11: Modified Release Drug Products & Devices

What is the typical drug product/dosage form? What are some potential issues with conventional formulations?

Immediate/fast release

• large peaks/valleys

• multiple doses = bad adherence

For IR solid oral drug products, what is the dissolution criterion?

80% dissolved in 30 minutes in 0.1 HCL

IR advantage

fast onset of action (solubilizes quickly)

IR disadvantages

frequent dosing

large blood conc.

peaks, valleys = adverse effects

not good for chronic diseases

Changing ka affects what?

Tmax, Cmax

What are ODTs? What is a benefit of them and what type of drug are they suitable for?

“Orally disintegrating tablets,” disintegrate rapidly in saliva after PO admin (drug dispersed in saliva and swallowed with little to no water)

• advantage: dose without water

• suitable for low dose drugs

What do modified-release (MR) products do?

Deliver therapeutics at a predetermined rate while maintaining blood concentration within therapeutic window over an intended duration

Advantages of MR products

• Improve adherence/compliance

• Use less drug (reduces toxicity and systemic SEs)

• improve efficacy (reduce fluctuation of Cp)

MR disadvantages

• takes longer to achieve therapeutic blood concentrations (may need loading dose)

• potential dose-dumping

• low dosage flexibility

• sustained concentration in overdose cases

• less possibility for high dosage

dose-dumping

patient exposed to entire dose @ once or very quickly; potential toxicity

What is a potential issue with solutions (fast absorption) and why does this occur?

may have more SEs; occurs because of high Cmax due to fast absorption

extended-release (ER); what are its two subtypes?

slowly release drug over time (at least 2-fold reduction in dosing frequency compared to IR dosage forms)

• controlled release

• prolonged release

ER PK properties

no peaks/valleys in Cp

controlled release

subcategory of ER

maintain constant drug levels

prolonged release

subcategory of ER

constant drug levels not maintained

delayed release dosage form PK

delayed absorption/elimination

delayed release PK

no absorption/elimination for first few hours → delayed abs & elimination; lower Cmax

liposome PK vs free drug

Cp remains high for much longer (longer circulation; allows drug delivery to specific sites)

biopharmaceutical factors for MR oral drug products

physiological conditions in GI tract

absorption window (in the optimum site for drug absorption)

biopharmaceutical factors for MR parenteral drug products

blood circulation time (PEGylation); want drug to stay in circulation longer to distribute to target site & avoid clearance

targeting ligand-receptor interaction — distribution important

PEGylation

adding PEG (hydrophilic polymer) to drug; allows drug to stay in circulation for longer

(note: some may be allergic)

D_0

dose of SR product

steady-state

point where drug input = drug output → Cp @ constant level

maintenance dose purpose

maintain steady state

why are drugs with short half-life (1-2 hours) not ideal for ER?

high drug dose in dosing unit causes product to be large & hard to swallow (especially for longer dosing duration, >12 hrs)

(ex: t1/2 = 1 hr; would need 24 doses in 1 dosing unit)

What are good drug candidates for ER products?

• wide therapeutic window (large safety window)

• small doses for efficacy

• used for chronic conditions & need multiple daily administrations

• moderate solubility, rate of absorption & secretion

What are bad drug candidates for ER products?

• very long or very short t1/2

• large dose for efficacy

• narrow therapeutic (risk of dose-dumping more dangerous)

• poor absorption in GI

What affects Cmax?

F, ka

What affects AUC?

F

What affects tmax?

ka

matrix-based ER products

drug uniformly suspended in hydrophilic or insoluble matrix

hydrophilic matrix system (include type of kinetics)

drug released by diffusion of drug through gel layer & gradual erosion of gel layer

first-order kinetics

insoluble matrix system (include type of kinetics)

slow diffusion of drug molecules from tablet

0-order release kinetics

dissolution

hydrophilic matrix gets smaller as it gets dissolved

1st-order kinetics

diffusion

insoluble matrix remains same size, but drug diffuses out

0-order release kinetics

reservoir-based ER oral products (membrane-controlled)

drug placed in reservoir surrounded by rate-controlling polymer membrane

dissolving membrane reservoir-based oral ER products

dissolution based; first-order kinetics

insoluble membrane reservoir-based oral ER product

diffusion based; zero-order kinetics

contains channels/holes to control how much drug escapes at a constant rate

How does drug release occur in reservoir-based oral ER products?

result of concentration gradient between dosage unit & surrounding medium

What does release/absorption of reservoir-based oral ER products depend on?

• film thickness (higher thickness, lower release)

• plasticizer (higher drug release if water-soluble)

• pore former (more pore former, more drug release)

• solvent (faster drug release from aqueous)

osmotic pump system oral ER product

systems film-coated w/ semi-permeable membrane through which only water can diffuse; osmotic pressure pushes dissolved drug out of access port

3 key elements of osmotic pump systems

1. exit port (controls rate / how much drug gets pumped out — hole plugging risks no therapeutic effect!)

2. osmotic-generating agents

3. semipermeable membrane on capsule (allows water in/out)

How do osmotic pump systems work?

1. isotonic inside; layer of sugar/salt causes increase in osmotic pressure inside

2. Water goes into system to balance osmotic pressure, pushing drug out

Osmotic ER oral products kinetics

zero-order (release rates independent of drug properties and environmental conditions)

What may happen if the membrane of an osmotic ER oral product breaks?

dose dumping (do not chew, divide, or crush tablet)

Are enteric-coated products dissolution or diffusion based?

Dissolution based; coating isn’t soluble under acidic pH (1-2) and dissolves in intestine (>6) to release drug in intestine

(this protects the stomach from the drug and the drug from the stomach)

What is the risk if the coating of enteric-coated products is damaged?

dose dumping

How can alcohol affect oral MR drug products?

May dissolve membrane and cause dose dumping

Define reservoir-type transdermal patches; what is their kinetics?

Diffusion based; membrane between drug and skin controls release rate from reservoir (CANNOT cut into smaller pieces)

Kinetics:

• zero-order release pattern (maintains constant serum drug level; delivery at constant rate)

• initial absorption-dominant phase, then steady state; elimination after patch is removed

Define matrix-type transdermal patches; what is their kinetics?

Dissolution based; drug contained in polymer matrix (can cut)— tend to be smaller and thinner (potent drugs are better)

Kinetics:

• releases at rate governed by components in the matrix

• 1st order

benefits of long-acting (LA) injectables and implants

long release duration (reduce dosing frequency, improve pt compliance)

made of biocompatible polymers (nontoxic, non-immunogenic, non-irritating)

Why would long-acting injectables/implants be non-biodegradable?

Want to be able to stop med at any given time; cannot remove med if broken down

Implants (LA drug products)

require surgical procedure or injector; diffusion (zero order)

Injectables (LA drug products), biodegradable or non-biodegradable?

Biodegradable; broken down so they can get eliminated out

Injectables: IM or SC; what does it do?

forms a depot that slowly hydrolyzes and releases the drug and soluble monomers

Injectable release mechanism

chemical degradation, erosion, diffusion

Injectable risk

high burst release (LARGE Cmax), poses risk of toxicity

(occurs because solvent is diffused out, peptide also soluble)

What is the purpose of nanotechnology-based delivery systems?

smaller size allows for drug to be untaken into cells to target organelles and give therapeutic outcomes

micelles

one layer of phospholipids; self-form to have hydrophobic core and hydrophilic outer layer

liposomes

single or multiple bilayers of phospholipids encapsulating small molecule drugs, DNA, peptides, antigens

(most successful nanoproduct)

liposome advantages

targeted drug delivery (circulate in system longer)

reduced toxicity (can’t leak out of liposome)

nanodisks

mimic RBCs, can interact better with target sites

What do size and shape of nano products matter?

affect other physical properties of colloidal systems (SA, aggregation behavior, microstructure)

affect in vivo performance of colloidal systems (bio distribution, cellular uptake, target efficiency)

What happens if a drug is too flat?

Sits on top of cell, doesn’t get too deep