B Pharmacy Sem 3: Pharmaceutics II
Subject : Pharmaceutics II
1. Sterile Product Technology: Parenteral Preparations
2. Aseptic Processing & Validation
3. Ophthalmic & Otic Dosage Forms
4. Inhalation & Pulmonary Drug Delivery Systems
5. Transdermal & Topical Delivery Systems
6. Introduction to Novel Drug Delivery (Nanoparticles, Liposomes)
Unit 1: Sterile Product Technology – Parenteral Preparations
This unit covers the design, formulation, sterilization, packaging, and quality control of parenteral (injectable) dosage forms, which must be free of viable microorganisms and pyrogens.
1.1 Classification of Parenteral Dosage Forms
1.1.1 Injectable Solutions
Type: True solutions of APIs in water, aqueous co‑solvent systems, or non‑aqueous vehicles.
Examples: Normal saline injections, diazepam injectable solution (propylene glycol).
1.1.2 Injectable Suspensions
Type: Solid drug particles dispersed in a liquid vehicle.
Considerations: Particle size (≤5 µm for IV), wetting agents, suspension stability.
Examples: Penicillin G potassium suspension, methylprednisolone acetate.
1.1.3 Emulsions
Type: Oil-in-water (O/W) or water-in-oil (W/O) systems to solubilize lipophilic drugs.
Stabilizers: Emulsifying agents (lecithin, poloxamers).
Example: Propofol injectable emulsion.
1.1.4 Lyophilized (Freeze‑Dried) Powders
Purpose: Improves stability of labile drugs.
Process: Freezing → primary drying (sublimation) → secondary drying (desorption).
Reconstitution: Sterile diluent added prior to administration (e.g., vancomycin HCl).
1.2 Formulation Considerations
1.2.1 Solvent & Vehicle Selection
Aqueous vehicles: WFI (Water for Injection), Bacteriostatic Water.
Non‑aqueous vehicles: Fixed oils (sesame oil), polyethylene glycol.
Co‑solvents: Ethanol, propylene glycol for poorly water‑soluble drugs.
1.2.2 pH & Tonicity Adjustment
pH range: Typically 4–8 to minimize pain and tissue irritation.
Buffers: Phosphate, citrate to maintain pH.
Isotonicity: 0.9% NaCl or 5% dextrose equivalence.
1.2.3 Excipients
Preservatives: Parabens, benzyl alcohol (multi‑dose vials only).
Antioxidants: Sodium metabisulfite, ascorbic acid.
Chelating agents: EDTA to complex trace metals.
1.3 Manufacturing Process & Equipment
1.3.1 Clean‐Room Environment
Classifications: ISO 5 (critical zone), ISO 7–8 (background).
Airflow: Unidirectional (laminar) flow hoods for aseptic filling.
1.3.2 Sterile Filtration & Filling
Filtration: 0.22 µm membrane filters remove microorganisms (for heat‑sensitive solutions).
Filling: Automated peristaltic or piston fillers under ISO 5 conditions.
1.3.3 Lyophilization Cycle
Freezing: Controlled to avoid eutectic collapse.
Primary drying: Chamber pressure <100 mTorr, shelf temperature optimization.
Secondary drying: Elevated shelf temperature to remove bound water.
1.4 Sterilization Methods
| Method | Mechanism | Typical Uses |
|---|---|---|
| Moist Heat (Autoclaving) | Denaturation of proteins | Glassware, aqueous solutions (not heat‑sensitive) |
| Dry Heat | Oxidation & protein damage | Empty containers, oils, syringes |
| Filtration Sterilization | Physical removal | Heat‑labile solutions, biologicals |
| Radiation (γ or e‑beam) | DNA damage in microbes | Pre‑sterilized single‑use devices |
| Ethylene Oxide Gas | Alkylation of cell components | Medical device packaging |
1.5 Container Closure Systems
1.5.1 Ampoules
Material: Type I borosilicate glass.
Sealing: Flame‑sealed neck to ensure integrity.
1.5.2 Vials
Stopper: Rubber or elastomeric; must be chemically compatible and allow needle penetration without coring.
Crimp Seal: Aluminum cap to secure stopper.
1.5.3 Prefilled Syringes & Cartridges
Advantages: Dose accuracy, reduced contamination risk.
Materials: Glass or cyclic olefin polymer; silicone‑lubricated plungers.
1.6 Quality Control Tests
1.6.1 Sterility Testing
Method: Direct inoculation or membrane filtration per pharmacopeial <71>.
Media: Fluid thioglycollate (anaerobes) and soybean–casein digest (aerobes).
1.6.2 Pyrogen/Endotoxin Testing
LAL Test: Limulus amebocyte lysate assay for bacterial endotoxins (<0.25 EU/mL for IV).
Rabbit Pyrogen Test: Historical in vivo method (used less frequently).
1.6.3 Particulate Matter
Limits: ≤6000 particles ≥10 µm and ≤600 particles ≥25 µm per container for small‑volume injectables.
Test: Light obscuration counting.
1.6.4 Physical & Chemical Tests
Clarity & Color: Visual inspection under defined illumination.
pH & Osmolality: Ensures compatibility with blood.
Assay & Degradation Products: HPLC or titrimetric analysis.
1.7 Pharmaceutical Examples
Gentamicin Injection: Aqueous solution, autoclaved in sealed ampoules.
Ceftriaxone for Injection: Lyophilized powder reconstituted with sterile water.
Etomidate Injectable Emulsion: Oil-in-water emulsion sterilized by filtration.
1.8 Key Points for Exams
Classify parenteral dosage forms and list one example of each.
Explain formulation requirements for pH, tonicity, and excipient selection.
Describe the principles and applications of at least two sterilization methods.
Outline the sterile-filtration and aseptic-filling process in an ISO 5 environment.
List four critical quality‑control tests for parenteral preparations and their acceptance criteria.
Unit 2: Aseptic Processing & Validation
This unit delves into the principles and practices that ensure parenteral products remain sterile from formulation through final packaging, and the qualification of facilities, equipment, and processes to guarantee consistent aseptic manufacture.
2.1 Principles of Aseptic Processing
Definition: Operations performed under controlled, sterile conditions to prevent microbial contamination of sterile products.
Core Elements:
Controlled Environment: Cleanrooms with defined airflow, pressurization, temperature, and particulate/microbial limits.
Personnel Practices: Gowning, aseptic techniques, and behavior designed to minimize contamination.
Sterile Components: Use of sterilized inputs (solutions, containers, closures).
Closed Systems: Minimizing open handling of sterile materials; use of barrier isolators and restricted-access barriers.
2.2 Cleanroom Design & Classification
2.2.1 ISO Cleanroom Classes
| ISO Class | Maximum Particles ≥0.5 µm per m³ | Typical Applications |
|---|---|---|
| ISO 5 | 3,520 | Critical zones (fill/finish) |
| ISO 7 | 352,000 | Background areas |
| ISO 8 | 3,520,000 | Support operations |
Air Changes per Hour (ACH): ISO 5 requires ≥240 ACH; lower classes require progressively fewer.
Pressure Differentials: Positive pressure in cleaner areas relative to adjacent zones (e.g., +15–20 Pa).
2.2.2 Airflow Patterns
Unidirectional (Laminar) Flow: HEPA‑filtered air moving in parallel streams; used in ISO 5 zones.
Non‑Unidirectional (Turbulent) Flow: Mixing airflow in ISO 7/8 zones; still HEPA‑filtered but less critical.
2.3 Personnel & Aseptic Technique
2.3.1 Gowning Procedure
Sequence: Shoe covers → hair cover → face mask → sterile gown → sterile gloves.
Materials: Low‑shedding, lint‑free fabrics; sterile, powder‑free gloves.
2.3.2 Operational Practices
Entry/Exit Protocols: Airlocks with sequential gowning and hand‑scrub stations.
Movement: Slow, deliberate motions; minimal talking; avoid crossing critical airflow paths.
Sterile Field Management: Maintain one‑inch‑away rule—keep non‑sterile items at least one inch from critical surfaces.
2.4 Process Validation for Aseptic Manufacturing
2.4.1 Installation Qualification (IQ)
Verifies that equipment and utilities (HVAC, isolators, airlocks) are installed per design specifications.
Documents: Equipment specifications, calibration records, piping and instrumentation diagrams.
2.4.2 Operational Qualification (OQ)
Confirms that each system component operates according to its intended limits.
Tests: Airflow velocity mapping, HEPA filter integrity (DOP/PARFOG challenge), differential pressure alarms.
2.4.3 Performance Qualification (PQ)
Demonstrates that routine production under worst‑case conditions yields sterile products.
Activities: Media fill (process simulation) runs, environmental monitoring, operator challenge studies.
2.5 Media Fill Simulation
Objective: To simulate the aseptic filling process using a microbiological growth medium instead of product solution to detect contamination events.
Procedure:
Prepare sterile culture medium in all product contact containers and closures.
Run full-scale simulated fill under normal conditions and personnel.
Incubate filled units at 20–25 °C for 7 days, then 30–35 °C for 7 days.
Evaluate turbidity or colony formation; no contamination indicates process control.
Acceptance Criteria: Zero positive units for ISO 5 processes; low-level positives may be permitted under tightly controlled investigations.
2.6 Environmental Monitoring
2.6.1 Monitoring Parameters
Viable Particulates:
Air Sampling: Active (SAS) and passive (settle plates) methods in critical zones.
Surface Sampling: Contact plates, swabs, and wipes on work surfaces, equipment, gloves.
Non‑Viable Particulates: Continuous particle counters to ensure ISO classification compliance.
2.6.2 Alert & Action Limits
Alert Level: Early warning threshold (e.g., 1 CFU/m³ in ISO 5).
Action Level: Indicates process may be out of control; triggers root cause investigation and corrective actions.
2.7 Equipment & Process Controls
Automated Filling Machines: Validated for precision, accuracy, and sterility assurance.
Barrier Technologies: Isolators and Restricted Access Barrier Systems (RABS) to further reduce contamination risk.
Cleaning & Sanitization: Validated cleaning agents, schedules, and rinse sampling to confirm removal of residues and bioburden.
2.8 Key Points for Exams
Define aseptic processing and list its four core elements.
Describe cleanroom classification (ISO 5–8), airflow types, and pressure differentials.
Outline the gowning sequence and two critical aseptic techniques.
Differentiate IQ, OQ, and PQ in process validation.
Explain media fill methodology and acceptance criteria for aseptic filling.
List environmental monitoring methods for viable and non‑viable particulates, and define alert/action limits.
Unit 3: Ophthalmic & Otic Dosage Forms
This unit details the formulation, manufacture, and quality control of sterile preparations for administration to the eye (ophthalmic) and ear (otic), emphasizing the specialized requirements for safety, efficacy, and patient comfort.
3.1 General Requirements for Ophthalmic & Otic Preparations
Sterility: Must be free of viable microorganisms (terminal sterilization or sterile filtration).
Isotonicity: Approximate to tear fluid (~0.9% NaCl, 300 mOsm/kg) to avoid irritation or cell damage.
pH & Buffering:
Ophthalmic: pH 7.0–7.4 preferred (range 6.5–8.5 acceptable).
Otic: pH 5.0–7.5 to match ear canal environment and drug stability.
Viscosity & Rheology: Optimized to prolong residence time without blurring vision (ophthalmic) or causing discomfort (otic).
Preservatives: Only if multi‑dose; must be non‑toxic to sensitive mucosa (e.g., benzalkonium chloride, chlorobutanol).
Packaging: Light‑resistant, hermetically sealed containers with sterile droppers or applicators.
3.2 Ophthalmic Dosage Forms
3.2.1 Eye Drops (Solutions & Suspensions)
Solutions:
Clear, sterile aqueous vehicles (WFI) with dissolved API.
Must be filtered through 0.22 µm membranes.
Suspensions:
Finely divided drug (mean particle size ≤10 µm) dispersed in vehicle.
Require wetting agents (e.g., polysorbate 80) and suspending agents (e.g., methylcellulose).
Formulation Considerations
| Parameter | Target Range/Agent | Rationale |
|---|---|---|
| Tonicity | 0.6–1.8% NaCl equivalent | Comfort, prevents corneal swelling |
| pH | 6.5–8.5 | Minimize irritation, maintain drug stability |
| Viscosity | 15–25 cP (drops) | Longer contact time, acceptable blinking |
| Preservative | Benzalkonium chloride 0.01–0.02% | Broad‑spectrum antimicrobial |
3.2.2 Ophthalmic Ointments & Gels
Ointments:
Semi‑solid vehicles (e.g., petrolatum–mineral oil) for prolonged contact.
Lower drug release rate; used at night.
Gels & In Situ Gelling Systems:
Polymers (carbomers, Pluronic) that gel upon contact with tear fluid.
Combine ease of instillation with extended retention.
3.2.3 Ophthalmic Inserts & Implantables
Soluble Inserts: Cellulose acetate or gelatin rods that dissolve, releasing drug over hours.
Contact‑Lens Systems: Drug‑loaded hydrogel lenses for sustained delivery.
Implants: Biodegradable polymers (e.g., PLGA) for long‑term therapy (weeks–months).
3.3 Otic Dosage Forms
3.3.1 Ear Drops (Solutions & Suspensions)
Solutions: Sterile aqueous or mixed solvent (propylene glycol–water) for antibiotics, antiseptics.
Suspensions: Suspended corticosteroids, cerumenolytics; particle size ≤50 µm.
3.3.2 Otic Gels & Powders
Gels: Carbomer or cellulose-based to adhere to canal walls and prolong retention.
Powders: Boric acid or aluminum acetate powders for dryness and mild antisepsis.
3.4 Manufacturing & Packaging
3.4.1 Aseptic Processing
Conducted in ISO 5 laminar‑flow hoods.
Components sterilized by filtration or autoclaving before filling.
3.4.2 Fill‑Finish & Container Closure
Droppers & Pipettes: Low‑dead‑volume designs to ensure accurate dosing.
Multi‑Dose Vials: Incorporate validated preservative; single‑dose units avoid preservatives.
3.4.3 Labeling & Patient Instructions
Indicate “For Ophthalmic Use Only” or “For Otic Use Only.”
Include directions for instillation angle, number of drops, and avoidance of contamination.
3.5 Quality Control Tests
| Test | Ophthalmic | Otic |
|---|---|---|
| Sterility | Membrane filtration per USP <71> | As above |
| Particulate Matter | Light obscuration (≤50 particles/mL ≥10 µm) | Visual/obscuration less critical but monitored |
| pH | 6.5–8.5 | 5.0–7.5 |
| Viscosity | Brookfield viscometer | Measured if gel form |
| Preservative Efficacy | USP <51> antimicrobial effectiveness test | If multi‑dose |
| Drop Size & Volume | ~25–50 µL/drop | 50–100 µL/drop |
3.6 Key Points for Exams
List two formulation differences between ophthalmic and otic drops.
Explain why ophthalmic solutions require smaller particle sizes than otic suspensions.
Describe three mechanisms by which in situ gelling systems prolong ocular drug contact.
Outline the sterility and particulate tests specific to eye drops.
Identify packaging features that prevent contamination and ensure accurate dosing for both dosage forms.
Unit 4: Inhalation & Pulmonary Drug Delivery Systems
This unit covers the science and technology underpinning delivery of drugs via the respiratory tract—including formulation design, device mechanics, aerosol physics, and quality control—to achieve local (e.g., asthma) or systemic (e.g., insulin) therapy through the lungs.
4.1 Introduction & Rationale
Advantages:
Rapid onset via large absorptive surface and thin alveolar–capillary membrane.
Targeted therapy for pulmonary diseases with reduced systemic side effects.
Non‑invasive alternative to injections for peptides and vaccines.
Anatomical Considerations:
Upper vs. Lower Airways: Mouth → trachea → bronchi → bronchioles → alveoli.
Deposition Sites: Determined by particle aerodynamic diameter.
4.2 Aerosol Physics & Deposition Mechanisms
4.2.1 Aerodynamic Particle Size
Mass Median Aerodynamic Diameter (MMAD): Critical metric; 1–5 µm particles reach lower airways.
Geometric Standard Deviation (GSD): Distribution breadth; tighter distribution (GSD < 1.5) improves predictability.
4.2.2 Deposition Mechanisms
Inertial Impaction: Particles >5 µm deposit in oropharynx and upper airways.
Gravitational Sedimentation: 1–5 µm particles settle in bronchioles and alveoli under gravity.
Brownian Diffusion: <1 µm particles deposit by diffusion in alveolar region or are exhaled.
4.3 Formulation Types & Devices
4.3.1 Pressurized Metered‑Dose Inhalers (pMDIs)
Propellants: Hydrofluoroalkanes (HFA‑134a, HFA‑227ea).
Formulation: Solution or suspension of API + co‑solvent (ethanol) + surfactant.
Actuation: Delivers metered plume; coordination with inhalation critical.
4.3.2 Dry Powder Inhalers (DPIs)
Formulation: Micronized API blended with larger carrier particles (lactose).
Device Types: Single‑dose, multi‑dose reservoir or blister.
Patient Effort: Inhalation flow de‑aggregates powder into respirable fraction.
4.3.3 Nebulizers
Jet Nebulizers: Compressed air or oxygen creates aerosol via Venturi effect.
Ultrasonic Nebulizers: Piezoelectric crystal generates high‑frequency vibration.
Mesh Nebulizers: Liquid pushed through micro‑pores; efficient, quiet.
4.3.4 Soft‑Mist Inhalers (SMIs)
Mechanism: Spring‑powered piston forces liquid through nozzle to generate fine mist.
Advantage: Slower plume velocity, longer aerosol cloud duration for ease of use.
4.4 Excipient Selection & Formulation Considerations
Solubility & Stability: API solubility in propellant or suspension media; use of co‑solvents.
Surfactants: Poloxamers or lecithin to stabilize suspensions in pMDIs.
Carrier Selection: Lactose monohydrate properties (particle size, surface roughness) for DPIs.
Hygroscopicity: Minimized to prevent powder agglomeration in DPIs.
Osmolarity & pH: For nebulized solutions, matched to pulmonary lining fluid (≈300 mOsm, pH 7.0–7.4).
4.5 Manufacturing & Quality Control
4.5.1 Filling & Assembly
pMDIs: Under low‑temperature, high‑pressure filling of propellant–API blend into canisters, crimping with metering valve.
DPIs: Blend milling → mixing → capsule or reservoir filling → sealing to protect from moisture.
4.5.2 Critical Quality Attributes
| Attribute | Method | Acceptance Criteria |
|---|---|---|
| Delivered Dose Uniformity | Dose collection apparatus (e.g., Copley) | RSD ≤10% across 10 doses |
| Aerodynamic Particle Size Distribution | Cascade impactor or laser diffraction | MMAD 1–5 µm; FPF (≤5 µm) >30% |
| Spray Pattern & Plume Geometry (pMDI/SMI) | High‑speed photography | Consistent plume angle (e.g., 15°–30°) and shot weight |
| Moisture Content (DPI) | Karl Fischer titration | <1% w/w |
| Microbial Load & Sterility (Nebulizer Solutions) | USP <61>/<71> | Sterile; bioburden limits as per pharmacopeia |
4.5.3 Stability Testing
Accelerated Conditions: 40 °C/75% RH for 6 months.
Propellant Compatibility: Check valve and canister integrity, spray characteristics over time.
4.6 Pharmacokinetics & Clinical Applications
Local Delivery: β₂‑agonists, corticosteroids for asthma/COPD; rapid bronchodilation and anti‑inflammation.
Systemic Delivery: Insulin, calcitonin—avoids needle‑related issues; absorption correlates with particle size and formulation matrix.
Dose Scaling: Fine‑tune inhaled dose based on lung deposition efficiency (~10–20% of nominal dose reaches deep lung).
4.7 Key Points for Exams
Define MMAD and explain its impact on regional lung deposition.
Compare pMDIs vs. DPIs in terms of formulation, patient technique, and advantages.
List three deposition mechanisms and the particle size range each governs.
Outline the steps and critical parameters in pMDI canister filling.
Describe two quality‑control tests for inhalation aerosols and their acceptance criteria.
Unit 5: Transdermal & Topical Delivery Systems
This unit explores drug delivery across and into the skin for both local (topical) and systemic (transdermal) therapy, covering skin physiology, formulation strategies, permeation enhancement, product types, manufacturing, and quality control.
5.1 Skin Structure & Barrier Function
5.1.1 Layers of Skin
Stratum Corneum: Outermost, keratin‑rich dead cell layer; primary barrier to drug penetration (~10–20 µm thick).
Epidermis: Viable cell layers beneath the stratum corneum; limited diffusional resistance.
Dermis: Vascularized connective tissue; site of systemic drug uptake.
Hypodermis: Fatty layer; minor role in transdermal uptake.
5.1.2 Routes of Penetration
Intercellular: Through lipid matrix between corneocytes (major route).
Transcellular: Across corneocytes and lipid bilayers (less common).
Appendageal: Via hair follicles and sweat ducts (minor, but faster for large molecules).
5.2 Transdermal Drug Delivery Systems (TDDS)
5.2.1 Advantages & Limitations
Advantages:
Bypasses first‑pass metabolism.
Provides controlled, sustained release.
Improves patient compliance.
Limitations:
Only potent, low‑dose drugs with suitable lipophilicity (log P 1–3) and molecular weight (<500 Da).
Skin irritation and sensitization risks.
5.2.2 Design Principles
| Parameter | Target/Strategy | Rationale |
|---|---|---|
| Drug Properties | MW < 500 Da; log P 1–3; low melting point | Facilitates skin permeation |
| Flux (J) | Maintain therapeutic flux (µg/cm²·h) | Controlled plasma levels |
| Patch Size & Loading | Balance dose with skin area tolerated | Minimize irritation, maximize compliance |
| Reservoir vs. Matrix | Reservoir: liquid/semi‑solid drug chamber; Matrix: drug dispersed in polymer | Matrix simpler, lower risk of dose dumping |
5.2.3 Patch Types
Matrix (Drug‑in‑Adhesive): Drug blended into adhesive layer; simplest design.
Reservoir: Drug solution or gel in a compartment; rate‑controlling membrane separates drug from skin.
Microreservoir: Drug micro‑droplets within polymer matrix combining features.
Drug‑in‑Adhesive on Film: Adhesive layer directly contacts skin, on backing film.
5.2.4 Permeation Enhancers
Chemical Enhancers: Ethanol, propylene glycol, oleic acid disrupt lipid bilayer.
Physical Methods: Iontophoresis (electrical current), sonophoresis (ultrasound), microneedles.
5.3 Topical Dosage Forms
5.3.1 Semisolid Preparations
Ointments: Hydrophobic bases (petrolatum, lanolin); occlusive, increase hydration and permeation.
Creams: Oil‑in‑water or water‑in‑oil emulsions; non‑greasy, patient‑friendly.
Gels: Hydrophilic polymer networks (carbomer, cellulose); rapid release, cooling effect.
Pastes: High powder content in ointment base; protective barrier for exuding lesions.
5.3.2 Solutions & Lotions
Aqueous or hydroalcoholic solutions for antiseptics, anti‑inflammatories; easy spreadability.
Lotions: Low‑viscosity suspensions or emulsions for hairy areas.
5.3.3 Transdermal Patches vs. Topical Formulations
| Feature | Transdermal Patch | Topical Cream/Gel |
|---|---|---|
| Purpose | Systemic drug delivery | Local skin/site-specific action |
| Contact Duration | 24 h or longer | Minutes to hours |
| Dose Control | Metered release by design | Less precise; depends on patient use |
5.4 Manufacturing & Packaging
5.4.1 Patch Fabrication
Coating/Printing: Adhesive/drug matrix coated onto backing film.
Lamination: Layering backing, drug matrix, release liner.
Cutting/Die‑Punching: Defined patch shapes.
Packaging: Aluminum pouches for moisture and light protection.
5.4.2 Semisolid Production
Homogenization: Uniform drug dispersion in base using high‑shear mixers.
Emulsification: Controlled temperature and stirring for O/W or W/O creams.
Filling: Tubes or jars under hygienic conditions.
5.5 Quality Control Tests
| Test | TDDS | Topical Semisolids |
|---|---|---|
| Content Uniformity | Single‑unit assay (HPLC) | Sampling from multiple sites in batch |
| In Vitro Release | Franz diffusion cell; receptor medium | Franz cell with synthetic membranes |
| Adhesion & Tack | Peel‑strength test; shear‑adhesion | Not applicable |
| Skin Irritation (In Vitro/In Vivo) | 3D skin models; patch test in volunteers | Patch test; Draize test in animals |
| Viscosity & Rheology | — | Brookfield viscometer; spreadability |
| Microbial Limits | Bioburden per USP <61>; preservative efficacy <51> | Bioburden and preservative efficacy |
5.6 Pharmaceutical Examples
Transdermal:
Nicotine Patch: Matrix system for smoking cessation.
Fentanyl Patch: Reservoir system for chronic pain.
Topical:
Hydrocortisone Cream: Emulsion for dermatitis.
Diclofenac Gel: Carbomer gel for musculoskeletal pain.
5.7 Key Points for Exams
Contrast matrix vs. reservoir patch designs and list one advantage of each.
Describe two chemical permeation enhancers and their mode of action.
Explain why the stratum corneum is the rate‑limiting barrier in transdermal delivery.
Outline the Franz diffusion cell setup and the parameters measured.
List three semisolid topical dosage forms and one key QC test for each.
Unit 6: Introduction to Novel Drug Delivery (Nanoparticles, Liposomes)
This unit introduces cutting‑edge particulate carriers—polymeric nanoparticles and liposomes—for targeted, controlled, and enhanced drug delivery, covering their design, preparation, characterization, applications, and quality considerations.
6.1 Rationale & Overview
Limitations of Conventional Systems: Poor solubility, rapid clearance, lack of targeting, systemic side effects.
Advantages of Nanocarriers:
Enhanced Solubility: Encapsulation of hydrophobic drugs.
Controlled Release: Sustained delivery via matrix diffusion or lipid bilayer release.
Targeting: Passive (EPR effect) and active (ligand‑mediated) targeting to tissues or cells.
Reduced Toxicity: Lower off‑target exposure.
6.2 Polymeric Nanoparticles
6.2.1 Types & Composition
| Type | Composition | Characteristics |
|---|---|---|
| Nanocapsules | Drug core + polymeric shell (e.g., PLGA) | Reservoir release, high encapsulation |
| Nanospheres | Drug dispersed throughout polymer matrix | Diffusion‑controlled release |
| Dendrimers | Branched, tree‑like polymers (e.g., PAMAM) | Precise size, surface functionality |
| Polymeric Micelles | Amphiphilic block‑copolymers (e.g., PEG‑PLA) | Self‑assembled core–shell carriers |
6.2.2 Preparation Methods
Emulsion‑Solvent Evaporation: Polymer + drug in organic solvent emulsified in water → solvent removal → nanoparticles.
Nanoprecipitation: Polymer + drug dissolved in water‑miscible solvent added to water → spontaneous nanoparticle formation.
Ionic Gelation: Polyelectrolyte (e.g., chitosan) crosslinked with multivalent counterions (e.g., TPP) trapping drug.
6.2.3 Characterization
| Parameter | Method | Acceptance/Target |
|---|---|---|
| Particle Size & PDI | Dynamic Light Scattering (DLS) | 50–300 nm; PDI ≤0.2 |
| Zeta Potential | Laser Doppler Electrophoresis | ±20 mV to ±40 mV for stability |
| Morphology | Transmission/Scanning Electron Microscopy | Spherical, uniform |
| Encapsulation Efficiency | Centrifugation + HPLC assay of supernatant | ≥70% commonly |
| In Vitro Release | Dialysis bag method; sampling over time | Controlled release profile (e.g., 20% at 1 h, 80% at 24 h) |
6.2.4 Applications
Cancer Therapy: Doxorubicin‑loaded PLGA nanoparticles for EPR‑mediated tumor targeting.
Vaccines: Antigen‑adsorbed chitosan nanoparticles enhancing mucosal immunity.
Gene Delivery: PAMAM dendrimers complexed with siRNA for cellular uptake.
6.3 Liposomes
6.3.1 Structure & Classification
Unilamellar Vesicles (ULV): Single phospholipid bilayer (Small: 20–100 nm; Large: 100–1000 nm).
Multilamellar Vesicles (MLV): Multiple concentric bilayers (0.5–10 μm).
Stealth (PEGylated) Liposomes: Surface‑grafted PEG to evade RES uptake.
Targeted Liposomes: Surface ligands (antibodies, peptides) for active targeting.
6.3.2 Composition
Phospholipids: Phosphatidylcholine, phosphatidylserine.
Cholesterol: Modulates bilayer fluidity and stability.
Charge Inducers: Phosphatidic acid (negative), stearylamine (positive).
6.3.3 Preparation Techniques
Thin‑Film Hydration: Lipid film hydrated with aqueous drug solution → MLVs → size reduction by sonication/extrusion.
Reverse‑Phase Evaporation: Water‑in‑oil emulsion formed then solvent removed → large aqueous core.
Ethanol Injection: Lipids in ethanol injected into aqueous phase → spontaneous ULV formation.
6.3.4 Characterization
| Parameter | Method | Acceptance/Target |
|---|---|---|
| Vesicle Size & PDI | DLS | 100–200 nm for stealth liposomes; PDI ≤0.2 |
| Lamellarity | Cryo‑TEM | Single vs. multiple bilayers |
| Encapsulation Efficiency | Separation (gel filtration) + assay | Hydrophilic drugs ~30–50%; lipophilic ~90% |
| Surface Charge | Zeta potential | Slightly negative (−10 to −30 mV) for stability |
| In Vitro Release | Dialysis or diffusion cell | Sustained release over 24–72 h |
6.3.5 Applications
Doxil®: PEGylated liposomal doxorubicin for reduced cardiotoxicity and enhanced tumor accumulation.
Visudyne®: Verteporfin liposomes for photodynamic therapy in macular degeneration.
AmBisome®: Amphotericin B liposomes for systemic fungal infections with reduced nephrotoxicity.
6.4 Regulatory & Stability Considerations
Sterilization:
Nanoparticles: Sterile filtration (0.22 µm) or aseptic processing.
Liposomes: Filtration for small vesicles; gamma irradiation sometimes used.
Stability:
Aggregation/Aggregation: Controlled by surface charge, cryoprotectants (trehalose) for lyophilization.
Oxidation/Hydrolysis: Phospholipid peroxidation prevented by antioxidants (α‑tocopherol) and pH control.
Regulatory Guidelines: ICH Q8–Q11 (pharmaceutical development, quality), USP <1131> Nanoparticles, EMA reflection papers.
6.5 Key Points for Exams
Compare nanocapsules vs. nanospheres in structure and drug release.
Outline the thin‑film hydration method for liposome preparation and subsequent size reduction steps.
List four characterization parameters common to both nanoparticles and liposomes, with target ranges.
Describe the EPR effect and its role in passive tumor targeting by nanoparticles.
Explain the purpose of PEGylation on liposomes and its impact on pharmacokinetics.