Transcript
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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
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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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