W1L3: Advanced Drug Delivery Introduction

Oral Drug Delivery

Convenient but limited by solubility, permeability, first pass metabolism

• Tablets, capsules, solutions, suspensions, chewables

Parenteral Drug Delivery

IV, SC, IM; bypasses absorption barriers; used for biologics

• IV infusion bags, pre‑filled syringes, autoinjectors, depot injections

Inhalation Drug Delivery

Rapid systemic uptake, local lung targeting

• Metered‑dose inhalers (MDIs), dry‑powder inhalers (DPIs), nebuliser solutions

Transdermal Drug Delivery

Controlled release, limited by skin barrier

• Patches, iontophoretic systems

Topical Drug Delivery

Local effect; minimal systemic exposure

• Creams, gels, ointments, lotions

Intrathecal/CNS Drug Delivery

Bypass BBB; used for severe CNS disease

• Intrathecal injections, implanted pumps

When do we need advanced delivery systems?

1. To overcome unfavourable physicochemical properties and biological barriers

2. To make medicines more practical for people

Examples:

• Monthly antipsychotic depots

• 3‑month contraceptive injections

• Once‑daily controlled‑release tablets instead of 3× daily

• Inhaled insulin for patients who cannot tolerate injections

Biopharmaceutical Classification System

Drug release

Refers to the processes by which drug molecules are transferred from their initial position in a drug delivery system to the outer surface and, in turn, as solutes, into the release medium

Immediate release capsules

Capsules designed to dissolve quickly (20-30 mins)

1. Capsule dissolves to allow solute access to API

2. API dissolves in solute (dissolution)

3. Dissolved API is available for absorption

Extended release

Over an extended period of time

Controlled release

At a controlled rate

Delayed release

After a lag

Why modify release?

• Smooth PK profile - constant level of drug in system

• Reduce dosing frequency

• Reduce toxicity peaks - adverse reactions

• Improve adherence

• Protect unstable APIs - not stable in some pHs

How are different release profiles achieved?

Using engineering strategies to produce formulation mechanisms

• Diffusion controlled

• Dissolution controlled

• Erosion controlled

• Osmotic systems

• Ion-exchange systems

Diffusion controlled systems

Drug molecules slowly diffuse out of a polymer matrix or through a membrane

1. Drug is embedded in a polymer

2. Water penetrates the tablet

3. Drug dissolves and diffuses out a controlled rate

The release rate depends on polymer thickness, drug solubility and diffusion distance

Dissolution controlled mechanisms

The formulation dissolves slowly, controlling how fast and for how long the drug is available

1. Tablet or coating dissolves gradually

2. Drug release is limited by dissolution rate

The release rate depends on matrix solubility and erosion rate

Erosion controlled systems

Tablet erodes over time, releasing drug as the structure breaks down

1. Polymer swells, then erodes

2. Drug is released as matrix disappears

The release rate depends on polymer erosion and not drug diffusion

Osmotic pump systems (OROS)

Water enters and so osmotic pressure builds and the drug is pushed out through a tiny orifice

1. Semi-permeable membrane allows water in

2. Osmotic pressure increases

3. Drug is pumped out a near constant rate

Provides zero-order release (constant rate)

Ion exchange release

Drug is bound to a charged resin and is released when ions in GI fluid swap places

1. Drug is attached to charged resin beads.

2. Ions in the stomach displace drug

3. Release depends on ion concentration

The release rate depends on ion exchange kinetics

Pharmacokinetic benefits of controlled drug delivery

• Lower peak concentrations

• Higher trough concentrations

• More stable plasma levels

• Reduced toxicity

• Improved efficacy for drugs with short half‑lives

Patient benefits of controlled drug delivery

• Less frequent dosing

• Better adherence

• Less fluctuation in symptoms

• Reduced GI irritation (e.g., NSAIDs)

Limitations of controlled drug delivery

• Cannot overcome solubility/permeability barriers

• Cannot bypass efflux or BBB

• Cannot protect fragile APIs

• Cannot provide long‑acting exposure (except IM depots - intramuscular drug that creates a temporary storage depot for slow release)

What makes a delivery system advanced?

• Ability to control release

• Able to protect API

• Ability to target tissues

• Able to bypass barriers

• Ability to improve patient convenience

• Physical complexity

Major classes of advanced delivery systems

• Liposomes

• Polymeric nanoparticles

• Micelles

• Viral vectors

• Lipid nanoparticles (LNP)

• Depots and implants

• Hydrogels

Liposomes

• Tiny spherical vesicles made of phospholipid bilayers.

• Mimic cell membranes and can carry both hydrophilic and hydrophobic drugs

• Inner aqueous core with hydrophilic drugs encapsulated

• Hydrophobic drugs embedded in the bilayer

1. Protect drug – shielded from chemical breakdown and biological clearance.

2. Reduce toxicity – API is packaged until it reaches target tissue.

3. Change biodistribution – liposomes can control tissue uptake.

Good for: Poorly soluble drugs, Highly toxic drugs, Drugs needing targeted delivery

Types of liposomes

• Conventional liposomes

• PEGylated liposomes

• Targeted liposomes

• Cationic liposomes

Conventional liposomes

Basic phospholipid vesicles; cleared quickly by immune systems

PEGylated liposomes

• Coated with polyethylene glycol (PEG) to evade immune system and extend circulation

Targeted liposomes

The use of surface ligands directs liposomes to specific tissues or receptors

Cationic liposomes

Positively charged; used for gene delivery

How liposomes deliver and release drugs

1. Liposomes in the bloodstream and may be tagged with targeting ligands to bind to specific receptors on target cells

2. Liposome ligands bind to receptors on cell membrane and trigger uptake often via receptor mediated endocytosis

3. Endocytosis - Cell membrane folds around liposome, internalises it into cell - endosome

4. Endosome in cell matures into lysosome

5. Lysosome destabilises due to avidity and enzymes and releases drug into cytosol

Polymeric nanoparticles

• Tiny polymer made from polymers to carry drugs or other cargo

• Encapsulated cargo in a polymer matrix

• Polymers degrade slowly = controlled release

• Tuneable properties (size, charge and release rates)

• Release occurs through diffusion and polymer erosion

• Protect API, targeting reduces toxicity, controlled release

Polymeric nanoparticles limitations

• Rapidly cleared by macrophages

• Limited loading for hydrophobic drugs

Lipid nanoparticles (LNP)

Ionisable lipid structures used to deliver nucleic acid. Delivered to the cells via endocytosis. Genetic material is released via endocytic membrane disruption.

• Protect mRNA/siRNA and enable intracellular delivery

• e.g. mRNA COVID-19 vaccines

• LNPs deliver genetic cargo, liposomes deliver small molecules

LNP Limitations

• Trigger inflammatory responses

• Rapidly cleared

Depots and injectables

• Long-acting injectable or implantable system placed in muscle or subcutaneous tissue

• Creates a local drug reservoir (depot) that gradually enters the bloodstream.

• Can reduce dosing frequency (weeks to months) and increase adherence and achieve stable plasma levels

• Erosion of the formulation, diffusion of the drug from the depot, breakdown of the carrier

e.g. Antipsychotics, contraceptive implants

Limitations of depots and injectables

• Invasive, primary care

• Cannot be removed easily if adverse effects occur

Doxil

• Doxil is a pegylated liposome formulation of doxorubicin

• Doxorubicin is a potent chemotherapy drug that treats a wide range of cancers by interfering with DNA replication in cancer cells.

• Administered via IV injection

• First used 1974 – still used today

Why does doxil need an advanced delivery system

• Doxorubicin has a cytotoxic mode of action: intercalates into cancer cell DNA and produces reactive oxygen species that damage DNA, leading to cancer cell death.

• Doxorubicin is not selective for cancer cells: cytotoxic mechanism is not tumor specific.

• Key toxicities include: cardiotoxicity, myelosuppression, GI toxicity

• Cytotoxicity causes pharmacological and toxicological effects

Doxil pharmacokinetic profile

• Large tissue distribution underlies toxicity

• Rapid clearance from circulation. Very little drug remains in circulation long enough to reach tumours.

How do liposomes help doxil

Liposomes increase size and improve tumour accumulation

Doxil is 100 nm. This size:

• Prevents renal clearance

• Prevents penetration to healthy tissues

• Allows accumulation in tumours via EPR

Doxorubicin molecule: Very small – 543 Da, Can diffuse across tissue. Can enter healthy and tumour cells

• PEGylation increases circulation time: Prevents immune clearance, Extends half life (t1/2) from minutes to hours, Allows more drug to reach tumours

• Liposome encapsulation reduces cardiotoxicity: Doxorubicin is packaged until it reaches tumour tissue

• Controlled release smooths PK: Doxorubicin is released slowly via diffusion, EPR trapping in the tumour allows for a build-up of doxil LNP, Less toxicity and better tumour exposure

Doxil LNP

Much bigger – 100 nm

• Too big to enter normal, healthy tissue

• Tumour tissues develop with disorganised, leaky vasculature which allows doxil to enter.

• The disorganised vasculature has poor lymphatic draining traps doxil LNP

• EPR: Enhanced Permeability and Retention

Doxil FDA approved indications

• Ovarian cancer after failure of platinum‑based chemotherapy

• AIDS‑related Kaposi’s sarcoma after failure of prior systemic therapy

• Multiple myeloma, in combination with bortezomib, in patients who have received at least one prior therapy