Exam 2- Lecture 7: Controlled Release

What does delayed release refer to?

A modified drug release profile that is delayed until the dosage form passes from the stomach into the small intestine (colonic)

What do delayed release formulations employ?

An exterior coating on certain solid oral dosage form, which allows them to bypass the stomach, delaying drug release by dissolution until the product reaches the small intestines

What are the reasons for employing delayed release?

1. Protect the API against acid-catalyzed degradation in the stomach (erythromycin, pancreatic, Omeprazole)

2. Minimize undesirable GI side-effects (nausea, gastric irritation, bleeding (aspirin, naproxen)

3. Create opportunities for night-time dosing (peak concentrations when waking) (prednisone)

4. Facilitating colonic drug delivery (released at colonic pH & not stomach/small intestine)

What are extended-release dosage form designed to deliver?

Its API in a predictable fashion over a prolonged duration (relative to IR delivery), enabling a reduction in dosing frequency (again relative to IR dosing)

What are extended-release dosage forms more broadly included under?

Description of “modified release” or “controlled release,” these products are designed to prolong drug delivery over long durations

What do ER products ideally provide?

24 hours of continuous, zero-order release when taken once daily

• Meaning rate of drug release does not change no matter [drug] left

What are the reasons for employing extended release?

1. Reduce the need for multiple daily doses

2. Benefit of therapy is only “felt” when the Cp is w/in the therapeutic window

3. Quarterly dosing is neither convenient nor very practical, esp. long term

4. Peaks/troughs in Cp vs. t profile (esp. those falling below MEC) are disruptive to therapeutic effect

What are enteric coating (EC) polymers?

A special type of polymer used to coat a SODF that enables delayed release depending on pH of surrounding environment (completely insoluble at gastric pH, readily soluble at intestinal pH; pKa ~ 3.5)

What do enteric coating enable the SODF to do?

Control the rate & timing of release of the API to occur when the product meets the environment where the drug is intended to be delivered

What are all EC polymers?

Poly acids, meaning that their monomer is subunits contain ionizable acidic FGs, all of which are required to have a pKa of approximately 3-5 (serves as a solubility trigger)

What does extent of ionization of WAs depend on?

Where the pH is relative to the pKa

What happens at pH < pKa?

Predominately protonated & in their free, unionizable form

What happens at pH > pKa?

Predominately unprotonated & in their ionizable form

What is the intrinsic solubility (S0) of a molecule?

The equilibrium value for the unionized form of a molecule

What will the solubility of a weakly acidic molecule equal?

Its intrinsic solubility at pH=pKa-2, where according to the role of 9, >99% of molecules will be in their protonated state.. or.. at gastric pH, the polymer is insoluble

What is S0 for EC polymers?

S0 is so low that they are considered to be completely insoluble at very low pH

What happens pH = pKa?

~50% of the FGs are ionized causing a rapid increase in solubility

• While at pH=pKa+2, ~99% of the FGs are ionized, & the molecule reaches saturation solubility of the more polar, ionized form

What happens as a drug moves from the acidic environment of the stomach, through the rest of the GIT?

PH will increase

• Means that WAs will become more soluble the further they are form the stomach

What is the approx pH for mouth?

6.2-7.4

What is the approx pH for stomach?

1.6-2.6

• Male: 2.16

• Female: 2.79

• Smokers: 1.56

What is the approx pH for duodenum?

5.0-6.5

What is the approx pH for jejunum?

6-7

What is the approx pH for colon?

6.5-7.5

What is the polymer at the stomach pH<2?

Polymer

What is the pH>2?

Polymer → disintegration

Granules/aggregates → deaggregated

Primary particles → dissolution

ADME

What do ideal candidates for extended delivery have or are used to?

• Moderate rates of absorption & excretion:

  • Drugs w/ slow absorption & excretion rates are inherently long acting (don’t require XR formulation)

  • Drugs w/ t1/2<hrs (very rapid excretion) must be dosed in prohibitively large quantities; XR meds would be too large to swallow

What else ideal candidates for extended delivery have or are used to?

• Uniformly absorbed from the GIT:

  • Ionization changes throughout the GIT, changing partitioning behavior

  • If K’ is too variable, the absorption rate will also be highly variable

• Administered in relatively small doses:

  • If dose required is too large, there may be difficulty in swallowing

• Good margin of safety:

  • Very narrow therapeutic windows require precision dosing, potential for adverse effect if patient misuses product

  • Wider therapeutic windows drugs are generally safer for formulations that require 2-3x IR dose for ER

• Used to treat chronic rather than acute conditions:

  • Drugs taken occasionally (acute) don’t require XR formulations

  • Drugs taken regularly (chronic) benefit from XR formulations, esp. for maintenance therapies

What are the ways to extend release from SODF include?

• Modify drug dissolution rate by controlling access of SODF to physiological fluids using a barrier coating -or- by embedding in a slowly dissolving matrix

  • Ex: RA capsules, XR matrices

• Control drug release by requiring diffusion through a membrane barrier at a known rate

  • Ex: asymmetric membrane tablets, pump products

• Reaction or interaction b/w API & pharmaceutical barrier or site-specific biological fluids/tissues

What does a repeat-action strategy use?

A version of dissolution rate control by filling capsules w/ granules coated w/ different thicknesses of a water-soluble polymer

What does the thickness of the pellet coating determine?

How long it will take before IR delivery process start

What will the dimensions of a particle inevitably change as?

Dissolution proceeds & therefore dissolution rate will also change w/ time

What does the Hixson-Crowell cube root law show?

Relative mass delivered via dissolution-control was related to time via cube-root dependence & is suitable for describing dissolution rates for spherical particles

• (Ws/W0)^1/3 = 1-DCst/phr0

What does the different thicknesses of water polymer impart in repeat action capsules?

Exposure of an immediate release pellet at varying time intervals, meaning a sequence dose is delivered that allows for continued pharmacological effect

What happens when the drug, including all coated & uncoated pellets, has been dissolved from the dosage form?

It will be time for another dose

What happens w/ the IR process (3, 6, 9, 12 hrs)?

Majority of drug will be released in 30 minutes or less

What does D stand for?

Diffusivity

What does Cs stand for?

Concentration

What does t stand for?

Time

What does p stand for?

Density

What does h stand for?

Width

What does r0 stand for?

Radius

What are the controlled systems (similar to delivery from transdermal patch devices) formulated?

Achieve zero-order delivery but in the instance of asymmetric membrane tablets, tablet is coated w/ a membrane consisting of a mixture of water soluble/insoluble polymers

• dW/dt = DAK/h * C1

What happens to the water-soluble portion on contact w/ GIF?

Dissolve, leaving behind pore through which water can penetrate to the core

What happens to the dissolved API from the core?

Diffuse through the pores to be delivered to the bulk of the GIF prior to absorption

What will diffusion occur via?

Path of least resistance

What do pores provide?

Little to no resistance, but do increase effective path length over which the molecules must diffuse to be delivered

What can the effect be captured using?

2 parameters & applied to the rate equation for passive diffusion:

• dW/dt = E/tau * DAK/h * C1

What is porosity (E)?

Fractional volume of the membrane attributed to pores or channels

What is tortuosity (tau)?

A factor used to compensate for the increase in path length caused by “twists” in the pores

What are matrix devices designed to become?

Viscous when water penetrates the core

• As polymer slowly dissolves over time, dissolved/suspended API migrates to matrix surface & dissolves into GIF

What is drug delivery controlled by?

Dissociation of a water-soluble polymer matrix in addition to dissolution of the API molecules

What did Higuchi adapt?

Same models of Fickian diffusion that Noyes-Whitney did to describe dissolution as a diffusion process as it pertains to those types of dosage forms

What do API particles form the surface do?

Dissolve into the surrounding GIF saturating the layer of water immediately in contact w/ matrix surface, creating a concentration gradient & allowing diffusion away from surface & into bulk solution

What is rate determined by?

Gradient in the static layer

What happens to surface area as the matrix dissolves away?

Exposed remains reasonably constant, but there is a depletion zone that grows as the matrix recedes unidirectionally, increases (h) by a margin of (h+dh), therefore slope of gradient will change when (h) is growing large & diffusion rate will decrease

What does Q stand for?

Applies to cumulative amount of drug released per unit of surface area

What does W stand for?

Total amount of drug released over some amount of time

What can matrix devices consist of either?

Homogenous matrix or a matrix containing pores

What must we include to account for impact on increased path length the pores creates?

Same parameters accounting for volume of membrane caused by pores (porosity, E) & the impact of twists & turns in pores (tortuously, tau)

What are osmotic pump systems specifically?

Manufactured delivery platforms capable of prolonged, zero-order release of API

What is a semi-permeable polymeric membrane surround?

A bi-layer core that consists of a drug reservoir & and osmotically active polymer

What does water penetrate?

Outer polymer coating & be imbibed into osmotically active polymer causing it to swell & extrude drug out of a precision drilled hole in the outer membrane