iron Oxide: For imaging, hyperthermia, or magnetic targeting.

3. Preparation Techniques

1. Emulsion‑Solvent Evaporation

   • Oil‑in‑water emulsion of polymer solution; solvent evaporation yields solid particles.

2. Salting‑Out / Precipitation

   • Polymer and drug dissolved in water‑miscible solvent; rapid mixing into non‑solvent precipitates nanoparticles.

3. High‑Pressure Homogenization

   • Lipid melt homogenized under high pressure; cooling solidifies droplets into SLNs.

4. Spray Drying

   • Aqueous suspension atomized into hot air; solvent evaporation forms dry microparticles.

5. Supercritical Fluid Technology

   • Use of supercritical CO₂ to precipitate particles with narrow size distribution.

4. Drug Loading & Release Mechanisms

• Encapsulation Efficiency (EE%): Ratio of drug entrapped vs. initial amount; influenced by polymer/drug solubility, method, and stabilizers.

• Release Profiles:

  • Diffusion‑controlled: Drug diffuses through polymer matrix.

  • Erosion‑controlled: Polymer degradation governs release.

  • Stimuli‑responsive: pH, temperature, enzymes trigger accelerated release.

5. Applications

6. Advantages & Limitations

• Advantages:

  • Controlled release and sustained plasma levels.

  • Enhanced solubility and bioavailability of poorly water‑soluble drugs.

  • Targeted delivery via size‑dependent tissue penetration or ligand attachment.

• Limitations:

  • Complex manufacturing and scale‑up challenges.

  • Potential cytotoxicity of certain nanomaterials.

  • Regulatory uncertainties for novel inorganic carriers.

  • Physical stability concerns: aggregation, sedimentation.

7. Characterization Techniques

• Particle Size & Distribution: Dynamic light scattering (DLS), laser diffraction.

• Morphology: Scanning/transmission electron microscopy (SEM/TEM).

• Surface Charge: Zeta potential to predict colloidal stability.

• Thermal Properties: DSC/TGA to assess polymer crystallinity and drug–polymer interactions.

• In Vitro Release: Dialysis, sample-and-separate methods under physiological conditions.

8. Key Exam Tips

• Differentiate microspheres vs. microcapsules vs. nanoparticles with definitions and size ranges.

• List three preparation methods and a key advantage of each (e.g., supercritical fluids for narrow size).

• Explain how polymer selection (e.g., PLA vs. PLGA) affects degradation rate and release kinetics.

• Describe one application that leverages the enhanced permeability of nanoparticles in cancer therapy.