controlled release 1
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Course Information
Controlled Release
Week 4: Formulation and Analysis of Drugs (5BBP0259)
Date: 22/10/2020
Faculty of Life Sciences & Medicine
Pharmacy Department
Instructor: Dr. Maya Thanou
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Learning Objectives
Understand the importance of timing for optimal drug delivery
Describe the mechanisms of modified release and their differences clearly
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Reading Materials
Pharmaceutics: The Science of Dosage Form Design by Michael E. Aulton
Drug Delivery and Targeting for Pharmacists and Pharmaceutical Scientists by Anya M. Hillery, Andrew W. Lloyd, James Swarbrick
Drug Delivery: Engineering Principles for Drug Therapy by W. Mark Saltzman
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Importance of Timing for Optimal Drug Therapy
Ideal dosage regimens:
Achieve therapeutic concentration immediately
Maintain therapeutic concentration for the desired treatment duration
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Importance of Timing for Optimal Drug Therapy
Repeated Dosing
Plasma concentration defined by minimum effective concentration (MEC) and maximum safe concentration (MSC)
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Timing and Plasma Concentration
Time after dose correlates with plasma concentration
MEC: Minimum effective concentration
MSC: Maximum safe concentration
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Modifying Drug Release
Objectives:
Smooth out variations in plasma concentration for a constant therapeutic effect
Reduce dosage frequency to improve compliance
Promote drug absorption
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Idealized Drug Delivery System
Components:
Sensor
Reservoir of drug
Energy source
Rate controller
Programmer
Delivery of drug at desired location in desired amount
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Advantages of Modified-Drug-Release Dosage Forms
Improve treatment of chronic illnesses
Maintenance of therapeutic effect overnight
Reduction of systemic side effects
Decrease in total drug amount administered during treatment
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Modified Release Oral Drug Delivery Terms
Delayed release
Examples: Enteric-coated, pulsatile release
Repeat action
Doses released at intermittent intervals
Prolonged release
Drug available for absorption over a longer period
Sustained release
Initial release to reach therapeutic concentration followed by gradual release
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Modified Release Oral Drug Delivery Terms (2)
Extended Release (ER)
Slow release for Cp maintenance over 8-12 hours
Allows reduction in dosing frequency by half
Controlled Release (CR)
Drug release at a constant rate maintaining steady Cp
Modified release
Dosage forms designed to meet specific therapeutic or convenience objectives
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Modified Drug Release
Sustained Release
Active agent released over an extended time
Avoids undesirable sawtooth kinetic patterns in plasma concentration profile
Controlled Release
Rate of active agent’s release controlled over time
Maintains constant drug concentrations in target tissues
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Release Kinetics
Zero-order Release
Constant amount of active agent released per time
Release rate independent of remaining dose
First-order Release
Percentage of remaining active agents released per time
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Drug Plasma Level vs Time
Zero-order release
Sustained release
Immediate release
Toxic range definition
Therapeutic range definition
Sub-therapeutic range definition
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Mechanisms of Modified Release
Diffusion-based systems
Dissolution-based systems
Ion exchange systems
Osmotically controlled systems
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Diffusion System a. Reservoir Devices
Drug contained in reservoir surrounded by an insoluble polymer membrane
Release rate determined by membrane type
Formula: J = -D dc/dx
dM/dt = (A DK ΔC) / d
M: amount of drug released
A: surface area of device
D: diffusion coefficient
K: partition coefficient
ΔC: concentration difference across membrane
d: thickness of membrane
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Diffusion System b. Matrix Devices
Drug dissolved or dispersed in a water-insoluble polymer matrix
As drug dissolves, the matrix empties
Formula: M = [Dse/τ (2Co - eS) t]1/2
M: amount of drug released
D: diffusion coefficient in polymer
S: solubility of drug
Co: initial concentration
e: porosity
τ: tortuosity
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Dissolution-Based Systems
Forms can include:
Drug particles
Inert particles coated with drug
Conventional tablet surrounded by dissolving film
Drug embedded in a slowly dissolving matrix
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Dissolution Controlled Release Systems
Drug release sustained via different dissolution rates of coating around active ingredient
Formula: dM/dt = AD/h (Cs - Cb)
dM/dt: dissolution rate
A: surface area
D: diffusion coefficient
h: thickness of coating
Cs: concentration at solid surface
Cb: concentration in bulk solution
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Osmotically Controlled Release Systems
Drug surrounded by semi-permeable membrane that is permeable only to water
Drug pumped out at rate equal to volume flow of water into core multiplied by drug concentration
Formula: dV/dΔΠ = Ak h(ΔΠ − ΔP)
k: membrane permeability
A: area of membrane
h: membrane thickness
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Contact Information
King's College London
Email: Maya.Thanou@kcl.ac.uk