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