controlled release drug delivery systems - types, methods and applications
DESCRIPTION
Controlled Release Drug Delivery Systems - Types, Methods and ApplicationsTRANSCRIPT
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CONTROLLED RELEASE DDS
Project date 20/09/2013
Al Ameen College of Pharmacy
BY:
SURAJ CHOUDHARYM.PHARM (PHARMACEUTICS)DEPT. OF PHARMACEUTICS
Factors & Types
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Ppt. package
RECAP
FACTORS (Listed)
Dissolution Controlled DDS
Diffusion Controlled DDS
References
Recent Trends
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RECAP
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THEME QUESTION -1THEME QUESTION -2FLASHBACKCOMPARISON - 1COMPARISON - 2MOVEMENT RESTRICTIONSCRDDS DESIGN CONSIDERATIONSPRE-REQUISITESCLASSIFICATIONCONCEPT-BASED ON CLASSESRECENT INNOVATIONS
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FACTORSAFFECTING THE DESING OF CRDDS
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FACTORS Considerationfor
CRDDS Design
o Selection of drug candidateo Medical Rationaleo Biological Factorso Physico-Chemical Propertieso In vitro analysiso Formulation optimizationo In vivo data generationo Discussion with Regulatory
Authoritieso Data submission to Regulatory
Authorities for Marketing, Authorization / Approval.
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SELECTION OF Drug Candidate
Very short or very long half-life
X
Significant first pass
metabolism X
Poor absorption throughout the
GI tract X
Low solubility X
Large no. of dose X
Narrow therapeutic window X
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MEDICAL Rationale
Frequency of Dosing Patient compliance Drug intake Fluctuation of serum
concentration Reduced side effect Sustained efficacy
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BIOLOGICAL Rationale
Absorption Distribution Elimination Dose Dependent Bio-
Availability Drug -Protein Binding Duration of Action (Half –
life) Margin of Safety Disease Condition
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PHARMACO-KINETIC/DYNAMIC Considerations
Dose Dumping
First Pass metabolism
Enzyme Induction/Inhibition upon
multiple dosing
Variability of urinary pH effect on drug
elimination
Prolonged drug absorption
Variability in GI Empting and motility
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PHYSICO-CHEMICAL Considerations
Solubility &
pKa
Partition
Coefficient
Molecular Size
& Diffusivity
Dose size
Complexation
Ionization
Constant
Drug stability
Protein Binding
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ORDER OF REACTION - a review Zero Order Release: Delivery
rate remains constant until
device is exhausted of active
agent.
First Order Release: Release is
directly proportional to amount
of drug loaded in device.
Square-root-of-time(t-1/2)
Release: Release that is linear
with reciprocal of square root of
time.(release rate remains finite
even after device approaches
exhaustion)
dMt/dt = kMt – Mass of drugK – Rate constantt - time
dMt/dt = k(M0 - Mt)Mt – Mass of drugM0 – Initial mass of drugK – Rate constantt - time
dMt/dt = k t1/2
Mt – Mass of drugK – Rate constantt - time
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PHYSICO-CHEMICAL FACTORS
AFFECTING THE DESING OF CRDDS
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SOLUBILITY&pKa
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SOLUBILITY & pKa• The solubility of a solid substance is defined as…….
“ the concentration at which the solution phase is in equilibrium with a given solid phase at a stated temperature & pressure.”
• To improve solubility:
Solvation Complexation
Hydration Recrystallization
Co-solvation Use of surface active
agents
• NOTE: A classification is given as per the
permeability & solubility profile, known as BCS
Classification.
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SOLUBILITY & pKa• Determination of solubility:
1. Semi-quantitative method
2. Accurate-quantitative method
3. pH-change method
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SOLUBILITY & pKa• Absorption of poorly soluble drugs is often
dissolution rate-limited.
• Such drugs do not require any further control over
their dissolution rate and thus may not seem to be
good candidates for oral controlled release
formulations.
• Controlled release formulations of such drugs may
be aimed at making their dissolution more uniform
rather than reducing it.
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PARTITIONCOEFFICIENT
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PARTITION COEFFICIENT• The partition coefficient is defined as…….
“ the concentration ratio of unionized drug
distributed between two phases at equilibrium.”
• Given by the Noyes-Whitney’s Equation:
P = [ ] /([ ]∞) 𝐴 𝑜 𝐴
• The logarithm (base 10) of the partition coefficient
(log10P) is often used.
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PARTITION COEFFICIENT• For ionizable drugs, where the ionized species does
not partition into the organic phase, the APPARENT
partition coefficient, (D), can be calculated as:……….
Acids : log10D = log10P – log10 (1 + 10
(pH-pKa))
Bases : log10D = log10P – log10 (1 + 10
(pKa-pH))
• The octanol-water partition coefficient, (log10Pow), has
been widely used as a measurement for determining
the relative lipophilicity of a drug.
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PARTITION COEFFICIENT
• Drugs that are very lipid soluble or very water-
soluble i.e., extremes in partition coefficient, will
demonstrate
either low flux into the tissues or
rapid flux followed by accumulation in
tissues.
• Both cases are undesirable for controlled release
system.
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MOLECULAR SIZE&
DIFFUSIVITY
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MOL. SIZE & DIFFUSIVITY• In addition to diffusion through a variety of biological
membranes, drugs in many CRDDS must diffuse
through a rate controlling membrane or matrix.
• The ability of drug to pass through membranes, its
so called diffusivity, is a function of its molecular
size (or molecular weight).
• An important influence upon the value of diffusivity,
D, in polymers is the molecular size of the diffusing
species.
• The value of D thus is related to the size and shape
of the cavities as well as size and shape of the drugs.
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MOL. SIZE & DIFFUSIVITY• Molecular size of the drug plays a major role when it
comes to diffusion of the drug through a biological
membrane.
1. Mass spectroscopy (MS or LC-MS) are
generally used as the most common methods
to determine the molecular size of the drug.
2. Fourier Transform IR- spectroscopy (FTIR) is
also used to determine the molecular
structure.
• Diffusion of the drug from the matrix or
encapsulated form determines the release rate of
the drug from the polymer.
• Diffusivity is the rate determining step in CRDDS.
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DOSESIZE
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DOSE SIZE• Size of the drug plays a major role in determining
the size of the final finished product.
• In case, the dose already high, then formulating the
same into controlled release will further increase the
overall dosage size & thereby reduced patient
compliance.
• For drugs with an elimination half-life of less than 2
hours as well as those administered in large doses,
a controlled release dosage form may need to carry
a prohibitively large quantity of drug.
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COMPLEXFORMATION
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COMPLEXATION
• Complexation is one of the well known method to
entrap the drug within a complexing agent like β-
cyclodextrin complex.
• These complexes could be helpful in entrapping
drugs of very high molecular weight which have low
diffusivity through the membrane.
• From formulation point of view, this property also
facilitates in increasing the solubility of the drug in
the required solvent.
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IONIZATIONCONSTANT
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IONIZATION CONSTANT• This factor have important effects on a wide range of
issues including, Dissolution, Membrane partition,
Complexation, Chemical stability & drug absorption.
• From the site of release of the drug, it’s absorption
depends upon its ionization constant.
• And, it has been depicted that drugs in unionized
form are absorbed faster than the ionized species.
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IONIZATION CONSTANT• The Henderson-Hasselbalch eq. provides an estimate
of ionized & unionized drug conc, by function of
pH…………
Acidic drugs: pKa = - log10(Ka) = pH +
log10([HA]/[A-])
Basic drugs : pKa = - log10(Kb) = pH +
log10([HB+]/[B-])
• Where:
Ka or Kb = ionization constant for acid/basic drugs
[HA] = conc. of unionized acid
[A-] = conc. of ionized acid
[HB+] = conc. of the unionized base
[B] = conc. of the ionized base
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STABILITYOF DRUG
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DRUG STABILITY• Since most oral controlled release systems are
designed to release their contents over much of the
length of GI tract,
drugs that are unstable in the environment
of the intestine
drugs that are unstable in the environment
of the stomach
• might be difficult to formulate into prolonged
release system.
• In order to counter-act such problems, several
modified-release methods have been adopted that
restricts the release at the required site of the GIT.
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PROTEINBINDING
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PROTEIN BINDING• It refers to the formation of complex with the blood
proteins (like albumin) with the absorbed drug.
• This complex leads to….
Inhibition of therapeutic effect of such
amount
Half-life is increased (compared to invitro
studies)
Toxicity profiles elevated
• Thus, in most of the cases, protein binding is
undesirable.
• Many drugs are highly protein binding (may be 95%),
thus the need of formulating a modified drug or drug
delivery system starts.
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NOTE- 1 & 2
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NOTE – 1
• Generally, the values of diffusion coefficient for
intermediate molecular weight drugs i.e., 150-400
Dalton, through flexible polymers range from 10-6 to
10-9 cm2/sec, with values on the order of 10-8 being
most common.
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NOTE – 2
• For drugs with molecular weight greater than 500
Dalton, the diffusion coefficients in many polymers
frequently are so small that they are difficult to
quantify, i.e., less than 10-12 cm2/sec.
• Thus, high molecular weight of drug should be
expected to display very slow release kinetics in
sustained release devices where diffusion through
polymeric membrane or matrix is the release
mechanism.
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Approaches in Design Considerations
Chemical approach
Biological approach
Pharmaceutical approach
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PHARMACEUTICAL Approaches
C. Dissolution-Diffusion
Controlled
(Combination)
A. Dissolution controlled
Release Encapsulation dissolution
control Matrix dissolution control
B. Diffusion Controlled
Release Membrane material Solution-diffusion
membrane Rate of permeation
• Drug diffusion coefficient in the polymer
• Polymer/solution partition coefficient
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PHARMACEUTICAL Approaches
A. Dissolution controlled Release
Encapsulation dissolution
control
Matrix dissolution control
B. Diffusion Controlled Release
Reservoir devices
Matrix devices
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DISSOLUTION CONTROLLED
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INTRODUCTION• Control – Dissolution of the drug from the
polymer matrix or encapsulated forms.• The dissolution process at a steady state is
described by Noyes Whitney equation: dc / dt = k A/V (Cs – C)
dc / dt = (D/h) A (Cs – C)where, dC/dt = dissolution rate
V = volume of the solution k = dissolution rate constant D = diffusion coefficient of drug through pores h = thickness of the diffusion layer A = surface area of the exposed solid Cs = saturated solubility of the drug C = conc. of drug in the bulk solution
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TYPES• Of following types based on TECHNICAL
SOPHISTICATION:
1. Matrix type
2. Encapsulation type
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MATRIX type(Dissolution-Controlled)
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MATRIX type• Matrix dissolution devices are prepared by compressing
the drug with slowly dissolving carrier into tablet • Controlled dissolution by: 1.Altering porosity of tablet. 2.Decreasing its wettebility. 3.Dissolving at slower rate.
Drug Reservoir
Rate-Controlling surface
Drug
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MATRIX type
• First order drug release.• There are 2 methods:
1. Congealing & 2. Aqueous dispersion method
• The drug release is determined by dissolution rate of the polymer.
• Examples: 1. Dimetane extencaps, 2. Dimetapp extentabs.
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ENCAPSULATED type(Dissolution-Controlled)
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ENCAPSULATION type
• The drug particle are coated or encapsulated by
microencapsulation technique
• The pellets are filled in hard gelatin capsule,
popularly called as ‘spansules’.
• Once the coating material dissolves the entire drug
inside the microcapsule is immediately available for
dissolution and absorption.
• Here the drug release is determined by dissolution
rate and thickness of polymer membrane which may
range from 1 to 200µ
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ENCAPSULATION type
• Called as Coating dissolution controlled system.
• Dissolution rate of coat depends upon stability &
thickness of coating.
• One of the microencapsulation method is used.
• Examples:
1. Ornade spansules,
2. Chlortrimeton Repetabs
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ENCAPSULATION type
Soluble drug
Slowly dissolving or erodible coat
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DIFFUSION CONTROLLED
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INTRODUCTION• This system is hollow containing an inner core of drug.
• The water insoluble polymeric material surrounds drug
reservoir.
• The drug partitions into the membrane and exchanges
with the surrounding fluid by diffusion.
• The release drug from a reservoir device follows Fick’s
first law of diffusion.
J = - D dc/dx
Where, J = flux, amount/area-time
D = diffusion coefficient of drug in the polymer,
area/time
dc/dx = change in conc. with respect to polymer
distance
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TYPES• Of following types based on TECHNICAL
SOPHISTICATION:
1. Reservoir Devices
2. Matrix Devices
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RESERVOIR Devices(Diffusion-Controlled)
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Reservoir device
a) Spherical type
b) Slab type
RESERVOIR DEVICES
Rate controlling steps :
• Polymeric content in coating,
• Thickness of coating, • Hardness of
microcapsule.
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RESERVOIR Devices• The drug core is encased by a water-insoluble
polymeric materials.
• The mesh (i.e., the space between macromolecular
chains) of these polymers, through which drug penetrates
or diffuses after partitioning, is of MOLECULAR LEVEL.
• The rate of drug release is dependent on the rate of drug
diffusion but not on the rate of dissolution.
• In short, mass transport phenomena at molecular level
occurs.
• Examples: Nico-400, Nitro-Bid
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Methods of Prep. (RESERVOIR Devices)
• Mostly it involves :
o Coated Beads/Pellets
o Microencapsulation
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Coated Beads/Pellets (RESERVOIR Devices)
• BEADS/PELLETS
Coating of drug solution onto preformed cores.
Covering of core by an insoluble (but permeable
coat).
NOTE: Pan coating or air-suspension technique is
generally used for coating.
NOTE: Pore forming additives may be added to the
coating solution.
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Microencapsulation (RESERVOIR Devices)
• This technique used to encapsulate small particles
of drug, solution of drug, or even gases in a coat
(usually a polymer coat).
• Generally, any method that can induce a polymer
barrier to deposit on the surface of a liquid droplet
or a solid surface can be used to form microcapsules.
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Microencapsulation (RESERVOIR Devices)
• Techniques:
1. Coacervation (Polymers: gelatin, acacia,
PA, EC, etc.)
2. Interfacial polymerization (Polymers:
polyurethanes, polyamides,
polysulfonamides, polyphtalamides, etc.)
3. Solvent evaporation
4. Others (thermal denaturation, hot melt,
spray-drying, salting out, etc.)
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MATRIX Devices(Diffusion-Controlled)
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matrix devicesDRUG DELIVERY FROM TYPICAL MATRIX DEVICES
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MATRIX Devices
• A matrix or monolithic device consists of an inert
polymeric matrix in which a drug is uniformly
distributed.
• Drugs can be dissolved in the matrix or the drugs
can be present as a dispersion.
NOTE : Matrix may be HOMOGENEOUS or POROUS
with water filled pores.
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MATRIX Devices
• State of presentation of this form affects the various
release patterns:
1. Dissolved drug (Fick’s Second law)
2. Dispersed drug (Fick’s First law)
3. Porous matrix (Higuchi’s theory for
porous form)
4. Hydrophilic matrix (gelation & diffusion)
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MATRIX Devices
• Rigid Matrix Diffusion
Materials used are insoluble plastics such as
PVP & fatty acids.
• Swellable Matrix Diffusion
1. Also called as Glassy hydrogels.Popular for
sustaining the release of highly water soluble drugs.
2. Materials used are hydrophilic gums.
Examples : Natural- Guar gum, Tragacanth.
Semisynthetic -HPMC, CMC, Xanthum gum.
Synthetic -Polyacrilamides.
• Examples: Glucotrol XL, Procardia XL
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RECENT Trends(Marketed Products)
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Recent Trends• Products in market:
Cordicant -uno®
Madopar DR
SULAR ER
• This technology controls amount,
timing and location of release in
body.
• Formulation with predictable and
reproducible drug release profile.
• Controls rate of drug diffusion
throughout release process,
ensuring 100% release Products
Recent trends: Geomatrix® (SKY Parma)
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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.
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THANK YOU.For Attention!!!!