Hydrogels in Drug Delivery Rassoul Dinarvand, PhD Professor of Pharmaceutics

Definition Three-dimensional networks of hydrophilic polymer chains that do not dissolve but can swell in water both solid like and liquid like properties high biocompatibility environmental stimuli respondent (temperature, pH, light, specific molecules) Ideal for controlled drug delivery

Classification - various criteria for the classification of hydrogels Origin Natural Synthetic Water content or degree of swelling Low swelling Medium swelling High swelling Superabsorbent Porosity Nonporous Microporous Macroporous Superporous Cross-linking Chemical (covalent bonding) Physical (noncovalent bonding) Biodegradability Biodegradable Nondegradable

Properties and Structures of Hydrogels R s = (W s -W d ) / W d R s = swelling ratio W s = weight of swollen hydrogels W d = weight of dried hydrogels Swelling property is influenced by: type and composition of monomers other environmental factors such as : temperature, pH, ionic strength cross-linking Mechanical strength and permeability Cross-linking and/or copolymerization with hydrophobic comonomers density↑, mechanical strength↑, swelling property ↓

Hydrogel Fabrication Chemical hydrogels Physical hydrogels ▪ Hydrogen bonding ▪ hydrophobic interaction ▪ crystallinity ▪ stereocomplex formation ▪ ionic complexation Covalently crosslinkedNoncovalently crosslinked Thermoset hydrogelsThermoplastic hydrogels Volume phase transitionSol-gel phase transition Reliable shape stability and memory Limited shape stability and memory

Hydrogel Fabrication + MonomerCrosslinker Vinyl group-containing water-soluble polymers Copolymerization Polymerization Hydrogel network Chemical crosslinking Polymerization of water soluble monomers in the presence of bi- or multifunctional cross-linking agent or

Hydrogel Fabrication Physical crosslinking Ionic hydrogel Chemical and Physical crosslinking Cross-linking without chemical reaction ionic interaction, hydrogen bonding, antigen-antibody interaction, supramolecular association

Monomers used in the synthesis hydrogels for pharmaceutical applications Monomer abbreviation Monomer HEMA Hydroxyethyl methacrylate HEEMA Hydroxyethoxyethyl methacrylate HDEEMA Hydroxydiethoxyethyl methacrylate MEMA Methoxyethyl methacrylate MEEMA Methoxyethoxyethyl methacrylate MDEEMA Methoxydiethoxyethyl methacrylate EGDMA Ethylene glycol dimethacrylate NVP N-vinyl-2-pyrrolidone NIPAAm N-isopropyl Aam AA Acrylic acid HPMA N-(2-hydroxypropyl) methacrylamide EG Ethylene glycol PEGMA PEG methacrylate

Applications of Hydrogels in Drug Delivery - Benefits of controlled drug delivery  more effective therapies with reduced side effects  the maintenance of effective drug concentration levels in the blood  patient’s convenience as medicines hence increased patient compliance - Release mechanisms of drug molecules : diffusion, dissolution, osmosis, ion exchange

Applications of Hydrogels in Drug Delivery - Diffusion controlled Drug Delivery (1) Polymer matrix Water-insoluble Polymer matrices (2) Reservoir system time Water-insoluble Polymer membrane time

Applications of Hydrogels in Drug Delivery Environment-Sensitive Hydrogels respond to environmental change : temperature, pH, specific molecule reversible volume phase transition or sol-gel phase transition “intelligent” or “smart” hydrogel Drug-loaded gel Change in pH for gel swelling Drug release through the swollen network Drug release by the squeezing action Change in temperature for gel collapse

Environmenta l Factor Typical polymersMain MechanismApplications TemperaturePNIPAAm, PDEAAm, PEO- PPO block copolymers Competition between hydrophobic interaction and hydrogen bonding On/off drug release, squeezing device pHPolyelectrolytes, PAA, PDEAEM Ionization of polymer chains upon pH change pH-dependent oral drug delivery GlucosepH-sensitive hydrogels; Concanavalin A-grafted polymers; polymers containing phenylborate groups pH change caused by glucose oxidase; reversible interaction between glucose- containing polymers and Concanavalin A; reversible solgel transformation Self-regulated insulin delivery Electric signalPolyelectrolytes (pH-sensitive)Reversible swelling or deswelling in the presence of electric field Actuator, artificial muscle, on off drug release LightCopolymer of PNIPAAm and light sensitive chromophore, such as triphenylmethane and leuco derivatives Temperature change via the incorporated photosensitive molecules; dissociation into ion pairs by UV irradiation Optical switches, ophthalmic drug delivery AntigenSemi-IPN with grafted antibodies or antigens Competition between polymer-grafted antigen and free antigen Modulated drug release in the presence of a specific antigen; sensor for immunoassay and antigen Environmental-Sensitive Hydrogels used for Drug Delivery

Specific applications of Hydrogels in Oral Drug Delivery

 Fast-disintegrating tablet formulations  fast swelling and superabsorbent properties  microparticles of superporous hydrogels  mucoadhesive hydrogels buccal drug delivery  Gastric emptying of oral dosage forms The physical properties (size and density) of the oral dosage form The presence of food in the stomach  Intragastric floating system low density float on top of the gastric juice Specific applications of Hydrogels in Oral Drug Delivery

 Mucoadhesive system cross-linked PAA highly mucoadhesive at pH (1-3) of the stomach ( ∵ hydrogen bonding)  Superporous hydrogels Swell to a very large size High swelling ratio ( > a few hundreds) Fast swelling property - avoid premature emptying by the housekeeper waves Gastric retention device (ex. Dogs-from several hours to a day) Ac-Di-Sol (cross-linked carboxymethylcellulose sodium) Specific applications of Hydrogels in Oral Drug Delivery

- Hydrotropic Hydrogels for delivery of poorly soluble drug -Hydrotropic agent : Diverse class of water soluble compounds at high concentration, enhance water solubilities of poorly soluble solutes ex) N,N-dimethylnicotinamide (3.5M), N,N-diethylnicotinamide - Many drugs : poorly soluble in water : low absorption and low bioavailability - Low-molecular-weight hydrotropes : high concentration - Polymeric forms of hydrotropes (e.g., hydrotropic hydrogels) Specific applications of Hydrogels in Oral Drug Delivery

Summary Hydrogels have played role in the development of various controlled-release formulation biocompatible and increasing the solubility of poorly soluble drug Hydrogels with novel properties will continue to play important role in drug delivery smart hydrogels and new controlled-release formulation