Introduction Mechanisms of controlled release Intelligent controlled release DDS Examples Recent advances References

Introduction:

Fluctuating plasma level in conventional DF.

Development of CR ,SR, TR Etc.

Targeted delivery

It has goal of delivering the drug to specific cell types, tissues or organs.

Controlled release

Assigned to release the DRUG at a PREDETERMINED Rate.

Modulated release

Release of drug at a variable rate controlled by

Environmental conditions, Biofeedback, Sensor input External control device.

Sustained release (SR)

In SR –Drug release is affected by External environment.

- Release is slow than conventional DF.

In CR – Release is dependant on the

design of dosage form.

DRUG RELEASE MODULATION

ADVANTAGES

DISADVANTAGES

DRUGS UNSUITABLE FOR CR

Different controlled release systems

Time of release

Cumulativerelease

Burst like release

Pulsatile release

Diffusion controlled release

Zero order (linear) release

Lag followed byBurst release

FACTORS GOVERNING THE

DESIGN OF CR DOSAGE FORMS

I. Drug related II. Biological III. Physiological IV. Pharmacokinetic V. Pharmacological

FACTORS GOVERNING THE DESIGN OF CR DOSAGE FORMS

aqueous solubility

protein bindingdrug stability

molecular size

partition coefficient

Drug relatedDrug related

FACTORS GOVERNING THE DESIGN OF CR DOSAGE FORMS

absorption

side effects

margin of safety

elimination

distribution

duration of action

disease state Biological

FACTORS GOVERNING THE DESIGN OF CR DOSAGE FORMS

Physiological

prolonged drug absorption

GI blood flow

variability on GI emptying & motility

FACTORS GOVERNING THE DESIGN OF CR DOSAGE FORMS

Pharmacokinetic

first pass metabolism

variability of urinary pH effect on drug elimination

dose dumping

FACTORS GOVERNING THE DESIGN OF CR DOSAGE FORMS

Pharmacological

changes in drug effect upon multiple dosing

Sensitivity / tolerance

BASIC PRINCIPLES OF CR

DIFFUSION

SWELLING

BIODEGRADABLE or BIOERODIBLE

Schematic depiction of various classes of controlled release system

Controlledrelease system Water penetration controlled

Swelling

Chemically controlled

Erodible

Hydrogel

DiffusionSwellingEnvironmental

Ion exchange resin

anioncation

Chemically

Diffusion

Reservoir and monolithic

Matrix

ReservoirDissolution

Encapsulation Matrix

Diffusion and Dissolution

osmotically

Drug linked polymer

DIFFUSION CONTROLLED SYSTEMS

MONOLITHIC-MATRIX SYSTEMS

Drug +

polymer

MONOLITHIC-MATRIX SYSTEMS Materials used as retardants in matrix tablet formulations :-MATRIX

CHARACTERISTICSMATERIAL

Insoluble, inert matrix

PolyethylenePolyvinyl chlorideEthylcellulose

Insoluble, erodable

Carnauba wax

Polyethylene glycol

Castor wax

hydrophilic

Methyl cellulose

Carboxypolymethylene

Sodium alginateHPMC

Oral system

RESERVOIR SYSTEMSRESERVOIR SYSTEMS

RESERVOIR SYSTEMS

First layer Of the drugcrystals

Polymer phase

Diffusion layer

DIFFUSION CONTROLLED SYSTEMS

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

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

Phase I – outer membrane layers

Phase II – reservoir matrix material

COMBINED RESERVOIR-MONOLITHIC SYSTEMS

Outer membrane layer (phase I)

Dispersed agent in polymer matrix(phase II)

COMBINED RESERVOIR-MONOLITHIC SYSTEMS

MonolithicMatrix (phase II)

Outer membrane(phase I)

Agent loadedMatrix layer

Agent depletedMatrix layer

Initially the release rate of diffusion through the phase 1 ,as the time progress ,a layer depleted from the active agent is generated in phase 11 reservoir material immediately adjacent to the membrane layer.

DISSOLUTION CONTROLLED RELEASE SYSTEMS

Two classes:Encapsulation dissolution control

Matrix dissolution control

Matrix Matrix dissolution controldissolution control

Membrane controlledMembrane controlled Polymer erosion controlledPolymer erosion controlled

drugdrug

membranemembrane

DIFFUSION & DISSOLUTION DIFFUSION & DISSOLUTION CONTROLLED SYSTEMSCONTROLLED SYSTEMS

Release rate is dependent on surface area diffusion coefficient

of drug though pore in coating

conc. of drug in dissolution media.

membrane

drug

WATER PENETRATION CONTROLLED SYSTEMS

rate control is obtained by penetration of water into the system.

classified into 2 parts.swelling controlled systems

osmotically controlled systems

SWELLING CONTROLLED SYSTEM

solvent

Swollen matrix Swelling zone

Unswollen polymer matrix

“Non-fickian case II” type diffusion

CHEMICALLY CONTROLLED SYSTEMS

delivery systems that change their chemical structure , when exposed to biological milieu

This system include biodegradable polymer that degrade within body as a result of natural biological process ,eliminating the need to remove the delivery system after exhausting of active agent from system

CHEMICALLY CONTROLLED SYSTEMS

The polymer degradation by 2 ways:

Bulk erosion surface erosion

MECHANISM OF POLYMER EROSION

Type IA – cleavage of cross links

Type IB – disintegration of water soluble polymer backbone

MECHANISM OF POLYMER EROSION

Type II – Water insoluble macromolecules are converted into water soluble compounds by hydrolysis, ionization or protonation of a pendent group.

hydrolysisIonizationprotonation

Water insoluble molecules Water soluble molecules

MECHANISM OF POLYMER EROSION

Type III – erosion mechanisim

Water insoluble molecules Water soluble molecules

Hydrolytic

cleavage

MECHANISM OF DRUG RELEASE

bioactive covalently linked to polymer backbone , scission of the bonds connecting the drug to polymer backbone.

List of biodegradable polymer

Polylactides (PLA). Polyglycolides (PGA).

Poly(lactide-co-glycolides) (PLGA).

Polyanhydrides. Polyorthoesters.

HYDROGELS

–Hydrogels are water swollen three dimensional structures composed of primarily hydrophilic polymers.

HYDROGELS

Classification:-1) Diffusion controlled release

- reservoir- matrix

2) Chemically controlled release - biodegradable polymers- covalently linked drug & polymer

3) Swelling controlled release4) Environmentally responsive hydrogel systems

Swelling controlled release consists of drug dispersion within glassy

polymer matrix. When the system comes in contact with biofluids, it starts swelling.

Drug releaseGlassypolymer

Swollen gel

water

HYDROGELS

Environmentally responsive hydrogel systems

The changes in network structure in response to external environment are reversible in nature.

T

pH pH

T-

-

Type of hydrogel Type of hydrogel

Super porous hydrogel pH sensitive hydrogel Temperature sensitive hydrogel Glucose sensitive system Neutral hydrogel Oral insulin hydrogel

Super porous hydrogelSuper porous hydrogel

Mainly for speedy swelling

Carried out by making very fine particle of dried hydrogel having short diffusion path length

Electronic microscopic fig of super porous hydrogel

Recent application of super Recent application of super porous gel in drug deliveryporous gel in drug delivery

DEVELOPMENT OF GASTRIC

RETENTION DEVICES

Development of fast dissolving tablet

Development per oral peptide delivery system

ION-EXCHANGE RESINION-EXCHANGE RESIN Zero order release obtained

kinetics Drug release depends only on the ionic environment of the resins containing drug

2 types.- cation exchange resin & anion exchange resin.

CATION EXCHANGE CATION EXCHANGE RESIN :-RESIN :-

Synthesized by copolymerization of divinyl benzene & styrene.

CH

CH

CH2

CH2

CH CH2

divinyl benzene

styrene

CH

SO3H

CH2 CH CH2

CH

CH

SO3H

CH2 CH2CH CH2

CH

CH

SO3H

CH2

CH

SO3H

CH2 CH

CH

CH2CH2CH2CH CHCH

SO3H CHCH

Anion exchange resinAnion exchange resin is prepared by

chloromethylation of benzene rings of three dimensional styrene-divinyl benzene copolymer network leading to insertion of –CH2Cl groups & forms strong anion exchange resin.

CH

Cl- (CH3)3N+CH2

CH2 CH CH2

CH

CH2 CH2CH CH2

CH

CH2

CH2 CH

CH

CH2CH2CH2CH CH

CHCH

CH2N+(CH3)3Cl-

CH

CH2N+(CH3)3Cl-

CH

CH2N+(CH3)3Cl-

CH

CH2N+(CH3)3Cl-

CH

INTELLIGENT CONTROLLED RELEASE DRUG DELIVERY SYSTEMS:-

Provide the bioactive in response to the physiological need & should ‘sense’ the changes & manipulate the drug release in response to external stimuli like heat, ultrasound, magnetic field, pH and/or conc. of specific molecules.

:-

CLASSIFICATION:CLASSIFICATION:

pulsatile systems responsive systems

systems utilizing chelation

systems utilizing enzymes

systems utilizing antibodies

INTELLIGENT CONTROLLED

RELEASE SYSTEMS

electically regulated ultrasonically modulated

magnetically modulated

photoresponsive

Glucose sensitive

inflammation responsive

thermosensitive

pH sensitive

urea responsive

glucose responsive

PULSATILE SYSTEMS :-

Magnetically modulated systems :-

No applied field

Field turn on Drug release

RESPONSIVE SYSTEMSRESPONSIVE SYSTEMS Glucose sensitive polymers :-

Glucose in Glycosylated insulin out

Polymer membrane

Glycosylated insulin

glucose

Concavalin A

Sepharose 4B beads

Glucose sensitive polymers :-

insulin

microcapsule

Polymer A Polymer B

release

glucose

RESPONSIVE SYSTEMSRESPONSIVE SYSTEMS

SYSTEMS UTILIZING ENZYMES

a) Urea responsive delivery systems Urea is converted into NH4HCO3 & NH4OH by the action of urease that increases the pH.

Hydrogel prepared by immobilizing urease In cross-linked bovine serum albumin

N-hyxyl half ester with dispersed drug

SYSTEMS UTILIZING ENZYMES b) Glucose responsive insulin

delivery :-This system utilizes enzyme-

glucose oxidase which converts glucose into gluconic acid.

Glucose + O2 gluconic acid + H2O

G

G

G

G

HNR2

HNR2

HNR2

HNR2

HNR2

HNR2

GluOx

G

NR2

NR2

NR2

NR2

NR2

NR2

GluOx

GluOx

G NR2

NR2

NR2

NR2

NR2

NR2

GluOx

GluOx

G

G

G

SYSTEMS UTILIZING ENZYMES

b) Glucose responsive insulin delivery :-

GOD GOD

HOOC COOH

insulin

GOD GOD

-OOC COO-

insulin

glucose

insulin

An insulin reservoir (like a regular syringe)

A small battery operated pump

A computer chip for control

Combination with Glucose sensors

Examples:

Insulin pump,Gluco

watch

Recent information

Polymer therapeuticscovers natural or synthetic polymers,

which have either inherent therapeutic potential or carry covalently bonded drugs. The covalently bonded drugs have to be released at the desired tissue or cell type. Polymeric therapeutics aree.g. polymeric drugs, polymer-protein conjugates, polymer-DNA complexes, polymer-drug conjugates or polymeric micelles.

Chemo mechanical polymer Chemo mechanical polymer drug delivery systemdrug delivery system

Chemomechanical polymers, developed by Professor Hans-Jorg Schneider and his team at the University of Saarland, Germany, have greatly improved functionality compared to existing expanding / contracting materials used to perform biomedical functions, and could be used in applications such as actuators, implants, drug release systems and drug screening.

New polymer enables near zero order drug release

Cavilink TMd

Highly porous polymer micro bead

Advance technologies in modified release from dosage form

TIMERx MASRx & COSRx systems

Procise (comprised of a compression coated core) Drug Delivery Systems Based on Geometric Configuration

Ringcap Technology – tablets

Advance technologies in modified release from dosage form

Smartrix system – multiple layered tab. Novel Erosion-Controlled Oral Delivery SystemTheriform Technology – novel method of fabrication based on three dimensional printing, a solid freeform fabrication technology- implantsAccudep technology – layered capsules

Advance technologies in modified release from dosage form

Threeform technology ,- Meltrex technology – melt extrusion process

Dissocubes –,IDD technology – insoluble drug delivery technology

Zydis oral fast dissolving dosage form. Orasolv & Durasolv – efficient

technologies for production of orally disintegrating tablets.

References:-

S.P.Vyas, R.K.Khar, Controlled drug delivery- concepts & advances., 1-50, 167

G.S.Banker, Modern Pharmaceutics, 3rd edition, 575 Chien Y.W., Novel fundamentals, developmental

concepts, biomedical assessments. Robinson & Lee, controlled drug delivery:

fundamentals and applications, 2nd edition. Donald L.Wise, Handbook of Pharmaceutical

controlled release technology, 443. Praveen Tyle , drug delivery devices: fundamentals

and applications, Marcel Dekker, 326-363, 376-382. James Swarbrick, James C. Boylan, Encyclopedia of

Pharmaceutical Technology, Marcel Dekker, III, 282, 297-311.

References:-

Remington: The Science and Practice of Pharmacy, 19th edition, 1660-1675

Leon Lachman, The Theory and Practice of Industrial Pharmacy, third edition, 453.

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Al-Shamkhani A. and Duncan R. Int. J. Pharm. 122(1995) , 107.

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References:-

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References:-

Joseph R. Robinson, Sustained release and controlled release drug delivery systems, volume 6,Marcel Dekker.

R.E. Notari, J. Pharm. Sci.,62, 865 (1973) G.L.Flynn, S.H. Yalkowsky and T.J. Roseman, J.

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