Presentation 1

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23/11/2010Polymers in Drug Delivery

SEMINAR ON

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1. INTRODUCTION3

DRUG DELIVERY

Historical Perspective4

Historical Perspective5

OBJECTIVE

Diseases with circadian rhythms.

Patients with chronic disorders.

To lowers Drug toxicity.

Drugs with short half life.

Delivery of proteins & peptides.

Improve patient therapeutic efficacy & compliance.

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pH Sensitive Polymers7

Smart / Intelligent/ Stimuli sensitive polymers Unique potential:-

modulation of drug release and targeting functionality.

Ex. N-isopropylacrylamide , CAP. Materials which will respond to the changes in the pH of the

surrounding medium by varying their dimensions

Such materials swell or collapse , goes soluble-insoluble phase

transition, accept or release depending on the pH of their

environment.

One which have acidic group (-COOH, -SO3H) and swell in

basic pH, Ex : Polyacrylic acid.

others which have basic groups (-NH2) and swell in acidic pH,

Ex: Chitosan .

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23/11/2010Polymers in Drug Delivery9

Sr. No.

Polymer Threshold pH

A. Polymethyl acrylates

1 Poly( methacrylic acid, ethyl acrylate) 1:1 5.5

2 Poly( methacrylic acid, methyl methacrylate) 1:1 6

3 Poly( methacrylic acid, methyl methacrylate, methyl 6.8 acrylate)

6.8

4 Poly( methacrylic acid, methyl methacrylate) 1:2 7

B. Polyvinyl acetate derivatives

5 Polyvinyl acetate phthalate 5

C. Cellulose derivatives

6 Hydroxy propyl methyl cellulose phthalate 4.5-4.8

7 Hydroxy propyl methyl cellulose phthalate 50 5.2

8 HPMC 55 5.4

9 Cellulose acetate trimelliate 5

10 Cellulose acetate phthalate 6

Specific absorption site.

Gastric fluid labile.

Targeting

Food-drug interactions

Reduced bioavailability

Circadian rhythm disease

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A = Release of drug as a “pulse” after a specific pH.B and C = extended release.

Figure No. 1 Drug release profile

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pH DEPENDENT DRUG DELIVERY SYSTEMS These are the controlled drug delivery systems, in which drug release

controlled by the stimuli (pH).

Before designing pH dependent DDS:- Symptoms of the disease Specific time for medication Drug plasma concentration Disease state, ex:Peptic ulcer. Drug pharmacokinetics Site specificity

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pH DEPENDENT DRUG DELIVERY SYSTEMS

Advantages:-

Decreased dose administration, side effects.

Improved drug utilization.

Improved patient compliance.

Drugs adapts to suit circadian rhythms of body function.

Protection of mucosa from irritating drugs.

Drug loss prevented.

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Approaches

Enteric coating systems

Colon targeted drug delivery systems

pH sensitive hydrogel

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1. Enteric Coated Systems

Intended for

Drug stabilization

Modified release

Narrow therapeutic index drugs

Short biological half-life

Drug targeting

Prevent irritation

Enteric coating:-

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Chemical name Abrivation

Functional group Soluble above pH

Trade name (Company)

Cellulose acetate phthalate CAPUSP23/NF18

Acetyl, phthalyl 6 CAP(Estaman comp.)Aquateric(Lehmann & voss)

Hydroxy propyl methyl cellulose phthalate HPMCPUSP23/NF18

MethoxyHydroxypropyl

Phthalyl

5 HP 50, HP55(Syntapharm)HP50 F, HP55 F(Syntapharm)

Hydroxy propyl methyl cellulose acetate succinateHPMCAS

MethoxyHydroxypropylAcetyl, Succinyl

5 HPMCAS-LHPMCAS-MHPMCAS-H(Syntapharm)

Carboxy methyl ethyl cellulose CMEC

Carboxy methyl ,Ethoxy.

5 Duodcell OQ (Lehmann & voss)

2. Colon targeted drug delivery systems

Therapeutics advantages:- Reducing the adverse effects For peptides and proteins delivery Avoid first pass metabolism Prevent gastric irritation Delayed release of drugs

Limitations:- Location Fluid content

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23/11/2010Polymers in Drug Delivery

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Polymer Threshold pHEudragit L 100 6.0

Eudragit S 100 7.0

Eudragit L-30D 5.6

Eudragit FS 30 6.8

Eudragit L 100-55 5.5

Polyvinyl acetate phthalate 5.0

Hydroxy propyl methyl cellulose phthalate 4.5-4.8

Hydroxy propyl methyl cellulose phthalate 50 5.2

HPMC 55 5.4

Cellulose acetate trimelliate 4.8

Cellulose acetate phthalate 5.0

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Specific polymers for colon targeting

Marketed formulation.

Drug Trade Name Coating Polymer / Formulation

Budesonide Budenofalk® Eudragit® S

(Dissolution Ph 7)

Mesalazine Mesazal® Eudragit® L100

(Dissolution pH-6)

Sulfasalazine Azulfidine® CAP (6.2-6.5)

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TYPE OF EUDRAGIT THRESHOLD PH

Eudragit E12.5 pH 5Eudragit E100 pH 5Eudragit E PO pH 5Eudragit L 12.5 P pH 6Eudragit L12.5 pH 6Eudragit L100 pH 6Eudragit L100-55 pH 5.5Eudragit L30 D-55 pH 5.5Eudragit S12.5 P pH 7Eudragit S12.5 pH 7

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MOSTLY USED POLYMER:- EUDRAGIT.

TYPE OF EUDRAGIT THRESHOLD pH

Eudragit S100 pH 7

Eudragit FS 30D pH 7

Eudragit RL 12.5 pH 5

Eudragit RL 100 pH 5

Eastacryl30 D PH 5.5

Kollicoat30 D pH 5.5

Acryl-EZE pH 5.5

Acryl-EZE MP pH 5.522

3. pH sensitive hydrogel

Intermediate behavior between solid and liquid materials.

Hydrogels are three-dimensional networks of hydrophilic

polymer chains that do not dissolve but can swell in water.

Bio-compatible

versatile materials

Contain ionizable group Ex. pH sensitive ionization of

polyelectrolyte's.

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Applications of Hydrogel.24

Controlled drug delivery:- Caffeine was loaded into Hydrogels made of copolymers of

methyl methacrylate & DMAEM released at zero-order at pH 3-5 .

Hydrogels made of polyanions (e.g., PAA) crosslinked with azoaromatic crosslinkers

Ofloxacin In situ gel with Carbopol ® 940 and Methocel E50LV (HPMC)

PVD hydrogel to release chlorpheniramine maleate.

RECENT APPROACHES

(1) TUMOR TARGETING :

Tumor Extracellular pH (pHe) Targeting

The acidic tumor pHe prompted researchers to design pH sensitive

targeting systems that targeted these tumors.

Two nanocarrier systems

1. Aggregation/shrinking (using weak acid) at tumor pHe

pH-sensitive polymers based on sulphonamide (SD) derivatives

capable of responding to pH changes as small as 0.2 pH units.

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2.Triggered Release by Polymeric Micelle Destabilization

block copolymers of poly(l-histidine) (polyHis) and PEG, and

the construction of polymeric micelles responded to the

local pH changes

micelles were stable at a pH of 7.4, their critical pH for

destabilization was approximately 7.0; below the pH, DOX

release was greatly accelerated

Continued…

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EUDRACOLTM

pH and time controlled multiple unit colon drug delivery systems

reduction of dosing frequency may be achieved. Due to its specific coating structure.

Different ratios at Eudragit L-100 and Eudragit S-100 Release of 5-ASA is depending on the thickness of the layer

and the ratio of Eudragit copolymers . Caffeine is used as marker drug

2. COLON TARGETING

(3) pH ACTIVATED DRUG DELIVERY30

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Biomimetic secretory granules.

Secretory granules with

polyanionic polymer network.

anionic microgels .

conjunction with

temperature-sensitive lipids.

NOVEL DRUG DELIVERY SYSTEM

(1) pH sensitive gel

(2) pH-SENSITIVE LIPOSOMES

stable at physiological pH & destabilize under acidic

conditions

stable pH-sensitive liposomes

can be produced using

NIPAAm copolymers.

Hyperbranched poly(glycidol)

(HPG)

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(3) pH-Sensitive Nanoparticles

Advantages:- translocated both transcellularly and paracellularly protect labile macromolecules increase transit times enhancing local and systemic delivery

pH-Sensitive Nanoparticles are matrix-type dispersed systems.

Application:-

natural polysaccharide pullulan for doxorubicin (DOX) release

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(4) pH-SENSITIVE MICROSPHERES

pH-dependent delivery system of nitrendipine in which they

have mixed three kinds of pH dependent microspheres made

up of acrylic resins Eudragit E-100, HPMCP and HPMCAS as

pH sensitive polymers.

For delivery of theophylline in colon mixture of the polymers,

i.e., Eudragit L and Eudragit S.

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Conclusion

Presently, oral delivery of drug is still by far the most preferable route of drug delivery .

sustained and controlled-release products provide a desired therapeutic effect, but fall short of diseases following biological rhythms.

Circadian disorders such as hypertension, osteoarthritis, asthma etc., which require chronopharmacotherapy. PSDDS can effectively tackle this problem as it is modulated according to body's circadian clock giving release of drug.

There are various technologies present in the market based on the various methodolgies. pH sensitive release systems should be promising in the future.

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