Hydrogels in Drug Delivery

Rassoul Dinarvand, PhDProfessor 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

Rs = (Ws-Wd) / Wd

Rs = swelling ratioWs = weight of swollen hydrogelsWd = 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 Mechanical

strength and strength and permeabilitypermeability

Cross-linking and/or copolymerization with hydrophobic comonomers density↑, mechanical strength↑, swelling property↓

Hydrogel FabricationChemical hydrogels

Physical hydrogels

▪ Hydrogen bonding

▪ hydrophobic interaction

▪ crystallinity

▪ stereocomplex formation

▪ ionic complexation

Covalently crosslinked

Noncovalently crosslinked

Thermoset hydrogels

Thermoplastic hydrogels

Volume phase transition

Sol-gel phase transition

Reliable shape stability and memory

Limited shape stability and memory

Hydrogel Fabrication

+

Monomer

Crosslinker

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 FabricationPhysical 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 methacrylateHEEMA Hydroxyethoxyethyl methacrylateHDEEMA Hydroxydiethoxyethyl methacrylateMEMA Methoxyethyl methacrylateMEEMA Methoxyethoxyethyl methacrylateMDEEMA Methoxydiethoxyethyl methacrylateEGDMA Ethylene glycol dimethacrylateNVP N-vinyl-2-pyrrolidoneNIPAAm N-isopropyl AamAA Acrylic acidHPMA N-(2-hydroxypropyl) methacrylamideEG Ethylene glycolPEGMA 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-insolublePolymer matrices

(2) Reservoir system

time

Water-insolublePolymer 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 gelChange in pH for gel swelling

Drug release through the swollen network

Drug release by the squeezing action

Change in temperature for gel collapse

Environmental Factor

Typical polymers Main Mechanism Applications

Temperature

PNIPAAm, PDEAAm, PEO-PPO block copolymers

Competition between hydrophobic interaction and hydrogen bonding

On/off drug release, squeezing device

pH Polyelectrolytes, PAA, PDEAEM

Ionization of polymer chains upon pH change

pH-dependent oral drug delivery

Glucose pH-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 signal

Polyelectrolytes (pH-sensitive)

Reversible swelling or deswelling in the presence of electric field

Actuator, artificial muscle, on off drug release

Light Copolymer 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

Antigen Semi-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