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.