FPS Exam 5 Lectures Hiew (Modified Release)

modified release oral delivery systems

rapid dissolution depends on the

drug solubility

absorption can take place in entire GI tract but typically takes place in

proximal small intestine

immediate release oral dosage forms

tablets

capsules

suspension

modified release dosage forms extend the period of drug release for

prolonged absorption

sustained release (prolonged release or extended release)

any drug delivery system that achieves a slow release of drug over an extended period of time

controlled release

usually reserved for zero-order systems (drug is released at a constant rate)

a drug delivery system in which the system controls the release of the drug in an "international" pattern

modified release drug products advantages

Improved medication adherence and quality of life

More stable plasma drug levels

Fewer local and systemic side effects

Potentially lower overall healthcare costs

modified release drug products disadvantages

Increase costs (manufacturing and materials)

Additional considerations regarding missed doses

Administration difficulties (large sizes)

Dangers of mishandling/technology failures ("dose dumping")

modified release application short elimination half-life (

usually need to load too much dose into it

still have all other excipients to incorporate (rate controlling tech)

end up with a large dosage form that people couldn't swallow

modified release application long elimination half-life

do I need a modified release dosage form

IR tablets that are once daily dosing

modified release application narrow therapeutic index

modified release applications poor solubility

drug is only available for absorption if it dissolves

essentially "hiding" it from the GI fluids

modified release applications carrier-mediated transport

modified release applications delayed pharmacodynamics effect

negative side effect

starting another medication (drug-drug interaction)

hard to manage and undo quickly

modified release applications extensive first-pass metabolism

Drugs absorbed from the intestines pass through the liver first (first-pass metabolism).

The liver metabolizes many drugs before they reach systemic circulation.

Strategy: Saturate liver enzymes to reduce first-pass metabolism and increase drug availability.

pharmacists should consider whether a particular modified release dosage for will work as

designed in an individual patient

not all drug compounds are well suited for

inclusion in modified release dosage forms

matrix extended-release system

take the drug dose that we are intending to administer over the dosing interval, incorporate in into the tablet or fill into a capsule

goal of matrix extended-release system

compressed solid most of the time

does not disintegrant

homogenous matrix system

drug is dissolved and/or dispersed uniformly in the polymer and released by diffusion through the polymer (eye patches)

inert matrix system

insoluble and does not swell or erode. fluid enters through pores and dissolves the drug, which diffuses out through the after-filled channels left behind as drug particles dissolve (caffeine)

hydrophilic (eroding) matrix system

dispersed n water-swellable polymer. On contact with fluid, the polymer hydrates to form a gel layer. drug is released by diffusion through the gel and by erosion as outer polymer chains disentangle and dissolve (gummy bears)

release pathway and impact on release profile

original drug has been removed from the depletion zone and additional drug from the core diffuses through the depletion zone to reach the external surface for release

impact of the depletion zone

The initial matrix is clear (A), while the drug-containing matrix appears white (B).

As the drug is released, a clear depletion zone forms at the outer surface.

The depletion zone increases in thickness over time as more drug is released.

drug release from matrix systems

matrix system follow "sqrt of time dependency" for drug release

when the x-axis is t1/2 the release curve is linear

translating drug release to drug plasma concentration

ZOCR = zero-order controlled release

SR = sustained release/ER

IR = immediate release

hydrophilic (eroding) matrix systems

advantages of hydrophilic matrix tablets

Uses common, water-hydratable polymers.

Can provide near zero-order (constant) drug release for part of the dosing period.

Drug release increases as the gel hydrates, while the tablet gradually shrinks as the gel dissolves or breaks off.

Low risk of ghost matrix (gel particles may occasionally appear in stool).

polymers used in the formulation of matrix ER dosage forms

hydrophilic polymers - Hypromellose (HPMC)

drug release is a function of total release surface area of the tablet

and the drug concentration at release surface

_____ and _____ are important for matrix release systems

size

geometry

gastroretenetive matrix technologies advantages

-useful for drugs only absorbed in the upper GI tract

-improved bioavailability of drugs unstable at alkaline pH

-improved targeted delivery for treatments directed to stomach or small intestine

gastroretentive matrix technologies disadvantages

-variable residence time and fed and fasted states

-longest in fed state

-residence time of floating systems may depend on posture-sitting, standing, supine/prone

membrane _____ ______ dissolve

does not

membrane controlled systems can give ________ drug release over much of the dosing interval

zero-order

membrane-controlled systems are examples of zero-order release systems due to

constant concentration gradient that forms across the release-controlling, rate-limiting, permeable membrane

which release profile would membrane-controlled systems have?

ZOCR pellet anatomy

outer to most inner

delayed-release membrane

sustained-release membrane

drug layer

inert core

release/dissolution behavior of a membrane-controlled system

all the beads retain their original shape - they look exactly as they did in the original capsule

the drug release rate is determined by the ____ of a component of the dosage form

dissolution

-the drug

-the matrix

-a coating layer

when a drug or matrix dissolution controls release, release profile may resemble

matrix release

dependent on _____ ______ ______ and ______ ______ (dissolution-controlled systems)

release surface area

drug concentration

when coating dissolution controls release, release profile consists of

"microbursts" of drug release

pulsatile release

dissolution-controlled systems

same amount of drug, varied thickness of dissolving coat

which release profile would "online-like" beads have?

combining different dissolution rates to achieve the desired extended release

what surrounds drug compartment?

semi-permeable membrane

this membrane does not dissolve

what allows drug (as a solution or suspension) to be released from tablet?

laser drilled orifice

porous membrane may also allow

sufficient drug release that a separate orifice is not necessary (less common)

osmotic delivery systems

may be difficult to optimize for zero-order release

what is a key component of dosage form, drug (API) is often described/named as the salt of the drug + resin?

ion exchange resin (polymer)

ion exchange extended release systems relies on what to displace drug molecules from resin resulting in drug release?

physiologic concentrations of counterions

no ions =

no release

drug is released only as GI cations displace it, so release doesn't depend on fluid volume or pH as much as dissolution does

maxtrix system

-diffusion-controlled and/or erosion-controlled

-can include gastroretntive properties (floating, mucoadhesive, swellable)

membrane (diffusion) controlled system

-polymer coated pellets or tablets

-diffusion-based release through coating (coating polymer is insoluble in GI tract)

dissolution-controlled system

-coating dissolves over time

-enteric, pH dependent coatings

osmotic system

osmotic pressure-driven release through laser-drilled orifice

ion exchange resin system

-drug bound to charged resin particles

-release via ionic exchange in GI fluids

these technologies can be used

singly or in combination to achieve the desired modified release profile that matches the drug, patient, and clinical need