Design and fabrication of Oral-CRDDS....2 - Copy.pptx

Design and fabrication of Oral Dissolution
and Diffusion CRDDS
1

Flow of Presentation
Introduction
Different Mechanisms For Oral-CRDDS Formulations
Dissolution Controlled Release
Diffusion Controlled Release
Diffusion & Dissolution Controlled Systems
Different Tablet Technologies
Conclusion
2

Introduction
• Controlled drug delivery is one which delivers the drug at a
predetermined rate, for locally or systemically, for a
specified period of time.
• Continuous oral delivery of drugs at predictable &
reproducible kinetics for predetermined period throughout
the course of GIT.
3

Controlled release mechanism of
drug
• Mechanisms of drug release from oral controlled delivery
systems can be broadly divided into following categories:
Controlled
Release
Dissolution
controlled
release
Matrix
dissolutio
n control
Reservoir
dissolutio
n control
Diffusion
controlled
release
Matrix
diffusion
control
Reservoir
diffusion
control
Dissolution &
Diffusion
controlled
release
Osmotic
controlled
release
Gastroretent
ive systems
Ion
exchange
resins
Regulated
systems
4

Mechanism aspects of Oral drug delivery
formulation
1.Dissolution Controlled : 1.Matrix System
2.Encapsulation Device
2.Diffusion Controlled : 1.Matrix System
2.Reservoir System
3. Combination of both Dissolution & Diffusion Controlled
Release
5

DISSOLUTION CONTROLLED
RELEASE
• Dissolution based controlled release oral formulations are
simplest to prepare.
• Some drugs have very high solubility that they don’t get enough
time to get absorb through GIT membrane and readily get
eliminated out.
• For this reason the controlled release systems can help to retain
the drug at absorption site.
• In dissolution controlled systems the release of drug from the
carrier controlled by two factors:
❖Dissolution of the drug
❖Dissolution of the carrier matrix
6

A. Slow dissolution rate of drugs
• Drugs with inherently slow dissolution rate : The drug with
slow dissolution rate are inherently sustained. e.g. Griseofulvin,
Digoxin, Nifedipine and Saliyclamide & they act as natural
prolonged release products.
• Drugs that transform into a slow dissolving form on contact
with GI fluid : Aluminum, Aspirin and ferrous sulfate produce
slow dissolving form when it comes in contact with GI fluids.
7

B. Slow Dissolution rate of the reservoir
membrane or matrix
• Drugs having high aqueous solubility and dissolution rate,
shows challenge in controlling their dissolution rate.
• Dissolution-controlled release can be obtained by
➢ slowing the dissolution rate of a drug in the GI medium,
➢incorporating the drug in an insoluble polymer
➢coating drug particles or granules with polymeric materials of
varying thickness.
8

Dissolution Controlled Release Systems
Comprise Two classes:
I. Encapsulation dissolution control
Where the drug is eencapsulated in the rate
controlling polymer coating from which the drug is
released at a definite rate.
II. Matrix dissolution control
In this system the drug is embeded in the
hydrophobic material in which the drug release rate is
controlled by the rate of dissolution of hydrophobic
matrix.
12

Encapsulation/Coating dissolution
controlled system (Reservoir Devices):
❖Encapsulation involves coating of individual particles, or
granules of drug with the slowly dissolving material.
❖ Dissolution rate of coat depends upon stability & thickness
of coating.
❖ Masks colour, odour, taste, minimising GI irritation.
13

❖ Called as Coating dissolution controlled system.
❖ One of the microencapsulation method is used.
❖ The particles obtained after coating can be compressed
directly into tablets as in SPACETABS or placed in capsules
as in the SPANSULE products.
❖ Examples: Ornade spansules, Chlortrimeton Repetabs
As the time required for dissolution of coat
is a function of its thickness and the
aqueous solubility of the polymer one can
obtain the coated particles of varying
thickness in the range of 1- 200 micron.
14

By using one of several microencapsulation techniques the drug
particles are coated or encapsulated with slowly dissolving
materials like
➢ Cellulose,
➢ Polyethylene Glycols,
➢ Polymethacrylates,
➢ Waxes etc.
Two methods of preparation are mainly employed :
1. Seed or granule coating
2. Microencapsulation
15

Seed coating
• Common procedure is to coat non-pareil seeds with the drug
followed by a coat of slowly dissolving materials like PEG,
polymeric materials and carbohydrate sugars and cellulose.
• One quarter to one-third of the seeds in non-sustained form to
provide immediate drug release.
• Remaining three quarters or two-third of the seeds being divided into
groups of varying coating thickness to provide for controlled effect
over the desired time period.
• Some of the important coating materials with their specific properties
are given in next slides:
16

20
Sodas® Multilayer Tablet
• Developed by Elan drug technologies
• Production of controlled release beads
• Enables the production of customized dosage forms leading to a pulsatile
drug release
• Shows controlled absorption with resultant reduction in peak to trough
ratios
• Gives targeted release of the drug within the gastrointestinal tract
• Absorption independent of the feeding state
• Suitable for use with one or more active drug candidate
• Once or twice daily dose resembling multiple daily dose profiles
Kovanya Moodley et al., Int. J. Mol. Sci., 2012, 13, 18-43

• Drug is encapsulated in the polymeric membrane in which slow
dissolution of the polymer wall results into controlled release of
the drug.
• Various techniques can be used for microencapsulation of
drugs.
• Varying the thickness of coat and type of material used for
microencapsulation can result in different release patterns from
the microcapsules.
• Microencapsulation has the additional advantage other than
controlled release that they can mask the taste of drug with
better GIT tolerability.
• For example Microencapsulated Aspirin and Potassium chloride
MICROENCAPSULATION PROCESSES
21

Different microencapsulation techniques
22

2. Matrix (or Monolith)/ Embedded
dissolution controlled system.
1. Since the drug is homogeneously dispersed throughout a rate
controlling medium matrix system are also called monoliths.
2. The waxes used for such system are beeswax, carnauba wax,
hydrogenated castor oil etc.
3. These waxes control the drug dissolution by controlling the
rate of dissolution fluid penetration into the matrix by altering
the porosity of tablet, decreasing its wettability or by itself
dissolved at a slower rate.
23

Controlled dissolution by:
1.Altering porosity of tablet.
2.Decreasing its wettebility.
3.Dissolving at slower rate.
➢The dispersion of drug in wax is prepared by dispersing the drug
in the molten wax followed by congealing and granulating the
same.
➢The process, compression parameters and size of particles
formed determine the release rate from this system. The drug
release is often first order from such matrices.
➢Drug release determined by dissolution rate of polymer.
➢Examples: Dimetane extencaps, Dimetapp extentabs.
24

25
Smartrix® technology
• Developed by Lohmann Therapie-Systeme
• Triple layered tablet
• Drug core with a specific shape (biconcave) is enclosed between two
rapidly erodible outer layers tightly bond to after compression
• Drug release controlled by thickness of the outer layers and the shape of
the drug core
• No specialized polymers required to perform the desired function
• Disadvantage- requirement of specialized dry tablet press machines

26
VersaTab® bilayered tablet technology
Time (hr) Time (hr)
Drug
release
(%)
Drug
release
(%)
One bioactive-controlled
release
Two bioactives-immediate release
and controlled release
• Linear drug release through controlled erosion
• Designs tablets with the ability to co-release multiple drugs with different
release rates
• Suitable for a large number of bioactives
• The tablet is highly versatile with a broad range of delivery profiles and
improved patient compliance
• Tablet with one bioactive provides controlled release or with two bioactives
to provide immediate release and controlled release

DIFFUSION CONTROLLED
➢ In these type of system the rate controlling step is not dissolution rate but
the diffusion of dissolved drug through a polymeric barrier.
➢Since the diffusional path length increases with time as the insoluble matrix
is gradually depleted by the drug and the release of drug is never zero order.
➢No energy required.
➢Drug molecules diffuse from a region of higher concentration to lower
concentration until equilibrium is attainded.
➢Directly proportional to the concentration gradient across the membrane.
➢This system are broadly classified into two categories
Reservoir system and
Monolithic system.
27

1. Reservoir devices :
➢ Hollow system containing an inner core surrounded in water
insoluble membrane
➢ Polymer can be applied by coating or micro encapsulation.
➢ Drug will partition in to the membrane and exchange with
fluid surrounding the particle or tablet.
➢ Rate controlling mechanism - partitioning into membrane
with subsequent release into surrounding fluid by diffusion.
➢ Additional drug will enter the membrane, diffuse to the
periphery and exchange with the surrounding media.
➢ Commonly used polymers - HPC, ethyl cellulose &
polyvinyl acetate.
➢ Examples: Nico-400, Nitro-Bid
28

Reservoir System
Rate controlling steps :
Polymeric content in
coating, thickness of
coating, hardness of
microcapsule.
29

Figure: Showing release of drug from a reservoir type of system
Contd…..
30

➢Coating or microencapsulation and Air suspension techniques
are used to apply polymer.
➢The permeability of membrane depend on thickness of the
coat/concentration of coating solution & on the nature of
polymer, ethyl cellulose and polyvinyl acetate are the commonly
used polymer in such devices.
31

Where,
A = is the active diffusion area.
D = is the diffusion coefficient of the drug across the coating membrane.
l = is the diffusional path length (thickness of polymer coat)
ΔC = is the concentration difference across membrane
K = is the partition coefficient of the drug between polymer and the
external medium.
➢ To obtain a constant drug release rate from a reservoir device it is
necessary to maintain constant surface area, diffusional path length,
concentration and diffusion coefficient.
➢ But in many of the formulations the above terms will change in the
product, thus giving rise to non-zero order release.
33

34
Table: Preparation and evaluation of Reservoir type Devices

2. Matrix diffusion controlled system
❖In these system the drug is dispersed in insoluble matrix of
rigid non swellable hydrophobic materials or swellable
hydrophilic substances.
❖ Insoluble plastics such as PVC and fatty materials like stearic
acid, beeswax etc are the material used for rigid matrix.
❖The drug is generally kneaded within the solution of plastic
material such as PVC in an organic solvent and granulated.
❖The wax drug matrix is prepared by dispersing the drug in
molten fat followed by congealing.
36

Matrix system
Rate controlling step:
Diffusion of dissolved drug
in matrix.
37

The equation describing drug release for this system is given by T. Higuchi.
Q=[Dἐ /T (2a-ἐCs)Cs t]1/2
Q = weight in gram of drug release/unit surface area
D = diffusion coefficient
Cs = solubility of drug in the release medium
ἐ = Porosity of matrix
T = tourtuosity of matrix
A = Concentration of drug in the tablet express as g/ml
38
Monolithic - Matrix Systems

MONOLITHIC-MATRIX SYSTEMS
Materials used as retardants in matrix tablet
formulations :-
MATRIX CHARACTERISTICS MATERIAL
Insoluble, inert matrix
Polyethylene
Polyvinyl chloride
Ethylcellulose
Insoluble, erodable
Carnauba wax
Polyethylene glycol
Castor wax
hydrophilic
Methyl cellulose
Carboxypolymethylene
Sodium alginate
HPMC
39

40
Table: Fabrication and Evalution of Matrix Devices

43
Geomatrix® Multilayer Tablet
• Developed by Conte and co-workers
• Triple-layered tablet- an active core of hydrophilic matrix layer with two
polymeric barrier layers on either side (hydrophobic or semi
permeable)
• Bilayered tablet- the drug layer and one barrier layer
• Barrier layer modifies swelling rate of the active core and reduces the
surface area available for diffusion of drug
• Zero-order drug release can be achieved
• Limited to one drug only

44
Geolock TM technology
• Devised for chronotherapy
focused-real time oral drug
delivery
• The timed delivery of drugs
with high degree of precision
• Employs a press-coating
technique
• An active drug core (middle
layer) surrounded by two
outer protective layers
• The inner core can be a
single or combination of
drugs

Diffusion Controlled Systems
Matrix system
o Achievement of zero order is
difficult
• Suitable for both degradable &
non-degradable systems
• No danger of dose dumping
• Not all drugs can be blended
with a given polymeric matrix
Reservoir system
• Achievement of zero order is
easy
• Degradable reservoir systems
may be difficult to design
• Rupture can result in dangerous
dose dumping
• Drug inactivation by contact
with the polymeric matrix can
be avoided
45

46
Dissolution & Diffusion Controlled Release system
• Drug encased in a partially soluble membrane.
• Pores are created due to dissolution of parts of
membrane.
• It permits entry of aqueous medium into core
& drug dissolution.
• Diffusion of dissolved drug out of system.
• Ex- Ethyl cellulose & PVP mixture dissolves
in water & create pores of insoluble ethyl
cellulose membrane.
Insoluble
membrane
Pore created by
dissolution of
soluble fraction of
membrane
Entry of
dissolution
fluid
Drug
diffusion

• The release profile of drug from this type of product can be
described by the following equation:
Release rate = AD(C1 – C2)/ l…………………(8)
Where
A = Surface area
D = Diffusion coefficient of drug through pore
l = Diffusional pathlength
C1= Concentration of drug in the core and
C2 = Concentration of drug in dissolution media
The fraction of soluble polymer in the coat will be the dominant
factor controlling drug release.
47

Diffusion & Dissolution Controlled Systems
Release rate is dependent on
• surface area
• diffusion coefficient of drug though
pore in coating
• conc. of drug in dissolution media.
48

Procise® Technology
49
Aerial schematic Two-dimensional schematic
• It is composed of a core which contains uniformly dispersed drug with
a core hole in the middle
• Altering the geometry of the core can change the drug release kinetics
into zero-order or even first order if desired
• Drug release occurs solely from the cylindrical area
• The device is also able to deliver up to two drugs simultaneously with
varying release profiles

Tablet Technology For OCDDS
50
Geomatrix®
Sodas®
Smartrix®
VersaTab®
Geolock TM
Procise ®
Dome Matrix ®

Polymeric formulations of multi-layered tablets and
possible drug release behaviour
51

Effect Of System Parameters On CDDS
52 52
✓Polymer & Solution Solubility
✓Polymer & Solution Diffusivity
✓Partition Co-efficient
✓Thickness of polymer diffusion path & hydro-
dynamic layer
✓Surface Area
✓Loading Dose

Conclusion
53
❖ From this discussion, we can conclude that the CDDS is very
helpful in increasing the efficiency of the dose as well as the
patient compliance.
❖ The OCDDS has received huge attention due to its flexibility,
prolong the drug release leading to minimize the peak and valley
and thus resulting reduced dosing frequency.
❖ The reasonable cost of OCDDS has lead ease of market
penetration as replacement of oral conventional drug delivery
system.
❖ Future research may thus focus further on modifying these
systems and using the basic technological principles to develop
novel systems that may be able to be applied in broader and more
complicated drug delivery.

References
1. Chien Y W; Novel Drug Delivery Systems; Informa Healthcare, 2nd
Edition, 2009.
2. Siegel R A and Rathbone M J; Overview of Controlled Release
Mechanisms; Advances in Delivery Science and Technology, 2012.
3. Bhowmik D, et.al; Recent trends in scope and opportunities of control
release oral drug delivery systems; Critical review in pharmaceutical
sciences, (1): 2012.
4. Ummadi S, Shravani B; Overview on Controlled Release Dosage Form;
International Journal of Pharma Sciences, 3(4); 2013.
5. Robinson J R and Lee H L V: Controlled drug Delivery , Fundamentals
and Applications; Marcel Dekker Inc., New york. 2nd Edition, 1987 , page
no. 373-412.
54

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