Key Concepts of Drug Delivery Systems

Why This Matters

Drug delivery systems represent one of the most critical intersections of engineering, biology, and chemistry in biomedical engineering. You're being tested not just on what these systems are, but on why specific delivery routes exist, how release mechanisms work, and when engineers choose one approach over another. The underlying principles—bioavailability, pharmacokinetics, controlled release kinetics, and targeting specificity—appear repeatedly across exam questions and FRQs.

Don't just memorize that nanoparticles exist or that patches go on skin. Instead, understand the engineering trade-offs: Why does bypassing first-pass metabolism matter? What makes zero-order release kinetically superior for chronic conditions? How do surface modifications enable targeting? These conceptual connections will help you tackle compare-and-contrast questions and design-based problems where you must justify selecting one delivery system over another.

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Route-Based Delivery: How Drugs Enter the Body

The administration route determines absorption rate, bioavailability, and patient compliance. Each route exploits different biological barriers and transport mechanisms to achieve therapeutic drug levels.

Oral Drug Delivery Systems

• Most common administration route—convenient, non-invasive, and preferred for patient compliance in chronic conditions
• Gastrointestinal absorption subjects drugs to first-pass metabolism in the liver, often significantly reducing bioavailability
• Bioavailability variables include gastric pH, food interactions, and GI motility—critical factors when calculating effective dosing

Transdermal Drug Delivery Systems

• Skin absorption for systemic effects—patches and gels deliver drugs through the stratum corneum barrier
• Bypasses first-pass metabolism entirely, resulting in higher bioavailability for drugs that would otherwise be degraded hepatically
• Zero-order release kinetics maintain steady plasma concentrations—ideal for drugs like nicotine, fentanyl, and hormones requiring consistent levels

Inhalation Drug Delivery Systems

• Direct pulmonary delivery exploits the lungs' massive surface area ($\approx 70 \text{ m}^2$) for rapid systemic absorption
• Particle size is critical—aerodynamic diameter of $1-5 \text{ μm}$ required for deep lung deposition; larger particles deposit in upper airways
• Rapid onset of action makes this route essential for acute conditions like asthma attacks and COPD exacerbations

Injectable Drug Delivery Systems

• Highest bioavailability (100% for IV)—bypasses all absorption barriers for immediate systemic distribution
• Route selection matters: IV for emergencies, IM for depot formulations, subcutaneous for self-administered biologics like insulin
• Essential for large molecules—proteins, monoclonal antibodies, and peptides that would be degraded orally

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Controlled Release: Engineering Drug Kinetics

Controlled release systems manipulate when and how fast drugs are released, transforming pharmacokinetic profiles. The goal is matching release rate to therapeutic need—whether that's sustained levels for chronic disease or pulsatile delivery for circadian rhythms.

Controlled Release Drug Delivery Systems

• Predetermined release rates reduce dosing frequency from multiple daily doses to once-daily or weekly formulations
• Release mechanisms include diffusion through polymer matrices, erosion/degradation of carriers, and osmotic pumping
• Zero-order kinetics (constant release rate) maintains drug levels within the therapeutic window, avoiding peaks that cause toxicity and troughs that reduce efficacy

Osmotic Drug Delivery Systems

• Osmotic pressure drives release—water influx through a semipermeable membrane pushes drug out at a controlled rate
• Highly predictable kinetics independent of pH or GI conditions—release rate determined by membrane permeability and osmotic gradient
• OROS technology (Osmotic Release Oral System) exemplifies this approach in commercial tablets like extended-release methylphenidate

Implantable Drug Delivery Systems

• Long-term internal placement provides months to years of continuous therapy without patient intervention
• Ideal for chronic conditions requiring strict adherence—contraception (Nexplanon), glaucoma, and hormone replacement
• Design options include reservoir systems with rate-controlling membranes and biodegradable matrix systems that don't require removal

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Nanoscale and Particulate Systems: Engineering at the Molecular Level

Nanoscale carriers solve fundamental drug delivery challenges: poor solubility, rapid clearance, off-target toxicity, and inability to cross biological barriers. These systems leverage size-dependent phenomena and surface engineering.

Nanoparticle-Based Drug Delivery Systems

• Size range of $1-1000 \text{ nm}$ enables unique biodistribution—small enough to extravasate through leaky tumor vasculature (EPR effect)
• Solubility enhancement through encapsulation allows delivery of hydrophobic drugs that would otherwise precipitate in blood
• Surface modification with PEG ("PEGylation") extends circulation time by reducing opsonization and immune clearance

Liposomal Drug Delivery Systems

• Lipid bilayer vesicles mimic cell membranes—biocompatible structures that encapsulate hydrophilic drugs in their aqueous core or hydrophobic drugs in the bilayer
• Reduced systemic toxicity keeps drugs sequestered until reaching target tissue—Doxil (liposomal doxorubicin) dramatically reduces cardiotoxicity
• Targeting strategies include passive accumulation via EPR effect and active targeting through surface-conjugated antibodies or ligands

Hydrogel-Based Drug Delivery Systems

• Three-dimensional polymer networks swell in water while maintaining structural integrity—can hold $>90\%$ water content
• Stimuli-responsive "smart" hydrogels release drugs in response to environmental triggers: pH changes, temperature shifts, or enzyme presence
• Localized delivery applications include wound healing, tissue engineering scaffolds, and injectable depots that gel in situ

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Targeted Delivery: Precision Medicine Engineering

Targeted systems aim to concentrate drugs at disease sites while minimizing systemic exposure. The engineering challenge is achieving selectivity—getting drugs where they're needed while avoiding where they're not.

Targeted Drug Delivery Systems

• Site-specific accumulation reduces required dose and minimizes off-target side effects—critical for cytotoxic chemotherapy agents
• Passive targeting exploits pathophysiology (EPR effect in tumors, inflammation-increased permeability) without active recognition
• Active targeting uses ligands, antibodies, or aptamers conjugated to carriers that bind receptors overexpressed on diseased cells

Gene Delivery Systems

• Nucleic acid therapeutics (DNA, mRNA, siRNA) require delivery vehicles because naked genetic material cannot cross cell membranes and is rapidly degraded
• Viral vectors (AAV, lentivirus) offer high transfection efficiency but raise immunogenicity and insertional mutagenesis concerns
• Non-viral vectors (lipid nanoparticles, polymeric carriers) are safer but less efficient—mRNA COVID vaccines use LNP technology

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Barrier-Crossing Technologies: Overcoming Biological Obstacles

Some delivery systems are engineered specifically to cross barriers that would otherwise block drug access—skin, mucosa, or cellular membranes. These technologies expand the range of drugs that can be delivered non-invasively.

Microneedle Drug Delivery Systems

• Micron-scale needles ($25-2000 \text{ μm}$) penetrate the stratum corneum without reaching pain-sensing nerve endings—painless transdermal delivery
• Design variants include solid (skin pretreatment), coated (drug on needle surface), dissolving (drug-loaded polymer), and hollow (liquid injection)
• Vaccine delivery advantage—targets antigen-presenting cells in the dermis, potentially improving immune response compared to intramuscular injection

Mucoadhesive Drug Delivery Systems

• Adhesion to mucosal surfaces extends residence time at absorption sites—buccal, nasal, ocular, and vaginal routes
• Polymer selection (chitosan, carbomers, cellulose derivatives) determines adhesion strength through hydrogen bonding and chain entanglement
• Enhanced permeation across mucosal epithelium improves bioavailability for drugs with poor oral absorption

Microfluidic Drug Delivery Systems

• Lab-on-a-chip technology enables precise control of fluid flow at microliter to nanoliter scales
• Real-time monitoring and feedback allows closed-loop delivery systems—insulin pumps with continuous glucose monitoring exemplify this approach
• Personalized medicine applications include point-of-care diagnostics integrated with on-demand drug release

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Quick Reference Table

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Self-Check Questions

1. Which two delivery systems both bypass first-pass metabolism but differ in their invasiveness and duration of action? Explain the engineering trade-offs between them.

2. A drug has poor aqueous solubility and causes severe systemic side effects. Which delivery system category would best address both problems, and what specific mechanisms would you employ?

3. Compare and contrast liposomal and polymeric nanoparticle delivery systems. Under what therapeutic circumstances would you choose one over the other?

4. An FRQ describes a patient requiring constant plasma drug levels for a chronic condition but with poor medication adherence. Rank three delivery system options and justify your top choice based on release kinetics and patient factors.

5. What distinguishes passive targeting from active targeting in nanomedicine? Identify one delivery system that can employ both strategies simultaneously and explain how.