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Role of polymers in drug delivery

Contents










Current available polymers
Soluble polymers as drug carrier
Biodegradable or bioerodible polymers
Mucoadhesive polymers
Polymers containing pendant bioactive substituents
Matrix systems
Heparin releasing polymers
Ionic polymers
Oligomers
Miscellaneous
Recent advances

I. Currently available polymers for
controlled release
Diffusion controlled systems
 Solvent activated systems
 Chemically controlled systems
 Magnetically controlled systems

Diffusion controlled systems

Reservoir type


Shape : spherical, cylindrical, disk-like
Core : powdered or liquid forms
Properties of the drug and the polymer : diffusion rate
and release rate into the bloodstream
Problems : removal of the system, accidental rupture

Matrix type

Uniform distribution and uniform release rate
No danger of drug dumping

Solvent activated systems  Osmotically controlled system     Semipermeable membrane Osmotic pressure decrease concentration gradient Inward movement of fluid : out of the device through a small orifice Swelling controlled system   Hydrophilic macromolecules cross-linked to form a three-dimensional network Permeability for solute at a controlled rate as the polymer swells .

Chemically controlled systems  Pendant-chain system     Drug : chemically linked to the backbone Chemical hydrolysis or enzymatic cleavage Linked directly or via a spacer group Bioerodable or biodegradable system     Drug : uniformly dispersed Slow released as the polymer disintegrates No removal from the body Irrespective of solubility of drug in water .

Magnetically controlled systems  Cancer chemotherapy    Selective targeting of antitumor agents Minimizing toxicity Magnetically responsive drug carrier systems    Albumin and magnetic microspheres High efficiency for in vivo targeting Controllable release of drug at the microvascular level .

II. Soluble polymers as drug carriers  Polymer systems    Soluble polymers Biodegradable or bioerodible polymers Mucoadhesive polymers .

biocompatible  .Pinocytosis Soluble synthetic polymers conjugated with drug  Mechanism for translocation of macromolecules across membranes  Retention of water solubility  Glomerular filtration. nonimmunogenic. reach all cell types  Degradable in lysosome  Nontoxic.

Fig. Intracellular fate of macromolecular drug conjugates. 1. .

1. accessibility of the conjugate to each cell type Affinity for cell surface receptors (adsorptive pinocytosis)   Rate of uptake : binding capacity Carrier mediated uptake : targeting drug carriers  Receptor-mediated uptake : carbohydrate moiety  Cell-specific antibody . Body distribution dependency : the rate of pinocytosis of individual cell type. Passively captured solely as a solute  2.

Ideal Soluble Polymers  Polymer-drug linkage      Controlled biodegradability Suitable molecular weight range Incorporation of residues : efficient pinocytic capture by the target cells Absence of toxic effect Nonpersistence in the body .

block) Charged polymer    Block copolymer of a hydrophilic portion.  Homopolymer. PEO and a hydrophobic polylysine    Prevent to bind to plasma protein (intravacular aggregate formation) Unimolecular micelle polyHPMA with glycylgalactosamine   Copolymer of 93% vinylpyrrolidone and 7% vinyl amine (cation)  Adhere to mammalian cell surface Pyran copolymer (anion)  Adsorb to rat peritoneal macrophages and enter cells by pinocytosis 100 times more rapidly Recognized by the asialoglycoprotein receptor on hepatocytes polyHPMA linked by di(oligopeptidyl)diamine   Target delivery of a cytotoxic drug Degradation of crosslinks by lysosomal enzymes . copolymer (random.

with bioadsorption of the polymer delayed until after drug depletion  . followed by drug diffusion  Diffusion controlled release of the physically entrapped drug. Biodegradable or bioerodible polymers Erosion of the polymer surface with concomitant release of physically entrapped drug  Cleavage of covalent bonds between the polymer and drug occurring in the polymer bulk or at the surface.III.

Fig. 2. Different approaches to drug delivery systems based on biodegradable polymers .

 Custom synthesis   Cleavage under mild hydrolytic conditions   Permeability. polyesters. polycarbonates. polyacetal. tensile strength Polyamides. polyketal. polysaccharide . polyorthoester Enzymatic attack  Polypeptide. biodegradability. biocompatibility. polyurethane.

polyorthoester : autocatalysis by acidic or basic groups Crystallinity of polymer  Amorphous phase : accessible to permeants and enzyme attack Glass transition temperature  Permeability and molecular chain mobility  Diffuse out of a glass polymer (PLA. water solubility  Polyester. surface-to-volume ratio  Stage of biodegradation when phagocytosis . PGA) Physical dimensions  Size. Rate of polymer degradation     Water permeability.

Drug Release by Matrix Solubilization  Enteric coating by polyacid    Upon ionization : water soluble Partially esterified copolymers of methyvinylether and maleic anhydride Partially esterified copolymers of ethylene and maleic anhydride .A.

narcotic antagonist Subdermal capsules for the release of levonorgestrel  Aliphatic polyester. Erodible Diffusional Systems 1.B. Erodibility    Constant rate of drug release from a reservoir type device Bioerosion : no removal of device Release of contraceptive steroids. Rate controlling polymer membrane  2. poly(-caprolactone) .

C. lifetime of device. physical dimension of device . Monolithic Systems Drug : physically incorporated into polymer matrix  Release by polymer erosion and drug diffusion     First order release : rapid diffusional release Zero order release : erosion confined surface and drug immobilized in the matrix Control drug delivery  Drug loading.

estradiol. dexamethasone    Copolymer of gluconic acid and –ethyl-L-glutamte   Cylindrical implants fabrication DL-lactic acid or glycolic acid : chain mobility increase : increased rate of matrix hydrolysis Bioerodible monolithic device PLA. Poly(L-lactic acid) for relaase of progesterone. PGA. PLGA for parenteral administration of polypeptide  Sustained release (weeks or months) .

polyurethane.IV. acrylate. epoxy resin. capping extraction wounds in dentistry Ester of cyanoacrylate. Mucoadhesive polymers  Super glue    Repair of osteochondral fracture. polystyrene Short-term adhesion   Mucus or epithelial cell surface of the GI tract Secondary force (hydrogen bond. van der Waals force) .

 Adhere to mucosal surface    Binding to the tissue itself By associating with the mucus coat Mucoadhesive-based sustained release action       Gastric retention Mucosal surface : columnar epithelial cell Mucus-secreting glands : cardiac and pyloric region Polymer embedding in the mucus  Dry powder or granule slowly hydrated  Substantial erosion of the polymer surface Linear or lightly cross-linked polymers Interaction : oligosaccharide side chain on the mucin .

Orahesive® : sodium carboxymethyl cellulose. SCMC . gelatin  Orabase ® : blend in a polymethylene/mineral oil base  Dry powder form better mucoadhesive agents    SCMC + PIB laminating onto a polyethylene sheet Mucoadhesive polymers  Poly(acrylic acid). Pectin. HPC.

 Mucoadhesion       Strong H-bonding groups (-OH. -COOH) Strong anionic charges Sufficient flexibility to penetrate the mucus network or tissue crevices Surface tension for wetting mucus/mucosal tissue surfaces High molecular weight to maximize adhesion Physical bond by entanglement with the substrate molecules  Segmental mobility of PEO .

skin. eye. mouth. Polymers containing pendant bioactive substituents  Bonding of drug to macromolecules     Decreasing toxicity Depot for extended periods because of slow excretion of highmolecular weight polymers High specificity for target organism (tumors) by attachment of a tumor-specific antibody Absorption of macromolecules     5000~10000 : prevent absorption through skin or mucosal tissue Local depot of GI tract.V. vagina etc Topically administered : susceptible to hydrolysis GI tract : for enteric coating .

 Biodegradable system   MW > 60.000 to 80.000 : not excreted via renal glomerular filtration Biostable polymer    lysosome and celluar overloading  toxic effect Erythrocyte aggregation and changes in platelet or leukocyte distribution More likely to function as antigen than biodegradable system .

 Action of target system  Extracellular Antibiotics acting on extracellualr bacteria  Inhibitors that block the deleterios effects of enzymes released by inflammation. shock. or theumatoid arthritis  Enzymes like asparaginase and urase  anticoagulants   Pericellualr (cell surface) Hydrolysis induced by enzyme in the plasma membrane  Release anti-inflammatory or antirheumatoid agents upon contactwith the neutral protease or collagenases secreted by cells involved in the irritation and development of inflammation   Intracellualr .

competitive binding and metabolism Changing and cross-reactive antigenicity Masking or interiorization of tumor cell-specific antigens . Intracellular    Via endocytosis of pinocytotic vesicles By attaching “homing molecules” to the adducts (specific tumor-associated antigens) Problems with antibody-targeting system      Circulatory antigen and antibody complex Metabolic/biochemical changes in adducts with loss of activity Transport kinetics tumor tissue vs.

 Overcoming problems     Complexing or removing Use of (Fab’) portion of the immunoglobulin to avoid F complement binding and reduce molecular size Therapy with intrartumor and intravenous injections of antibody adducts Surgical or radiation reduction of primary lesion tumor burden coupled with systemic administration of antibody adducts for elimination of metastasis .

macroscopic pore and channel .VI. Matrix systemes  Controlled release devices  Dissolved systems   At or below the saturation solubility of the drug in the polymer Dispersed systems Exceeds the saturation solubility in the polymer  Reservoir-dispersed matrix system  Barrier layer : surface of device   Porous matrix system  Leaching out of drug.

charged species Moderate foreign tissue response upon subdermal implantation Permeability : not easily varied by alterations in polymer composition . Matrix device    Ease of manufacture : molding and curing Useful for dispersed type matrix device Polydimethyl siloxane matrix         Elastomer with good mechanical properties Highly permeable to hydrophobic solutes Nontoxic A wide variety of shape and simple polymerized Permeability : not affected vial prolonged contact with biological fluids Not permeable to highly water soluble solutes.

 Hydroxyalkyl methacrylate      Not toxic A minimal forign tissue response Highly permeable to both hydrophobic and water soluble solutes Variable permeability depending upon copolymer composition and cross-link density Copolymer   Increased mechanical strength Blood and tissue compatibility .

saturation solubility  Heterogeneous matrix   Initial drug load > 10% w/w Drug : to form continuous pore and channel within matrix  Rate of release : diffusion within channel  Porous or granular matrix  . and  10% w/w Release rate : D. initial drug load. Diffusion of solute within the matrix phase  Initial drug load saturation solubility Rate of release : D of drug and initial drug load  Homogeneous matrix   Initial drug load >saturation solubility.

Heparin releasing polymers colloidal graphite : thromboresistance by venous implantation  Graphite-benzalkonium-heparin (GBH) surface : retained quantities of heparin after 3 months    Coated rigid materials Flexing with flaking off of the GBH coating .VII.

•Chemically modified polymer surface by forming permanent surface-associated quaternary ammonium groups •Chloromethylation of styrene followed by quaternization with dimethylaniline •Radiation grafting of vinylpyridine by quaternization with methyl iodide or benzyl chloride •Incorporation of quaternizable monomers such as vinyl pyridine into copolymer formulations •After quaternization the surfaces were placed in a heparin solution and heparin was ionically bound to the ammonium groups •Heparinized cellulose membrane : kidney dialysis •Ionically bound heparin to cellulose membrane vial an ethyleneimine intermediate •Heparin into silicone rubber with prostaglandins •Coagulation and adverse platelet interaction are controlled .

VIII. Ionic polymers  Ionic exchange resins     Prolonged effect of drug by insoluble poly-salt resinates Oral route  2 h in stomach : acidic pH  intestine for 6 h or more : basic pH Biological half life : 2 to 6 h Drug    8 h or more half life Absorped from all the region of GI tract Stable in the gastric juice .

-NH2+. -PO32. -N+.  Ioic groups  -SO3-.in cationic exchangers  -NH3+. -COO-.in anionic exchangers Carboxylic acid type exchangers   Polymerization of acrylic or methacrylic acid (crosslinking agent : diacrylate or divinylbenzene) Rate of ion-exchange  Particle size and cross-linkages .

Oligomers Prolonged pharmaceutical activity  Oral.IX. intradermal administration  Active principles across physiological barriers  Preparation of oligomeric or polymeric derivatives of drugs    Polymerizable derivative of the drug Oligomeric or polymeric matrices carrying chemical functions able to react selectively with some constituents present in the drug molecules .

X. Miscellaneous  Sustained release medications        Ethylcellulose and methyl stearate mixtures Hydrated hydroxyalkyl cellulose Salts of polymeric carboxylates Chelated hydrogels Water-insoluble hydrophilic copolymers Cellulose ether compositions Partial esters o f acrylate-unsaturated anhydride copolymer .

antiseptics. Commercial Preparations of Drug-Polymer Combinations Corporation Drug Polymer as a Matrix Scios Nova & MIT Gentamycin & Carmustine BIODEL Delivery system DynaGen Vaccine. & antiinflammatories HYAFF series (modified hyaluronic acids) .Table 1. immunogens Sleeper system Kabi Pharmacia & Berol Nobel Drugs for blood disorders Bioadhesive thermogel Fidia Antibiotics.

Recent advances  Medisorb    Microencapsulation (50 m) by PLA.XI. PGA. contraception. PLGA Drug release : week to one year Alzamer   Bioerodible polymer : release at a controlled rate Chronic disease. topical therapy .

3.Fig. . Ringsdorf’s model of polymeric prodrugs.

pyrogenicity. hemolytic activity. Polymeric prodrugs     Cellulose and polyarabogalactants as drug carrier Naproxen with polyphosphazene : bioerodable implant Conjugate of poly(glutamic acid) and pphenylenediamine using immunoglobulin as a homing device Immunogenicity. osmotic property. interaction with plasma components .

changing the solubility of drug. adding other compounds that either speed up or delay the release Mixture of two or more substances : Polycaprolactone and cellulose propionate . Sustained release tablet     Compressed plastic matrix Diffuse through a network of channels Release controlled by altering the porosity or surface area of the matrix.

film deposition on the substrate Tackiness or film rupturing Hydrogel   Swelling and biocompatibility Multiblock copolymers . Aqueous polymeric dispersion    Latex or pseudo-latex    Safety hazards associated with use of organic solvent Water-based coating formulation To coat pellets or tablets.

Conclusion Polymer of plastic age  Creation of polymers and polymeric materials for pharmaceutical application  Extensive investigation for following topics  Soluble synthetic polymers.XII. pseudo-latex dispersion. microsphers. oligomers. polymer-coating liposome. copolymers. swellable polymers. encapsulated drug for cancer. polymeric prodrug. hydrogel. matrix devices. liquid crystalline photoreactive and performance polymers  Drug delivery device composed of polymers  Osmotic pumps. microsealed drug delivery system. insulin delivery. dermal and oral drug delivery system  Specific targeting  . bioerodible and biodegradable polymers. implants. polymeric implants. colloid carrier system.