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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

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

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

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

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!!!!