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1
Formulation and evaluation of
modified release oral solid dosage
forms
prof. dr. Saša Baumgartner
University of Ljubljana
Faculty of Pharmacy
Content
Terminology
Why modified release?
How to select appropriate API
Physiological consideration important at dosage from designing
Types of modified release – prolonged release Matrix systems
Reservoir systems
Osmotic controlled systems
Gastric retentive dosage forms
2
Modified/conventional release Conventional release dosage form
Preparations showing a release of API which is not deliberately
modified by special formulation and/or manufacturing method. In
case of a solid dosage form, the dissolution profile of API depends
essentially on the intrinsic properties of API
Synonymous: Immediate release dosage form
Modified release dosage forms
Preparations where the rate and/or place of release of API is different
from that of the conventional dosage form administered by the same
route. This deliberate modification is achieved by special formulation
design and/or manufacturing method. Modified release dosage forms
include:
prolonged release
delayed release
pulsatile release.
Modified release
Prolonged release dosage forms
Modified release dosage forms showing a slower release than that of the conventional
release dosage form administered by the same route. Prolonged release is achieved
by special formulation design/and/or manufacturing method.
Synonymous: extended release dosage form
Delayed release dosage form Modified release dosage forms showing a release of API which is delayed. Delayed
release is achieved by special formulation design and/or manufacturing method. The
release of API is delayed for a predefined period after administration or application of
the dosage form and then releases as a conventional dosage form resulting in a lag
time without any change in other pharmacokinetic parameters.
Pulsatile drug release
Pulsed or pulsatile drug release is defined as the rapid and transient release of a
certain amount of drug molecules within a short time-period immediately after a
predetermined off-release period
3
Some expressions regarding
modified release Controlled-release
Extended release
Sustained-release
Timed-release
Long-acting
Prolonged-action
Sustained-action
Why do we formulate modified release dosage
forms?
The main objectives is to produce safe, effective and patient-friendly drug delivery systems To reduce dosing frequency and thus increase acceptability
by patients
To increase the effectiveness of the API with a retention of the dosage form at the site of action
To decrease API doses and at the same time to maintain an optimum concentration of API in plasma and in this way to reduce the side effects associated with fluctuations in the plasma concentrations of "classic" dosage forms
To prolong the life cycle of the product
4
Comparison of plasma profils of API from conventional and
prolonged release tablets
Feasibility assessment of chemical entity for
controlled release delivery
Physical, chemical, biopharmaceutical therapeutic properties of API
Solubility (if <0.01mg/mL – inappropriate for incorporation into prolonged drug delivery systems)
Dosage(max 1g)
Stability (pH, enzymes, flora)
Lipofilicity /permeability, absorption site
Elimination t1/2 (from 2 to 8 h)
Therapeutic window – the risk of overdose
First-pass metabolism
PK / PD ratio
5
The importance of physiological factors
for proper formulation of prolged release
dosage forms The variable physiological factors: pH
enzymes
The movement of GIT - mechanical stress Transit time through the GIT
gastric emptying
Passage through the small intestine
Retention in the colon
Pathologic conditions
The possibility of local irritations (irritation of mucous membranes)
Gastrointestinal tract
6
Total transit time of dosage forms
through GIT
Depends on the physiological conditions (in
particular of the movement of the upper GIT)
and the properties of dosage form
most oral dosage forms with prolonged
release passes through the places where the
API can be absorbed faster than in 12 hours
total transit time can be influenced only by
keeping the dosage form in the stomach -
prolonged GRT
7
The impact of GIT movements on transit
of dosage forms
gastric movement gastric emptying
fasted fed fluids solid particles
4 phases (I)MMC peristalsis caloric content
volume
osmolarity, pH
retention of particle size
dosage form phase (I)MMC
in stomach volume
Motoric activity in fasted state – 4
phases of (I)MMC cycle
Faza I
Faza II
Faza III
Faza IV
Trajanje
(min)
45 – 60
30 – 45
5 – 15
0 - 5
1 min
8
Transit time of some dosage
forms Fluids and pellets (< 2mm) fast emptying from stomach
Single-unit dosage forms FO (>7 mm) – can stay in stomach for more than 10 h, if taken together with food
Transit time through intestine for most dosage forms is 3-4 h
Transit time can be prolonged only by retention of dosage form in the stomach
Transit time through the places of drug absorption is important – dosage forms with 12h of release can be designed (+ elimination time)
Single vs multiple unit dosage
forms
Single-unit dosage forms
Tablets, film coated tablets, matrix tablets,
capsules
Multiple-unit dosage forms
Granules, pellets, micropellets,
microspheres
Advantages and disadvantages
9
Composition of modified release dosage
forms (in general)
API
Controlled release substance Matrix former
Membrane former
Substances that modified properties of matrix or membrane Pore-formers
Surface active substances
Solubilazers/pH modifiers
Lubricants
Additional coatings for the delay of release
Mechanisms of prolonged
release Diffusion controlled release
Erosion controlled release
Dissolution controlled release
Osmotically controlled release
Ion-exchange controlled release
These mechanisms carried out
independently, together or sequentially
10
Diffusion controlled drug release
Matrix systems Hydrophobic matrices (polyvinyl chloride,
polyvinyl acetate, waxes, fatty acids, ethyilcellulose, copolymers of metacrylic acid)
Hydrophilic matrices (HPMC, HPC, HEC, PEO, xanthan, sodium alginate, polyacrylic acid)
Reservoir systems Insoluble polymers (ethyilcellulose, acrylates) +
plasticizer + pore formers
Tablets, granules, microspheres,...
u č in k o v in a
r e z e rv o a r
F ilm sk a o b lo g a
učin kovina
m atriks - ogrodje
11
Hydrophobic matrices
Diffusion rate depends on: Surface
Diffusion path
Concentration gradient
Diffusion coefficient
Diffusion controlled release -
theoretical background
Fick’s second law gets into more detail, telling us the
rate at which concentration (C) is changing at any
given point in time (t); D is diffusion constant and as
a default is constant
Analytical solutions equation with respect to certain
boundary conditions
z
CD
zy
CD
yx
CD
xt
C
12
A simplified solution for description the
diffusion-controlled release (Higuchi)
The boundary conditions are hypothetical matrix system, which does not dissolve and
does not swell
maintenance of pseudo steady-state during the release (constant thickness of the diffusion layer and a constant concentration gradient, which is only possible if the particles are infinitely large and flat)?!
particle diameter is smaller than the average distance of diffusion path of API through the polymer mesh
sink conditions
the diffusion coefficient in the matrix is constant
only diffusion takes place
The concentration of the API in the matrix is greater than its solubility in the polymer;
no interaction between the API and a polymer
(Higuchi) –a simplified and idealized example of
the release kinetics from the matrix system
2/1
02
tpCC
T
pCDSQ
sss
Q – amount of released drug; Ds – diffusion coefficient in
dissolution medium, Cs – drug solubility in medium; p –
porosity of matrix; T – tortuosity of matrix; C0 – total amount
of API in matrix
Higuchi also assumed that the dissolution of the active ingredient is
faster than its diffusion
tkQ 1
13
Hydrophilic matrix systems
Named also swelling matrix systems
The most important among modified release systems
Hydrophilic polymers in contact with the medium swell, forming a hydrogel, which slowly erodes and through the gel API is diffusing
Prolonged release matrix tablets
Non-swollen polymer
Swelling polymer with water-concentration-gradient
Disentageling polymer molecules
in water
Water
14
Analytical methods for investigation of hydrophilic
matrix tablets
P. Colombo et al . Journal of Controlled
Release 61 (1999) 83– 91
Tip
Tablet
Texture profiling of the XLBG matrix after different times of swelling in water
with 200 mM CaCl2 added.
Pavli et al. E-polymers, 2009
Analytical methods for investigation of hydrophilic
matrix tablets– oscillatory rheometry
Dependence of viscoelastic properties of 3% xanthan dispersion (G' and G'') from ionic strength (NaCl from 0.00 till 0.20 M. G'-full line in G'' – dashed line:
■□ - water, ▲∆ - = 0.01M, •○ - = 0.20M
Baumgartner et al. Eur.J Pharm Biopharm. 2008
gel
15
Composition of hydrophilic
matrix tablets API
Hydrophilic polymer (20 – 80%)
Fillers influencing matrix properties (sugars, polyols, salts) Enable faster and more even hydration
May cause cross-linking of polymer chains (alginate + calcium ions)
Influence on ionization of API - solubility
Solubilizers and pH modifiers
lubricants
Hydrophilic matrix tablets
Is this really that simple??
16
HPMC – golden standard for matrix
tablets - is there anything left
HPMC batches of the same viscosity and
substitution type, but with different
substituent pattern: great influence on
polymer erosion and drug release
Anna Viridén et al. European Journal of Pharmaceutics and Biopharmaceutics, 2011
The influence of xanthan polymer
structure on the drug release
natural origin,
biocompatible, GRAS
quality
XAN behavior
is related to its
polyelectrolyte nature
candidate for
controlled
release formulations
17
Natural polymers: synrgistic effect between
Xanthan gum (XAN) and locust bean gum (LBG)
0
1 0
2 0
3 0
4 0
5 0
6 0
7 0
8 0
9 0
1 0 0
0 2 4 6 8 1 0
t im e (h )
re
lea
se
d d
ru
g (
%)
X A N X A N -C a C l2
L B G L B G -C a C l2
X L B G = 3 :1 X L B G = 3 :1 -C a C l2
X L B G = 1 :3 X L B G = 1 :3 -C a C l2
Multi-layer tablets– hydrophilic
matrix tablets
18
Carrageenan based matrix
tablets Kappa (κ)-carrageenan
Iota ()-carrageenan
Lambda () - carrageenan
Doxazosin mesilate
Erosion and water uptake studies of ι-,
κ-, and λ-CARR matrices
0
20
40
60
80
100
120
0 2 4 6 8 10
Time (h)
Ero
sio
n
(%)
iotaiota NaClkappakappa NaCllambdalambda NaCl
0
500
1000
1500
2000
2500
0 2 4 6 8 10
Time (h)
Wate
r u
pta
ke (
%)
iotaiota NaClkappakappa NaCllambdalambda NaCl
Pavli M et ali, Int. J. Pharm, 2010
19
Dual release controll
DM release from
different CARR
matrices at 37 °C in a
pH 7.0 phosphate
buffer.
Advantages of hydrophilic
matrix tablets Simple manufacture (direct
compression, all types of
granulation)
Most ingredients are
relatively inexpensive and of
GRAS quality
Many of the active
ingredients can be
incorporated
Complete matrix erosion
Known manufacturing
technology
It is possible to achieve a
variety of release profiles
20
Disadvantages of hydrophilic
matrix tablets
Release depends on water diffusion into
matrix and API diffusion out of formed
hydrogel
Erosion can complicate the release
Problematic scale-up
Reservoir systems - mainly multi-
unit dosage forms
Multi-unit dosage forms
After application they are evenly distributed across
the GIT and therefore a lower risk for local
irritation and less likely for 'dose dumping'
Multiple Unit Pellet System - MUPS
ethyl cellulose film - to enable prolonged drug
release
21
Composition of reservoir
systems Core API
Filler
Solubilizer (can be, but not necessary)
Coating Polymer
Plasticizer
Pore former (if necessary)
Coloring agent
The addition of pore-former (HPMC) in ethyl
cellulose (EC) coated pellets influence drug
release
sugar core (550-750 μm)
dipiridamol (low soluble API, 20 mg) suspended into Opadry dispersion (HPMC E6 and PEG 400) and than it is by layering added to sugar cores
Pellets with API were then coated by Surelease E-7-19050 dispersion (water dispersion of EC wit oleic acid as plasticizer)
The influence of different ratios between EC (Surelease) coating and HPMC (Opadry) as pore former in it on the release of API
22
Dipiridamol release from EC coated pellets – no
pore former
Dipiridamol release from pellets coated by
EC/HPMC (coating12 % wg)
23
Press-coating – release mechanism can be
changed by different additives in coatings
Water soluble API in core ;
Coating from ethyl cellulose, additives of: spray-dried lactose
(SDL) or HPMC
Advantages and disadvantages
of reservoir systems Advantages of multi-unit More uniform gastric emptying
Less problems with dose dumping
Adoption of appropriate kinetics
Disadvantages Single unit systems - dose dumping
Multi-unit systems can not stay prolonged time in stomach – no influence on transit time
More complicated production than matrix systems
24
Lipid matrix systems Diffusion, dissolution or erosion controlled release
Direct compression, melting technologies
Usual composition: API
Lipid matrix former Melting T higher than 37°C, from 20 to 40% of total tablet
mass
Pore-former NaCl, sugars, polyols, API (20 – 30% of formulation)
Solubilizer and pH modifier
Lubricants
Dissolution controlled release
Low water soluble substance, inherently enable a prolonged release
Highly soluble API can be incorporated into slow dissolving carrier
a layer of API is exchanged with a layer slowly soluble coating (pulsatile release)
particles are coated with different thick coatings - (initial dose, maintenance dose)
25
Noyes-Whitney equation for description
of dissolution in steady state
Dissolution process can be described
also as layer by layer diffusion controlled
process (SIMPLIFICATIONS!!!)
CCA
h
DCCAk
dt
dC
SSd
dC/dt – dissolution rate; kd- dissolution rate constant; Cs –
saturated solubility; C – conc. solute in medium; D – diffusion
coefficient; h – thickness of diffusion layer; A – surface of
dissolving particle
26
The osmotically controlled release
Elementary Osmotic Pump
Core with API and osmotically active substances
(osmogene)
Semipermeable membrane with one or more laser
drilled orifice
API
H2O H2O
H2O
Semipermeable
membrane
osmogens
Delivery orifice
Drug release from
EOP
• Influx of water trough membrane into
core of dosage forms. Dissolution of
soluble components – solution of API is
forming
• Osmotic pressure forced API solution trough
delivery orifice
• Tablet membrane remains unchanged
API
H2O
Delivery orifice
H2O
H2O
H2O
H2O
H2O
H2O
H2O
27
System size
Osmotic pressure in system
Permeability of membrane for water
Membrane thickness
Drug release:
h
ACPP
h
AC
dt
dmd
W
t
Release rate is proportional with JW and can changed by
changing:
w
t
ACJdt
dm
h
PJ
W
w
= water flux into
system
PW = permeability of membrane for water
= difference in osmotic pressure through membrane
A = surface of the system
h = membrane thickness
C = conc. Od dissolved API in the core
Pd = permeability of membrane for API
Semipermeable membrane
core- tablet
Porous lower membrane layer
Thin coating for changing the tablet appearance
Upper membrane layer
•Water permeable, non permeable for API
•Non deformable
28
OROS Push-Pull systems
Before
application
After
application
Delivery
orifice Semipermeable
membrane
Pushing
layer
Layer with API
core
OROS Push-Pull systems
http://www.pharmatutor.org/articles/recent-advance-
pulsatile-drug-delivery-system?page=0,3
29
Advantages and disadvantages of OROS
systems Advantages They typically give a zero order release profile after an initial lag.
Deliveries may be delayed or pulsed if desired.
Drug release is independent of gastric pH and hydrodynamic condition; is minimally affected by the presence of food in gastrointestinal tract
They are well characterized and understood.
The release mechanisms are not dependent on drug.
A high degree of in-vitro and in-vivo correlation (ivivc) is obtained in osmotic systems.
The release rate of osmotic systems is highly predictable and can be programmed by modulating the release control parameters.
Disadvantages Expensive
If the coating process is not well controlled there is a risk of film defects, which results in dose dumping
Size hole is critical
Dose dumping
How to prolong GRT? - and increase biologic availability
- decrease of frquency of applications
The most important characteristics of dosage
forms to prolong GRT: size and density
To prolong GRT:
High density systems
Systems of different geometric shapes
Systems based on super-poruos biodegradable
hydrogels
Mucoadhesive systems
Magnetic systems
Floating systems
30
Mucoadhesive systems FO adheres to the surface of the gastric mucosa
Examples of bioadhesive substances:
partially cross-linked polyacrylic acid (Carbopol®,
Polycarbophil®), chitosan, polylactic acid, Na-alginate,
Disadvantages :
The surface of the mucosa, is completely renewed in
three hours
non-selective binding of the other substances present in
the stomach
improvements:
More specific Mucoadhesive materials - lectins
(binding to specific carbohydrates)
There is still no success
31
Floating systems
condition:
(dosage form) < (gastric fluid)
Hydrodynamically balanced systems(HBS)
Gas forming floating systems
Raft-forming systems - liquids
Low core density systems
Floating
tablet
Gel layer
Dry tablet core
Gastric fluid,
Density > 1
Erosion layer
Density of
swollen tablet < 1
Diffusion of API
Hydrodynamically
balanced
systems(HBS)
32
Gas forming floating systems
Improved floating mechanism Bubble formation (decreasing density)
composition: NaHCO3 + citric acid
Dry conditions at manufacture and keeping
Single unit systems: all or nothing
Multiparticulate systems
Systems with low core density
< 1 g/cm3
no ‘’lag-time’’, immediate floating
Oil or air is entrapped in core
Multi-unit systems, microbaloons, cross-linked hollow microspheres (dried by lyophilization)
The most promising floating systems
Frequent water intake is necessary
33
Design of floating tablets
investigation of tablet matrices (swelling, erosion, ...)
determination of tablet floating properties and selection of optimal matrix former
incorporation of API
optimization
evaluation
Floating properties of tablets
H P M C E 4 M H P M C K 4 M H P M C K 1 0 0 M H P C H EC
p re ssure A B A B A B A B A B
1 < 1 > 2 4 < 1 > 2 4 < 1 > 2 4 < 1 3 / /
2 < 1 > 2 4 < 1 > 2 4 < 1 > 2 4 1 - 8 0 ,3 - 1 ,5 / /
3 < 1 > 2 4 < 1 > 2 4 1 - 2 0 > 2 4 > 1 4 4 0 < 0 ,6 < 1 > 2 4
4 6 - 1 1 > 2 4 2 0 - 2 5 > 2 4 2 1 0 > 2 4 / / 7 - 9 0 ,3 - 1
5 1 0 - 2 0 > 2 4 5 7 > 2 4 > 1 4 4 0 < 0 ,6 / / > 1 4 4 0 < 0 ,6
A – time - tablets took to emerge on water surface (min)
B – time - tablets took to sink (h)
34
Formulation of tablets with API
Model API
Appropriate ratio between
API and polymer
Granulation and further
tableting
Low compressibility
Poor floating properties
High dosage
Standardization
of manufacture
Basic formulation
HPMC K4M : API.
Release
evaluation Highuci kinetics
35
Optimization of floating properties and release
Fast swellable polymer cetostearol
Increased incorporation of API
Primojel HPMC K100M
Decreased release
NaHCO 3 and citric acid Improved floating
Highuchi kinetic
Ac-Di-Sol
36
To conclude:
For the successful development of the
prolonged release dosage froms we need to
combine knowledge from different fields:
physiology
pharmaceutical technology
biopharmacy
pharmaceutical chemistry
Physics ...
Literatura
Qiu Y. Zhang G. Research and Development Aspects of Oral Controlled-Release Dosage forms. In. Wise DL (ed). Handbook of Pharmaceutical Controlled Release Technology; Marcel Dekker, NY, Basel, 2000.
P.L. Bardonneta, b, V. Faivrea, W.J. Pughc, J.C. Piffarettid and F. Falsona: Gastroretentive dosage forms: Overview and special case of Helicobacter pylori.Journal of Controlled Release.Volume 111, Issues 1-2 , 10 March 2006, Pages 1-18
Aulton’s Pharmaceutics
Ipd.