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    Recent updates in synthetic  polymers used in drug delivery systems Recent updates in synthetic polymers used in drug delivery systems Presentation Transcript

    • Recent updates in synthetic polymers used in drug delivery systems KUSUM SINGH NEELAM SINGH I.T.S. PHARMACY COLLEGE,GHAZIABAD, INDIA
    • CONTENTS
      • INTRODUCTION
      • DEFINITION
      • CLASSIFICATION
      • PROPERTIES & SELECTION OF SYNTHETIC POLYMERS
      • SYNTHETIC POLYMERS USED IN DRUG DELIVERY SYSTEMS
    • INTRODUCTION
      • Significant advances have been made in development of various drug delivery devices with the help of polymers.
      • The earliest DDS first introduced in 1970s were based on polymers formed from lactic acid.
      • Today polymeric materials still provides most important avenues of research primarily because of ease of processing & ability of researchers to readily control their chemical & physical properties via. Molecular system.
    • DEFINITION
      • POLYMERS :-
      • Compounds with high molecular masses formed by combination of large number of simple molecules called as monomers.
      • Prepared by addition / condensation polymerization.
      • In Greek , Poly means many & meros means units/parts.
      • Polymers are of 3 types:-
      • Natural, Semisynthetic, Synthetic.
    • CLASSIFICATION OF SYNTHETIC POLYMERS ON THE BASIS OF STRUCTURE BRANCHED CHAIN POLYMERS EXAMPLES :- Low Density Polythene CROSS LINKED POLYMERS EXAMPLES:- Bakelite, MF Resin LINEAR POYMERS EXAMPLES :- PEG, Polyesters
    • CONTD… ON THE BASIS OF DEGRADABILITY OF POLYMERS BIODEGRADABLE POLYMERS NONBIODEGRADABLE POLYMERS ENVIRONMENT RESPONSIVE POLYMERS ELECTRICALLY & CHEMICALLY CONTROLLED POLYMERS THERMOSENSITIVE POLYMERS pH-SENSITIVE POLYMERS
    • SYNTHETIC POLYMER :- CLASS EXAMPLES
      • BIODEGRADABLE POLYMERS
      • POLYESTERS
      • POLYANHYDRIDES
      • POLYAMIDE
      • PHOSPHOROUSBASED
      • OTHERS
      PLA, PGA, PHB PCL, PMA, POLYDIOXANONES POLYSEBACIC ACID, PTA POLYPHOSPHAZENES, POLYPHOSPHONATE POLYCYANOACRYLATES, POLYURETHENES, POLYORTHOESTERS B) NONBIODEGRADABLE CELLULOSE DERIVATIVE SILICONES ACRYLIC POLYMERS OTHERS CMC, EC, CA, CAP PDS, COLLOIDAL SILICA PMA, PMMA, PHEMA PVP, EVA. POLYOXAMER
    • ON THE BASIS OF MONOMERIC UNITS CONTD… HOMOPOLYMERS COPOLYMERS GRAFTED COPOLYMERS ALTERNATING COPOLYMERS BLOCK COPOLYMERS RANDOM COPOLYMERS
    • PROPERTIES & SELECTION OF POLYMERS
      • POLYMER IS CHOOSEN ON BASIS OF :-
      • Physicochemical properties
      • Need for biochemical characterization.
      • Chemical composition
      • Micro structural design
      • Surface properties like lubricity, hydrophilicity, smoothness, surface energy
    • PROPERTIES OF SYNTHETIC POLYMER THAT NEED TO BE CONSIDERD FOR APPLICATION OF POLYMERS TO DRUG DELIVERY SYSTEMS
      • Solubility
      • Viscosity
      • Polymer- Solvent interaction
      • Crystallinity
      • Polymer dissolution
      • Bioadhesivity of Hydrophilic polymer
      • Polymer erosion & Biodegradation
    • SYNTHETIC POLYMERS USED IN DRUG DELIVERY SYSTEMS
      • SYNTHETIC POLYMERS IN DENDRITIC
      • DRUG DELIVERY SYSTEMS
      • DENDRIMERS-
      • Transport extremely high
      • densities of drug molecules.
      • It is suitable carrier system because:-
      • Their size & structure can be controlled.
      • Encapsulate small drug molecule to form Polymer micelles.
      • Serves as “hubs” onto which large number of drug molecules can attached via covalent bond.
      • PAMAM Dendrimer – Used in gene delivery. It has amine
      • Terminal group which binds to DNA by electrostatic charge.
      • Prepared either as Divergent /Convergent type.
      • Starburst TM PAMAM dendrimer in intact (Polyfect (R) ) &
      • fractured form (Superfect ® ).
      • Fractured form shows better gene expression.
      • Polyethyleneimine(PEI)-
      • To prepare PEI- gene complex.
      • After internalization release of gene complex by endosome occurs due to
      • protonation of internal 3° Nitrogen by endosomal protons
      • which then results in swelling of endosome & ultimately
      • releases DNA.
    • SYNTHETIC POLYMER APPLICABILITY Poly Amino Amine dendrimer
      • To deliver 5-Fluro uracil.
      • For occular drug delivery of Pilocarpine Nitrate.
      • Increases solubility of Nifedipine
      Poly aryl ether dendrimer To deliver Methotrexate
    • SYNTHETIC POLYMER USED IN MUCOADHESIVE BUCCAL DRUG DELIVERY SYSTEMS
      • Factors to be considered :-
      • Chain flexibility
      • Low molecular weight
      • Ability to form H-bonding
      • Concentration & swelling of polymers.
      • Synthetic Polymers used as Permeation enhancers :-
      CLASS SYNTHETIC POLYMERS SURFACTANTS Polyoxyethylene, Polyoxyethylene-9-lauryl ether,Polyoxyethylene-20-cetyl ether THIOLATED POLYMERS Polycarbophil, Polyacrylic acid
    • BIOADHESIVE POLYMERS IN MUCOADHESIVE DRUG DELIVERY SYSTEMS BIOADHESIVE PROPERTIES CHARACTERISTICS Poly-hydroxyl Butyrate Poly(e-caprolactone) Polyorthoesters Polyphosphazenes Polycyanoacrylates Polyvinyl Acetate Polyethyleneoxide-b-propylene oxide Biodegradable Properties can be changed by chemical modification Surface eroding polymer Can be tailored with versatile side chain functioning Biodegradable Biocompatible Amphiphillic surfactant Biocompatible Matrix for DDS Cell encapsulation Sustained DDS, opthalmology To make films, Hydrogels in DDS Surgical adhesives, glues in DDS Gels & Blended membranes in DD & Immobilization Protein delivery
    • SYNTHETIC POLYMERS USED IN SUSTAINED RELEASE DRUG DELIVERY SYSTEMS
      • Sustained Release DDS follows 1 st order release kinetics.
      • Increased crosslinking of polymers decreases diffusion rate & thus improves sustained release properties of polymers & decreases mucoadhesivity.
      • Synthetic Absorbable Polymers- include homopolymers like PLA, PGA, PCL, Polytrimethylene carbonate, Poly(p-dioxanone) & copolymers like- Poly lactide-co-glycolide, Poly (glycolide-co-trimethylene carbonate).
    • SYNTHETIC POLYMER APPLICABILITY Poly(Monosteroyl Glycerol-co-succinate) For Sustained release of Theophylline/ Risperidone from microparticles in-vitro Polyvinyl Acetate For sustained release capsules of Nifedipine Eudragit RLPM, RSPM & HPMC Sustained release of theophylline
    • SYNTHETIC POLYMER BASED VECTORS IN GENE THERAPY
      • Cationic Polymers of high mol. wt. is used.
      • Synthetic Polymers used :-
      • PAMAM, Poly(4-Vinyl imidazole), PPL-Poly-L-lysine, PDMAEMA.
      • Poly-L-lysine :- Biodegradable, lacks –NH 2 gp. with a pK a between 5 & 7 allowing no endosmolysis, resulting in low transgene expression.
      • This drawback requires inclusion of endosmolytic agent like Fusogenic peptide like –
      • Copolymer of Poly-L-lysine with Poly-L-histidine/ L-tryptophan.
      • Polyethyleneimine- Shows efficient transfecting ability without use of fusogenic agent.
      • PEI offers high charge density due to which it offers increased protection against serum nucleases.
    • SYNTHETIC POLYMERS USED IN OPTHALAMIC DRUG DELIVERY SYSTEMS
      • Properties of synthetic Polymers considered for Opthalamic DDS-
      • Non-Toxic, Biodegradable, Biocompatible, Optically transparent, Do not impede vision, Tolerable, good retention properties, mucoadhesivity.
      • Non-Biodegradable polymeric bioadhesives used as drug delivery systems:-
      • Copolymers based on Vinylpyrrolidone, Methacrylic acid, Polydimethylene- siloxane, Poly (N-isopropyl acrylamide), PAMAM dendrimers.
    • CONTD… SYNTHETIC POLYMERS APPLICABILITY Polyhydroxy ethyl - methacrylate Used to formulate liposomes loaded with Dimyristoyl phosphatidylcholine (DMPC). It is optically transparent & release drug for a period of 8 days. Poly (D,L-lactide) Biodegradable polymer used for sustained retinal delivery of Celecoxib to inhibit diabetes induced Retinal oxidative demage Polyanhydrides, Polyorthoesters For sustained release of 5-FU Poly (Ɛ-caprolactone) rod shaped implants Tolerated by retinal tissues & used to release corticosteroid triamcinolone acetide over 4 weeks
    • SYNTHETC POLYMERS USED IN TRANSDERMAL DRUG DELIVERY SYSTEM
      • Polymers are the backbone of TDDS.
      • TDDS are fabricated as multilayered polymeric laminates or drug- polymer matrix is sandwiched between two polymeric layers i.e. backing layer & inner polymeric layer which act as adhesive & Rate- controlling membrane.
      • TDDS is formulated either as Matrix form / Reservoir form.
    • IN TDDS POLYMERS ACTS AS MATRIX FORMERS BACKING LAYERS RELEASE LINERS RATE –CONTROLING MEMBRANE PRESSURE- SENSITIVE ADHESIVES (PSAs)
      • MATRIX FORMERS
      • Selected on the basis of:-
      • Release properties
      • Adhesion cohesion balance
      • Physicochemical properties
      • e.g.-Monolithic solid state design is preffered for Passive TDDS
      • Synthetic polymers used-
      • Cross linked PEG network
      • Biocompatible
      • Used for protein drug delivery.
      • b) Acrylic acid matrices
      • Acrylic acid + Plasticizer :- used to make drug- polymer matrix
      • film.
      • Eudragit RLPM, Eudragit S-100, Eudragit E-100, ethyl acetate
      • & MMA
      • c) Polyvinylpyrrolidone
      • Matrix formers with 30% Dibutyl Phthalate to deliver Diltiazem
      • Hydrochloride & Domethacin
      • d) HPMC
      • Hydrophillic, swellable polymer used for Oral Controlled DDS
      • Matrix formers in Propranolol HCl
      • For fast release of drug.
      • 2) RATE CONTROLLING MEMBRANE
      • Ethyl Vinyl Acetate
      • By altering Vinyl Acetate content membrane permeability can be controlled
      • b) Silicone Rubber
      • Biocompatible
      • Highly permeable to steroids
      • Ease of fabrication
      • Low microscopic viscosity & used in Controlled Release devices.
      • c) Poly Urethane
      • Rubbery & increased permeability
      • Two types:- Polyether urethanes & Polyester Urethanes
      • Due to more Biodegradability Polyester Urethanes are more
      • preffered. It is used for Hydrophillic polar drugs.
      • PRESSURE SENSITIVE ADHESIVES
      • Characteristic of visco- elastic material
      • Poly Iso Butylene
      • Formed by cationic polymers
      • b) Poly Acrylates
      • Amorphous, gives water clear color in solution & stable towards
      • ageing & have good mechanical properties.
      • c) Silicones
      • Contains low viscosity Dimethyl siloxane polymer.
      • Silicate Resin + PDMS undergoes condensation to form Silicone PSA
    • 4) BACKING MATERIALS
    • SYNTHETIC POLYMERS USED IN HYDROGEL DRUG DELIVERY SYSTEM
      • HYROGELS :-
      • Three dimensional, water swollen systems.
      • Composed of Hydrophilic polymers.
      • Rendered insoluble due to crosslinking.
      • Synthetic Polymers used in Hydrogel DDS
      • PVA, PE, PEG, PMMA, Polyacrylamide, PEA, PEMA, HEMA, PVP
      • Poly (N-isopropylacrylamide), Poly dimethyl aminoethyl methacrylate,
      • Poly (N- Butyl acrylate), Itaconic acid monoester, HPMA,
      • Poly Ethylene oxide dimethacrylate (PEODM),
      • Poly (2- dimethylamino) ethyl methacrylate (DEAEMA),
      • Poly (2- diethylamino) ethyl methacrylate (DMAEMA)
    • SYNTHETIC BIODEGRADABLE POLYMER PROPERTIES & APPLICABILITY
      • CROSS-LINKED HYDROGELS
      • Poly (a- amino acids), Poly (g- benzyl-L-glutamate), Polycaprolactone.
      • INTERPENETRATING HYDROGEL NETWORK like-
      • PCL with HEMA
      • To prepare cross –linked Poly (2- hydroxyethyl-L-glutamine) (PHEG).
      • To enhance polymer compatibility.
      • To prevent phase separation.
      • Have hybrid properties.
      • B) NON CROSS-LINKED HYDROGELS/ PHYSICAL GELS
      • PEO- PLA Block copolymer
      • PVA & PLGA Blend
      • PEO provides elasticity, hydrophilicity
      • PLA provides mechanical strength
      • Water uptake depends on PEO conc.
      • H 2 O content ↑es from 30-80% as PVA content ↑ed FROM 25-95%.
      • C) GLUCOSE- SENSITIVE HYDROGEL
      • Poly (methacrylic acid-g-poly (ethylene glycol)) , PVP, PHEMA, PDMAEMA
      • Forms hydogel membrane which immobilizes GO-Enzyme,.
      • This system focuses on INSULIN containing “Reservoir”
    • SYNTHETIC POLYMERS PROPERTIES & APPLICABILITY
      • D) pH- Sensitive Hydrogels
      • Cationic polmers- Polyacrylamide, PAA, PMMA, PDEAEMA, PDMAEMA.
      • Anionic copolymers of PMMA & PHEMA.
      • Polyorthoesters
      • have –NH 2 as ionizable pendant group
      • PDMAEMA & PMMA forms hydrophilic hydrogel containing Caffeine. This system swells in sol n with p H<6.6 due to protonation of 3 o –NH 2 gp.
      • Have –COOH as Pendant gp.
      • Swells at basic/ neutral media.
      • For Insulin delivery.
      • E) Temperature –sensitive Hydrogel
      • Poly (N- isopropyl acrylamide) (PNIPAAm).
      • PEG-PLGA-PEG triblock copolymer
      • LCST of gel was 34.4°C .
      • Used in “ON-OFF” DDS like for controlling INSULIN release.
      • Becomes gel at body Temp., Biodeg. injectable themosensitive hydrogel.
      • F) Neutral Hydrogels
      • PEG & PEO
      • PVA, Poly ( N-vinyl-2-pyrrolidone)
      • Provides Stealth properties & Protein resistance.
      • Mucoadhesive, to control release rate of Theophylline.
    • SYNTHETIC POLYMER PROPERTIES & APPLICABILITY G) Polyacrylic acid Hydrogel
      • Have bioadhesivity, superabsorbancy, ability to form extended polymer network through H-bonding.
      • H) Superporous Hydrogels (SPHs)-
      • Ist Generation (CSPHs)- formed of hydrophiic (Acrylamide)/ Ionic (salts of acrylic acid/ sulfopyridine acrylate) monomers.
      • IInd Generation (SPH composites, SPHCs)-consists of IPNs
      • IIIrd Generation (SPH Hybrids, SPHHs)- Consists of Integrated IPNs.
      • SPHs are made up of porous hyrophilic crosslinked polymers which can absorb aqueous fluid upto 100 times of its weight.
      • Maximum swelling occurs in fractions of minutes with SPHs having Average pores of 200 μ m in size.
    • SYNTHETIC POLYMERS USED IN GASTRORETENTIVE DRUG DELIVERY SYSTEMS (GRDDS)
      • GRDDS are Oral controlled DDS.
      • Releases drug prior to Absorption window.
      • Prolongs Drug release rate.
      • Ensures optimal BA.
      • SYNTHETIC POLYMERS USED IN GRDDS-
      • FLOATING SYSTEMS
      • Matrix formers like- Polystyrene, PMMA, Polyacrylates,
      • Polycarbonates, Polycarbophil & Highly swellable gel- forming
      • hydrocolloid like- HEC, HPMC, HPC, Na CMC.
      • They hydrates, swells & maintains density <1 thus, confers
      • buoyancy to dosage form & leads to GRDDS & ↓ PDC fluctuations.
      • 2) BIOADHESIVE/ MUCOADHESIVE SYSTEM
      • 3 ) SWELLING SYSTEMS
      • Polymer should be swellable, hydrophilic, of appt. mol. Wt.
      • Swelling depends on degree of crosslinking.
    • SYNTHETIC POLYMERS USED IN CONTROLLED DDS
      • CRDDS follows Zero- order release Kinetics.
      • Requires swellable polymers which are capable of forming external
      • gel layer controlling drug release.
      SYNTHETIC POLYMER APPLICABILITY Poly (DL- lactide- co- glycolide) microsphere For Live Rotavirus vaccine, For encapsulating ß - lactoglo- bulin microspheres Polyacrylic acid Polyanion excipient to shield Transforming Growth Factor (TGF) from inactivation with Alginates Poly- Ɛ- caprolactone nanoparticles For encapsulating Cyclosporine A Polyester Tetanus Toxoid (vaccine) encapsulating microspheres for single- injection immunization
    • SYNTHETIC POLYMERS USED IN CONTROLLED & TARGETED DRUG DELIVERY SYSTEMS
      • SYNTHETIC POLYMERS USED IN NANOPARTICLE DRUG DELIVERY SYSTEMS
      • Nanoparticles are sub-micron sized colloidal structures.
      • Ist Nanoparticles were based on Non-Biodegradable polymers like Polyacrylamide, PS, PMMA.
      • Now, Biodegradable polymers like Poly(cyanoacrylates) were used in NP.
      • Synthetic Hydrophobic polymers used in NP-
      • PCL, PLA, PLGA, PS.
      • PMMA, PICA, PBCA, PHCA
    • SYNTHETIC POLYMER PROPERTIES & APPLICABILITY
      • FOR STEALTH NP
      • POLAXAMER - ABA Block str.
      • PEO/PEG-PPO/PPG-PEO/PEG
      • POLAXAMINES - Tetrafunctional block copolymer with central ethylenediamine bridge
      • (PEO-PPO) 2 -X-(PPO-PEO) 2
      • (PEG-PPG) 2 -X-(PEG-PPG) 2
      • Forms hydrated, hydrophillic steric barrier on NP surface.
      • To modify PS- NP surface to deliver Salmon Calcitonin.
      • 2) FOR BIOADHESION OF NP
      • Polyacrylic acid (Carbomer/ Carbopol)
      • Swells 1000 times in H 2 O & provides Controlled release.
      • 3) FOR OCCULAR DELIVERY
      • Polyalkyl cyanoacrylates
      • PCL, Polyester, PVA, HPMC
      • Adheres to conjuctival mucin & ↑ residence time of NP in precorneal area.
      • To deliver Pilocarpine & Betaxolol
      • 4) FOR BRAIN TARGETING
      • Polybutyl cyanoacrylates coated with Polysorbate- 80
      • To deliver Hexapeptide dalargin, Met- enkephalin Kyotropin, Doxorubicin.
    • SYNTHETIC POLYMER APPLICABILITY
      • 5) FOR LYMPHATIC TARGETING
      • Polyalkyl cyanoacrylates
      • (PEO-PLys) block copolymer
      • To deliver Insulin for peroral peptide delivery through Peyer’s pathes.
      • Conjugated to cis- diaminedichloro- Platinum (cDDP) to treat lymph node metastases.
      • 6) FOR TUMOR TARGETING
      • Polyalkylcyanoacrylates
      • Polybutylcyanoacrylates
      • Polyisobutylcyanoacrylates
      • N-(2-HPMA)
      • To deliver Doxorubicin.
      • To deliver Mitoxantrone, Acyclovir.
      • To deliver Adacinomycin
      • Act as lysosmotropic drug carrier for site specific delivery of MAb (IgG, Ab B72.3)
      • 7) ADJUVANT EFFECT FOR VACCINES
      • PMMA
      • For Inluenza Ag & adjuvant to HIV-2 whole virus vaccine.
    • SYNTHETIC POLYMERS USED IN MICELLAR DRUG DELIVERY SYSTEM
      • Polymeric Micelles are few tens in nm ,
      • crosslinked combination of hydrophilic & hydrophobic
      • monomers.
      • Forms shell- like structure , hydrophilic portion forms outer shell &
      • it protects core contents from chemical attacks in aqueous media in
      • which they travels.
      • Drug release occur via polymer degradation.
      • Have low CMC, slow dissociation rate & long retention of loaded drug
      • as compared to surfactant micelle.
      • pH-sensitive Micelle based on titrable groups
      • Synthetic block copolymers containing weak basic group :-
      • Poly(2-Vinyl pyridine)-b-PEO, PEO-DMAEMA, PDMAEMA-b-PDAEMA,
      • PEO-b-DMAEMA-b-DEAEMA, DMAEMA-b-Poly[2-(N-morpholino)ethyl
      • methacrylate.
      • Copolymers containing weak acidic groups :-
      • Poly[sodium-2-(acrylamido)-2-methyl propanesulfonate-b-poly
      • (sodium-6-acryl amido hexanoate) & Poly(sodium-4-styrene
      • sulfonate)-b-Poly(sodium-4-vinyl benzoate)
      • Forms micelle at pH <5
      • PLLA-b-PEO-b-Polysulfamethoxine- have sulfonamide as acidic gp.
      • AMPHIPHILIC STAR POLYMER
      • Prepared from Ethyl methacrylate,
      • PEG-MA, t-butyl MA
      • For delivery of hydrophobic drug
      • like Progesterone.
      • B) pH-sensitive Polyelectrolyte complexes
      • Formed by electrostatic interaction of two oppositely charged Block
      • copolymer.
      • Examples :-
      • [PEO-b-Poly(L-lysine)] & [PEO-b-Poly(Aspartic acid)]
      • (PEO-b-PMANa) & Poly (N-ethyl-4-vinyl pyridinium bromide)
      • Cationic block copolymer forms complex with Polyanionic biomolecules like
      • DNA & ODNs like PEO-b-Polyspermine which make complex with ODNs.
      • PEO-b-PPO triblock combination for Doxorubicin delivery.
    • POLYMER VESCICLES
      • Microscopic sac that encloses a volume with molecularly thin membrane. The membrane are self- directing assemblies of amphiphilic molecues with dual hydrophobic- hydrophobic characters.
      SYNTHETIC POLYMER APPLICABILITY Non-ionic Polyethylene-oxide- Poly butadiene To form vesicles in aqueous solution PMOXA- PDMS- PMOXA Water soluble & midblock is hydrophilic (PEO- Polyethylethylene To form polymerosomes in aqueous solution for encapsulating Doxorubicin
      • SYNTHETIC POLYMERS USED IN
      • LIPOSOME DRUG DELIVERY SYSTEMS
      • Polymer properties to be considered :-
      • Low immunogenic.
      • structural versatility.
      • Improves liposomal stability.
      • Easy to associate with liposome surface.
      • A) pH-Sensitive Polymer –Liposome system
      • pH-sensitive synthetic polymers used:-
      • Poly-L-lysine & Poly (His) –
      • Positively charged at low Ph
      • Interact with negatively charged membranes & promotes fusogenic
      • properties.
      • PAMAM – Shows pH-dependent membrane destabilization & thus used for
      • cytoplasmic gene delivery.
      • N-isopropylacrylamide -
      • Provide Temp-responsive properties.
      • STEALTH LIPOSOMES
      • POLYETHYLENE GLYCOL –
      • Hydrophilic, Flexible
      • ↑ Repulsive forces at surface & thus ↓ interaction & plasma protein
      • adsorption.
      • POLOXAMER -
      • Amphipathic polymer with ABA Block structure.
      • PEO-PPO-PEG
      • POLOXAMINES-
      • Tetrafunctional Block copolymer with four PEO-PPO Blocks joined together
      • by central Ethylene diamine bridge.
      • [(PEO-PPO) 2 - X- (PPO-PEO) 2 ]
      • [(PEG-PPG) 2 - X- (PEG-PPG) 2 ]
    • REFERENCES
      • Remington, “The Science & Practice of Pharmacy”
      • Volume- І , B.I. Publications Pvt. Ltd, Lippincott Williams & Wilkins company.
      • Lachman Leon, Lieberman HA, Kanig J.L, “The Theory & Practice of Industrial Pharmacy”, 3 rd edition, Varghese Publication.
      • Banker G.S., Rhodes C.T., “Modern Pharmaceutics”, 4 th edition Revised, Informa Health care.
      • Vyas S.P., Khar R.K., “Targeted & Controlled Drug Delivery” CBS Publishers & Distributors
      • Jain N.K., “Pharmaceutical Product Development”,
      • 1 st edition, Cbs Publishers & Distributors.
      • Wiseman N, Xiao.H, Cherie. O, “Retention acid system of cationic
      • microparticles & anionic polymers experiments & pilot machine trials”, Tappi Journal, Volume 83
      • Hoshino Y, Urakani T, Kodama Takashi, Oku Naota, Shea J.K, “ Design of Synthetic Polymer NP that capture & neutralize a toxic peptide”, Wiley Interscience.
      • Heller J, “The use of Polymer is construction of Controlled Release Devices”,National Institute on Drug Abuse Research monograph series.
      • Girish Y, Punitha S, “Polymers in mucoadhesive buccal DDS –A Review”, Int. J. Res. Pharm. Sci. Vol- 1, Issue-2, 170-186, 2010.
      • Jain N.K., “Progress in Controlled & Novel Drug Delivery systems”, 1st edition, CBS Publishers & Distributors
      • Jauhar S.P., “ Modern’s Chemistry”, Modern Publishers
      • Kandavilli S, Nair V, Panchagnula R, “Polymers in Transdermal Drug Delivery Systems”, Pharm. Tech. J.
      • Kshirsagar NA, “Drug Delivery System”, Journal of Pharmacology.
      • Twaites B, Heras C, Alexander C, “Synthetic Polymers as Drugs &
      • Therapeutics”, Journal of material chemistry.
      • Duncan R, “Designing Polymer conjugates as lysosmotropic nanomedicines”, Biochemical society Transaction (2007) Vol 35,
      • Part 1
      • Elvira C, Gallardo A, Roman J.S., Cifuentes A, “ Covalent Polymer Drug Conjugates”, MDPI