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Polymers in Drug Delivery 23/11/2010

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SEMINAR
ON
 1. INTRODUCTION
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 DRUG DELIVERY
 Historical Perspective
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 Historical Perspective
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 OBJECTIVE
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 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.
 pH Sensitive Polymers
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 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
 Continued…
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 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 .
Sr. Polymer Threshold pH
No.
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

910 Cellulose acetate phthalate Polymers in Drug Delivery 23/11/2010 6
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 Specific absorption site.

 Gastric fluid labile.
 Targeting
 Food-drug interactions
 Reduced bioavailability
 Circadian rhythm disease
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Figure No. 1 Drug release profile

A = Release of drug as a “pulse” after a specific pH.

B and C = extended release.
 pH DEPENDENT DRUG DELIVERY
SYSTEMS
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 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
 pH DEPENDENT DRUG DELIVERY
SYSTEMS
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 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.
 Approaches
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 Enteric coating systems

 Colon targeted drug delivery systems

 pH sensitive hydrogel
 1. Enteric Coated Systems
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 Intended for
 Drug stabilization
 Modified release
 Narrow therapeutic index drugs
 Short biological half-life
 Drug targeting
 Prevent irritation
 Enteric coating:-
Chemical name Functional group Soluble above Trade name
Abrivation pH (Company)
Cellulose acetate Acetyl, phthalyl 6 CAP(Estaman
phthalate comp.)
CAP Aquateric(Lehma
USP23/NF18 nn & voss)
Hydroxy propyl Methoxy 5 HP 50, HP55
methyl cellulose Hydroxypropyl (Syntapharm)
phthalate Phthalyl HP50 F, HP55 F
HPMCP (Syntapharm)
USP23/NF18
Hydroxy propyl Methoxy 5 HPMCAS-L
methyl cellulose Hydroxypropyl HPMCAS-M
acetate succinate Acetyl, Succinyl HPMCAS-H
HPMCAS (Syntapharm)
Carboxy methyl Carboxy methyl , 5 Duodcell OQ
ethyl cellulose Ethoxy. (Lehmann & voss)
CMEC
 2. Colon targeted drug delivery systems
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 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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Polymers in Drug Delivery 23/11/2010

 Specific polymers for colon targeting
19 Polymer Threshold pH
Eudragit 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
 Marketed formulation.
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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)
 MOSTLY USED POLYMER:- EUDRAGIT.
TYPE OF EUDRAGIT THRESHOLD PH

Eudragit E12.5 pH 5
Eudragit E100 pH 5
Eudragit E PO pH 5
Eudragit L 12.5 P pH 6
Eudragit L12.5 pH 6
Eudragit L100 pH 6
Eudragit L100-55 pH 5.5
Eudragit L30 D-55 pH 5.5
Eudragit S12.5 P pH 7
Eudragit S12.5 pH 7 21
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 5.5
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 3. pH sensitive hydrogel
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 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.
 Applications of Hydrogel.
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 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
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(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.
 Continued…
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 Continued…
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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
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 2. COLON TARGETING
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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
 (3) pH ACTIVATED DRUG DELIVERY
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 NOVEL DRUG DELIVERY SYSTEM
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(1) pH sensitive gel

 Biomimetic secretory granules.
 Secretory granules with

polyanionic polymer network.

 anionic microgels .
 conjunction with

temperature-sensitive lipids.
 (2) pH-SENSITIVE LIPOSOMES
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 stable at physiological pH & destabilize under acidic

conditions
 stable pH-sensitive liposomes

can be produced using

NIPAAm copolymers.
 Hyperbranched poly(glycidol)

(HPG)
 (3) pH-Sensitive Nanoparticles
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 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
 (4) pH-SENSITIVE MICROSPHERES
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 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.
 Conclusion
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 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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