Download - Role of Polymer Bin Dds 1
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
Pinocytosis
Soluble synthetic polymers conjugated with drug Mechanism for translocation of macromolecules
across membranes Retention of water solubility Glomerular filtration, reach all cell types Degradable in lysosome Nontoxic, nonimmunogenic, biocompatible
Fig. 1. Intracellular fate of macromolecular drug conjugates.
1. Passively captured solely as a solute Body distribution dependency : the rate of pinocytosis
of individual cell type, accessibility of the conjugate to each cell type
2. 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
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
Homopolymer, copolymer (random, block) Charged polymer
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 Block copolymer of a hydrophilic portion, PEO and a hydrophobic
polylysine Prevent to bind to plasma protein (intravacular aggregate formation) Unimolecular micelle
polyHPMA with glycylgalactosamine 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
III. 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, followed by drug diffusion
Diffusion controlled release of the physically entrapped drug, with bioadsorption of the polymer delayed until after drug depletion
Fig. 2. Different approaches to drug delivery systems based on biodegradable polymers
Custom synthesis Permeability, biodegradability, biocompatibility,
tensile strength
Cleavage under mild hydrolytic conditions Polyamides, polyurethane, polyesters, polycarbonates,
polyacetal, polyketal, polyorthoester
Enzymatic attack Polypeptide, polysaccharide
Rate of polymer degradation Water permeability, water solubility
Polyester, 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, PGA)
Physical dimensions Size, surface-to-volume ratio Stage of biodegradation when phagocytosis
A. 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
B. Erodible Diffusional Systems
1. Rate controlling polymer membrane Constant rate of drug release from a reservoir type
device
2. Erodibility Bioerosion : no removal of device
Release of contraceptive steroids, narcotic antagonist
Subdermal capsules for the release of levonorgestrel
Aliphatic polyester, poly(-caprolactone)
C. 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, lifetime of device, physical dimension
of device
Poly(L-lactic acid) for relaase of progesterone, -estradiol, dexamethasone Cylindrical implants fabrication DL-lactic acid or glycolic acid : chain mobility increase :
increased rate of matrix hydrolysis Copolymer of gluconic acid and –ethyl-L-glutamte
Bioerodible monolithic device PLA, PGA, PLGA for parenteral administration of
polypeptide Sustained release (weeks or months)
IV. Mucoadhesive polymers
Super glue Repair of osteochondral fracture, capping extraction
wounds in dentistry Ester of cyanoacrylate, polyurethane, epoxy resin,
acrylate, 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, Pectin, 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), HPC, SCMC
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
V. Polymers containing pendant bioactive substituents
Bonding of drug to macromolecules Decreasing toxicity Depot for extended periods because of slow excretion of high-
molecular 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, eye, mouth, skin, 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
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. competitive binding
and metabolism Changing and cross-reactive antigenicity Masking or interiorization of tumor cell-specific antigens
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
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, macroscopic pore and channel
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, charged species Moderate foreign tissue response upon subdermal implantation Permeability : not easily varied by alterations in polymer
composition
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
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, and 10% w/w Release rate : D, initial drug load, 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
VII. 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
•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
Ioic groups -SO3
-, -COO-, -PO32- in cationic exchangers
-NH3+, -NH2
+, -N+- in anionic exchangers
Carboxylic acid type exchangers Polymerization of acrylic or methacrylic acid (cross-
linking agent : diacrylate or divinylbenzene)
Rate of ion-exchange Particle size and cross-linkages
IX. Oligomers
Prolonged pharmaceutical activity Oral, 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
Table 1. Commercial Preparations of Drug-Polymer Combinations
Corporation Drug Polymer as a Matrix
Scios Nova & MIT Gentamycin & Carmustine
BIODEL Delivery system
DynaGen Vaccine, immunogens Sleeper system
Kabi Pharmacia & Berol Nobel
Drugs for blood disorders
Bioadhesive thermogel
Fidia Antibiotics, antiseptics, & anti-inflammatories
HYAFF series (modified hyaluronic acids)
XI. Recent advances
Medisorb Microencapsulation (50 m) by PLA, PGA, PLGA Drug release : week to one year
Alzamer Bioerodible polymer : release at a controlled rate Chronic disease, contraception, topical therapy
Fig. 3. Ringsdorf’s model of polymeric prodrugs.
Polymeric prodrugs Cellulose and polyarabogalactants as drug carrier Naproxen with polyphosphazene : bioerodable implant Conjugate of poly(glutamic acid) and p-
phenylenediamine using immunoglobulin as a homing device
Immunogenicity, hemolytic activity, pyrogenicity, osmotic property, interaction with plasma components
Sustained release tablet Compressed plastic matrix Diffuse through a network of channels Release controlled by altering the porosity or surface
area of the matrix, 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
Aqueous polymeric dispersion Safety hazards associated with use of organic solvent Water-based coating formulation
Latex or pseudo-latex To coat pellets or tablets, film deposition on the
substrate Tackiness or film rupturing
Hydrogel Swelling and biocompatibility Multiblock copolymers
XII. Conclusion
Polymer of plastic age Creation of polymers and polymeric materials for pharmaceutical
application Extensive investigation for following topics
Soluble synthetic polymers, oligomers, copolymers, bioerodible and biodegradable polymers, polymer-coating liposome, encapsulated drug for cancer, colloid carrier system, microsphers, microsealed drug delivery system, matrix devices, swellable polymers, pseudo-latex dispersion, polymeric prodrug, hydrogel, insulin delivery, polymeric implants, liquid crystalline photoreactive and performance polymers
Drug delivery device composed of polymers Osmotic pumps, implants, dermal and oral drug delivery system Specific targeting