INTRODUCTION:

The design of a drug delivery system is usually based on the drug’s physicochemical and pharmacokinetic properties. Conventional delivery systems suffer from the limitations of minimal synchronization between the required time for therapeutically effective drug plasma concentrations and the actual drug release profile exhibited by the dosage form. An increased understanding of the concept of chronopharmacokinetics and variations in disease symptoms because of diurnal rhythmshas upraised the importance of drug delivery systems mimicking the symptomatic requirement of disease ^[1]. These considerations have shifted the focus of pharmaceutical scientists towards idealized drug delivery, wherein the required amount of active agent is made available at the desired time and site of action in the body. Hydrogels have emerged as a promising option in this regard. Several terms have been coined for hydrogels, such as ‘intelligent gels’ or ‘smart hydrogels’^[2]. The smartness of any material is the key to its ability to receive, transmit or process a stimulus, and respond by producing a useful effect. Once acted on, stimuli can result in changes in phases, shapes, optics, mechanics, electric fields, surface energies, recognition, reaction rates and permeation rates.

Hydrogels are ‘smart’ or ‘intelligent’ in the sense that they can perceive the prevailing stimuli and respond by exhibiting changes in their physical or chemical behaviour, resulting in the release of entrapped drug in a controlled manner ^[3].

Definition

Hydrogels are three-dimensional, hydrophilic, polymeric networks capable of imbibing large amounts of water or

biological fluids ^[4].The networks are composed of homopolymers or copolymers, and are insoluble due to the presence of chemical crosslinks (tie-points, junctions),or physical crosslinks, such as entanglements or crystallites^[5,6].The latter provide the network structure and physical integrity. These hydrogels exhibit a thermodynamic compatibility with water which allows them to swell in aqueous media ^[7,8,9]. There are numerous applications of these hydrogels, in particular in the medical and pharmaceutical sectors. Hydrogels resemble natural living tissue more than another class of synthetic biomaterials. This is due to their high water contents and soft consistency which is similar to natural tissue. Furthermore, the high water content of the materials contributes to their biocompatibility. Thus, hydrogels can be used as contact lenses, membranes for biosensors, linings for artificial hearts, materials for artificial skin, and drug delivery devices.

Physical, chemical and toxicological properties of hydrogels

Factors affecting swelling of hydrogels

The crosslinking ratio is one of the most important factors that affects the swelling of hydrogels. It is defined as the ratio of moles of crosslinking agent to the moles of polymer repeating units. The higher the crosslinking ratio, the more crosslinking agent is incorporated in the hydrogel structure.Highly crosslinked hydrogels have a tighter structure, and will swell less compared to the same hydrogels with lower crosslinking ratios. Crosslinking hinders the mobility of the polymer chain, hence lowering the swelling ratio.The chemical structure of the polymer may also affect the swelling ratio of the hydrogels. Hydrogels containing hydrophilic groups swell to a higher degree compared to those containing hydrophobic groups. Hydrophobic groups collapse in the presence of water, thus minimizing their exposure to the water molecule. As a result, the hydrogels will swell much less compared to hydrogels containing hydrophilic groups. Swelling of environmentally-sensitive hydrogels can be affected by specific stimuli. Swelling of temperature-sensitive hydrogels can be affected by changes in the temperatureof the swelling media. Ionic strength and pH affect the swelling of ionic strength- and pH-sensitive hydrogels, respectively. There are many other specific stimuli that can affect the swelling of other environmentally-responsive hydrogels.

Dynamics of swelling

The swelling kinetics of hydrogels can be classified as diffusion-controlled (Fickian) and relaxation-controlled (non-Fickian) swelling. When water diffusion into thehydrogel occurs much faster than the relaxation of the polymerchains, the swelling kinetics is diffusion-controlled. A nice mathematical analysis of the dynamics of swelling ispresented by Peppas and Colombo ^[10].

Mechanical properties

Mechanical properties of hydrogels are very important for pharmaceutical applications. For example, the integrityof the drug delivery device during the lifetime of the application is very important to obtain FDA approval, unless the device is designed as a biodegradable system. A drug delivery system designed to protect a sensitive therapeutic agent, such as protein, must maintain its integrity to be able to protect the protein until it is released out of the system. Changing the degree of crosslinking has been utilized to achieve the desired mechanical property of the hydrogel.Increasing the degree of crosslinking of the system will result in a stronger gel. However, a higher degree of crosslinking creates a more brittle structure. Hence, there is an optimum degree of crosslinking to achieve a relatively strong and yet elastic hydrogel. Copolymerization has alsobeen utilized to achieve the desired mechanical properties of hydrogels. Incorporating a comonomer that will contribute to H-bonding can increase the strength of the hydrogel.

Cytotoxicity and in-vivo toxicity

Cell culture methods, also known as cytotoxicity tests, can be used to evaluate the toxicity of hydrogels. Three common assays to evaluate the toxicity of hydrogels include extract dilution, direct contact and agar diffusion. Most of the problems with toxicity associated with hydrogel carriers are the unreacted monomers, oligomers and initiators that leach out during application. Therefore, an understanding the toxicity of the various monomers used as the building blocks of the hydrogels is very important.The relationship between chemical structures and the cytotoxicity of acrylate and methacrylate monomers has been studied extensively ^[11]. Several measures have been taken to solve this problem, including modifying the kinetics of polymerization in order to achieve a higher conversion, and extensive washing of the resulting hydrogel.The formation of hydrogels without any initiators has been explored to eliminate the problem of the residual initiator. The most commonly used technique has been gamma irradiation. Hydrogels of PVA(polyvinyl acetate) have been also made without the presence of initiators by using thermal cycle to induce crystallization ^[12,13]. The crystals formed act as physical crosslinks. These crystals will be able to absorb the load applied to the hydrogels.

Classification

Hydrogels can be classified as neutral or ionic, based onthe nature of the side groups. Additionally, they can be homopolymer or copolymer networks, based on the method of preparation. Finally, they can be classified based on the physical structure of the networks as amorphous, semicrystalline, hydrogen-bonded structures, supermolecular structures and hydrocolloidal aggregates. Hydrogels may also show a swelling behavior dependent on the external environment. These polymers are physiologically-responsive hydrogel, where polymer complexes can be broken or the network can be swollen as a result of the changing external environment. These systems tend to show drastic changes in their swelling ratio as a result ^[14].

Temperature Responsive Hydrogels

Temperature sensitive hydrogels can be classified as negatively thermosensitive, positively thermosensitive and thermally reversible hydrogels. Negatively thermosensitive hydrogels are those showing lower critical solution temperature (LCST) behaviour, while positively thermosensitive gels are known to have an upper critical solution temperature (UCST). The LCST polymers exhibit a hydrophilic-to-hydrophobic transition with increasing temperature, whereas the UCST systems undergo the opposite transition.Thermally reversible hydrogels are those that can experience cyclic phase transitions (sol-gel transition),such as poloxamers, gelatin and other natural polymers. Temperature-sensitive hydrogels are probably the most commonly studied class of environment-sensitive polymer systems in drug delivery research. These hydrogels are able to swell or deswell as a result of changing in the temperature of the surrounding fluid ^[15,16].Negative temperature-sensitive hydrogels have a lower critical solution temperature (LCST) and contract upon heating above the LCST. Copolymers of (N-isopropylacrylamide) (PNIAAm) are usually used for negative temperature release. Hydrogels show an onoff drug release with on at a low temperature and off at high temperature allowing pulsatile drug release. LCST systems are mainly relevant for controlled release of drugs, and of proteins in particular. A positive temperature-sensitive hydrogel has an upper critical solution temperature (UCST), such hydrogel contracts upon cooling below the UCST. Polymer networks of poly(acrylic acid) (PAA) and polyacrylamide (PAAm) or poly(acrylamide-co-butyl methacrylate) have positive temperature dependence of swelling. The most commonly used thermoreversible gels are those prepared from poly(ethylene oxide)-b-poly(propylene oxide)-b-poly(ethylene oxide) (Pluronics®, Tetronics®, poloxamer). Polymer solution is a free-flowing liquid at ambient temperature and gels at body temperature, such a system would be easy to administer into desired body cavity. Recently new series of biodegradable triblock copolymers were designed. The polymers consisting of poly(ethylene glycol)-poly-(DL-lactic acid-co-glycolic acid)-poly(ethylene glycol) (PEGPLGAPEG)or PLGA-PEG-PLGA were investigated for sustained injectable drug delivery systems. Some natural polymers like xyloglucan may also form thermoreversible gels^[17].

Electric signal-sensitive hydrogels

Hydrogels sensitive to electric current are usually made of polyelectrolytes such as the pH-sensitive hydrogels^[16]. Electro-sensitive hydrogels undergo shrinking or swelling in the presence of an applied electric field. S. Ramanathan and L. H. Block evaluated and characterized the use of chitosan gels as matrices for electrically modulated drug delivery. In electrification studies, release-time profiles for neutral (hydrocortisone), anionic (benzoic acid) and cationic (lidocaine hydrochloride) drug molecules from hydrated chitosan gels were monitored in response to different milliamperages of current as a function of time. Likewise, chondroitin 4-sulphate hydrogels were examined by Jensen et al. ^[18] as potential matrices for the electro-controlled delivery of peptides and proteins.

Light-sensitive hydrogels

Photoresponsive hydrogels typically consist of a polymeric network and a photoreactive moiety, usually a photochromic chromophore as the functional part. The optical signal is first captured by the photochromic molecules. Next the chromophores in the photoreceptor convert the photoirradiation to a chemical signal through a photoreaction such as isomerization, cleavage and dimerization. The latter signal is transferred to the functional part of hydrogel and controls its properties. The change of the chromophores upon photoirradiation strongly depends on their molecular structures and as a result thereof the required irradiation also varies. Three categories of light-induced reactions can be distinguished; photoisomerization, photocleavage and photodimerization. Some photoreactions are reversible and can be repeated several times, in which the reverse reaction occurs under photoirradiation with a different wavelength or upon other stimuli such as temperature or catalytic reagents. Photoresponsive hydrogels that can show changes upon photoirradiation in their physical and/or chemical properties such as elasticity, viscosity, shape, and degree of swelling are of interest for various biomedical applications. Light-sensitive hydrogels can be used in the development of photo-responsive artificial muscle or as the in situ forming gels for cartilage tissue engineering. In one of the study, gels that may undergo transdermal photopolymerization after subcutaneous injection were found to be applicable for drug release devices ^[19].

pH-sensitive hydrogels

All the pH-sensitive polymers contain pendant acidic or basic groups that either accept or release protons in response to changes in environmental pH ^[16] These hydrogels respond to changes in pH of the external environment. These gels have ionic groups (which are readily ionizable side groups) attached to impart peculiar characteristics. Some of the pH sensitive polymers used in hydrogels’ preparations are polymethyl methacrylate (PMMA), polyacrylamide (PAAm), polyacrylic acid (PAA), poly dimethyl aminoethyl methacrylate (PDEAEMA) and polyethylene glycol. These polymers though in nature are hydrophobic but swells in water depending upon the pH prevalent in the external environment. Any change in pH of the biological environment causes changes in the swelling behaviour, for example, the hydrogel of caffeine is prepared with polymer PDEAEMA at pH below 6.6. As the polymer shows high swellability but when pH changes to higher side, the polymer showed shrinkage leading to drug release. The other pH sensitive hydrogels are copolymer of PMMA and polyhydroxyethyl methyl acrylate (PHEMA) which are anionic copolymers, swell high in neutral or high pH but do not swell in acidic medium. It was also observed that pH and ionic strength determines kinetics of swelling of PHEMA and guar gum.pH sensitive hydrogels have also been used to encapsulate proteins in acrylamide polymer cross-linked with bisacrylamide acetal cross linkers. At pH of around 5, the pore size of the acetal cross-linked hydrogels increases leading to release of protein. However at neutral pH, the acetal groups remain intact as cross linkers and protein do not diffuse out easily ^[20].

Ion-sensitive hydrogels

Polymers may undergo phase transition in presence of various ions. Some of the polysaccharides fall into the class of ion-sensitive ones ^{[16, 21]}. While β-carrageenan forms rigid, brittle gels in reply of small amount of K+, β-carrageenan forms elastic gels mainly in the presence of Ca2+. Gellan gum commercially available as Gelrite® is an anionic polysaccharide that undergoes in situ gelling in the presence of mono- and divalent cations, including Ca2+, Mg2+, K+ and Na+. Gelation of the low-methoxy pectins can be caused by divalent cations, especially Ca2+. Likewise, alginic acid undergoes gelation in presence of divalent/polyvalent cations e. g. Ca2+ due to the interaction with glucuronic acid blocks in alginate chains.

Glucose-sensitive hydrogels

Intelligent stimuli-responsive delivery systems using hydrogels that can release insulin have been investigated. Cationic pH-sensitive polymers containing immobilized insulin and glucose oxidase can swell in response to blood glucose level releasing the entrapped insulin in a pulsatile fashion. Another approach is based on competitive binding of insulin or insulin and glucose to a fixed number of binding sites in concanavalin A, where insulin is displaced in response to glucose stimuli, thus functioning as a self regulating insulin delivery system ^[22].

Nanohydrogels

Nanohydrogels are the hydrogels which are prepared in water by self aggregation of polymers of natural origin like dextran. These types of hydrogels are formed from natural polysaccharides like dextran, pullulan, or cholesterol-containing polysaccharide. The cholesterol containing polysaccharide is stirred at 50°C for 12 h in aqueous buffer which leads to swelling of the cholesterol containing polysaccharide. After sonication at 25°C for 10 min, nanoparticles of hydrogels are formed. The size and density of hydrogel nanoparticles can be controlled by changing the degree of substitution of cholesterol groups of such polysaccharides. These hydrogels are of nano dimensions usually of 20-30 nm and are used for cell targeting as they release the entrapped drug by swelling caused by change in the pH of the surrounding environment. Drugs like adriamycin has been delivered to tumor cells and the drug showed pH dependent release and the highest release was when pH was below 6.8.These nanoparticles of hydrogels have been used for controlled release of proteins like lysozyme, albumin, immunoglobulin. The amount of protein released is dependent on the square root of time. Hydrogels especially of dextran are made biodegradable by encapsulation of enzyme dextranase. The nanohydrogel of polysaccharide-mannose from Saccharomyces cerevisiae have been prepared for encapsulating insulin. The incorporation of calcium phosphate prevents the initial burst release thus these hydrogels are used for controlled drug delivery ^[23].

Release mechanism from hydrogel matrices

Since the most common mechanism of drug release from hydrogels is passive diffusion, molecules of different sizes and characteristics would freely diffuse into/out of hydrogel matrix during the loading and storage periods. The hydrophilic nature of a hydrogel makes it highly different from non-hydrophilic polymer matrices with respect to the release behavior of the incorporated agents. From various modelistic studies on the possible release mechanisms of an active compound from a hydrogel device, focused on the rate-limiting step of the release phenomena, drug release mechanisms from hydrogels can be categorized as: i) diffusion-controlled, ii) swelling-controlled, and iii) chemically- controlled. According to Fick's first law of diffusion (with constant or variable diffusion coefficients), the diffusion-controlled behavior is the most dominantly applicable mechanism to describe the drug release from hydrogels. The drug diffusion out of a hydrogel matrix is primarily dependent on the mesh sizes within the matrix of the gel , which, in turn, is affected by several parameters, including, mainly, the degree of crosslinking, chemical structure of the composing monomers, and, when applicable, type as well as intensity of the external stimuli. Meanwhile, mechanical strength, degradability, diffusivity, and other physical properties of a hydrogel network are greatly dependent on its mesh size. Typical mesh sizes reported for biomedical hydrogels range from 5 to 100 nm (in their swollen state), which are much larger than most small-molecule drugs. As a result, diffusion of these drugs is not considerably retarded in swollen state, whereas macromolecules like oligonucleotides, peptides, and proteins, due to their hydrodynamic radii, will have a sustained release unless the structure and mesh size of the swollen hydrogels are designed appropriately to obtain desired rates of macromolecular diffusion . In the case of the swelling-controlled mechanism, when diffusion of a drug is significantly faster than hydrogel distention, swelling is considered to be controlling for the release behavior. Finally, chemically-controlled release is determined by chemical reactions occurring within the gel matrix. These reactions include polymeric chain cleavage via hydrolytic or enzymatic degradation, or reversible/irreversible reactions occurring between the polymer network and the releasing drug. In addition to the above mentioned release mechanisms, under certain circumstances, surface or bulk erosion of hydrogels or the binding equilibrium among the drug binding moieties incorporated within the hydrogels, are two different mechanisms reported as controlling the rate of drug release. Interestingly, hydrogel nanoparticulate materials would demonstrate the features and characteristics hydrogels and nanoparticles separately posses, at the same time. Therefore, it seems that the pharmacy world will benefit from the hydrophilicity, flexibility, versatility, high water absorptivity, and biocompatibility of these particles and all the advantages of the nanoparticles, mainly long life span in circulation and the possibility of being actively or passively targeted to the desired biophase, e.g. tumor sites ^[24].

Preparation of Hydrogel

Several techniques have been reported for the synthesis of hydrogels. The first approach involves copolymerization/ crosslinking of co-monomers using multifunctional co-monomer, which acts as crosslinking agent. The polymerization reaction is initiated by chemical initiator. The polymerization reaction can be carried out in bulk, in solution, or in suspension. The second method involves crosslinking of linear polymers by irradiation, or by chemical compounds ^[25]. The monomers used in the preparation of the ionic polymer network contain an ionizable group, a group that can be ionized, or a group that can undergo a substitution reaction after the polymerization is completed. As a result, hydrogels synthesized contain weakly acidic groups like carboxylic acids, or a weakly basic group like substituted amines, or a strong acidic and basic group like sulfonic acids, and quaternary ammonium compounds. Some of the commonly used crosslinking agents include N, N'-methylenebisacrylamide, divinyl benzene, and ethylene glycol methacrylate.

Solution polymerization/Crosslinking

In solution, co-polymerization/crosslinking reactions, anionic or neutral monomers are mixed with the multifunctional crosslinking agent. The polymerization is initiated thermally, by UV-light, or by redox initiator system. The presence of solvent serves as heat sink, and minimizes temperature control problems. The prepared hydrogels need to be washed with distilled water to remove the unreacted monomers, crosslinking agent, and the initiator. The best example is preparation of poly(2-hydroxyethyl methacrylatehydrogels from hydroxyethyl methacrylate, using ethylene glycol dimethacrylate as crosslinking agent. Using the above method, a great variety of hydrogels has been synthesized. The hydrogels can be made pH- sensitive or temperature-sensitive, by incorporating methacrylic acid, or N-Isopropylacrylamide as monomer ^[26].

Suspension polymerization

This method is employed to prepare spherical hydrogel microparticles with size range of 1 µm to 1mm. In suspension polymerization, the monomer solution is dispersed in the non-solvent forming fine droplets, which are stabilized by the addition of stabilizer. The polymerization is initiated by thermal decomposition of free radicals. The prepared microparticles then washed to remove unreacted monomers, crosslinking agent, and initiator. Hydrogel microparticles of poly(vinyl alcohol) and poly(hydroxy ethyl methacrylate) have been prepared by this method ^[27].

Polymerization by irradiation

High energy radiation like gamma and electron beam, have been used to prepare the hydrogels of unsaturated compounds. The irradiation of aqueous polymer solution results in the formation of radicals on the polymer chains. Also, radiolysis of water molecules results in the formation hydroxyl radicals, which also attack the polymer chains, resulting in the formation of macroradicals. Recombination of the macroradicals on different chains results in the formation of covalent bonds, and finally a crosslinked structure is formed ^[28]. During radiation, polymerization macroradicals can interact with oxygen, and as a result, radiation is performed in an inert atmosphere using nitrogen or argon gas. Examples of polymers crosslinked by radiation method include poly(vinyl alcohol), poly (ethylene glycol), poly(acrylic acid). The major advantage over chemical initiation is the production of relatively pure, residue-free hydrogels.

Chemically crosslinked hydrogel

Polymers containing functional groups like -OH, -COOH, -NH₂, are soluble in water. The presence of these functional groups on the polymer chain, can be used to prepare hydrogels by forming covalent linkages between the polymer chains and complementary reactivity, such as amine-carboxylic acid, isocyanate-OH/NH₂ or by Schiff base formation ^[29]. Gluteraldehyde can be used as a crosslinking agent to prepare hydrogels of polymers containing -OH groups like poly(vinyl alcohol). Also, polymers containing amine groups (albumin, gelatin polysaccharides) ^[30], can be crosslinked using gluteraldhyde. Polymers that are water soluble, can be converted to hydrogels, using bis or higher functional crosslinking agents like divinylsulfone, and 1,6-hexanedibromide. The crosslinking agents react with the functional groups present on the polymer, via addition reaction. These crosslinking agents are highly toxic, and hence unreacted agents have to be extracted. Moreover the reaction has to be carried out in organic solvent, as water can react with the crosslinking agent. The drugs have to be loaded after the hydrogels are formed, as a result the release will be typically first order. Crosslinking between polymers through hydrogen bond formation occur as in the case of poly(methacrylic acid) and poly(ethylene glycol). The hydrogen bond formation takes place between the oxygen of poly(ethylene glycol) and carboxylic acid group of poly(methacrylic acid)^[31].

Physically Crosslinked Hydrogels

Most of the covalent crosslinking agents are known to be toxic, even in small traces. A method to overcome this problem and to avoid a purification step is to prepare hydrogels by reversible ionic crosslinking. Chitosan, a polycationic polymer can react with positively charged components, either ions or molecules, forming a network through ionic bridges between the polymeric chains. Among anionic molecules, phosphate bearing groups, particularly sodium tripolyphosphate is widely studied. Ionic crosslinking is a simple and mild procedure. In contrast to covalent crosslinking, no auxiliary molecules such as catalysts are required. Chitosan is also known to form polyelectrolyte complex with poly(acrylic acid). The polyelectrolyte complex undergoes slow erosion, which gives a more biodegradable material than covalently crosslinked hydrogel ^{[32, 33]}.

Characterization of Hydrogel

Generally hydrogels are characterized for their morphology, swelling property and elasticity. Morphology is indicative of their porous structure. Swelling determines the release mechanism of the drug from the swollen polymeric mass while elasticity affects the mechanical strength of the network and determines the stability of these drug carriers. Some of the important features for characterization of hydrogels are as follows:

Morphological characterization

Hydrogels are characterized for morphology which is analyzed by equipment like stereomicroscope. Also the texture of these biomaterials is analyzed by SEM to ensure that hydrogels, especially of starch, retain their granular structures.

X-ray diffraction

It is also used to understand whether the polymers retain their crystalline structure or they get deformed during the processing pressurization process.

In-vitro release study for drugs

Since hydrogels are the swollen polymeric networks, interior of which is occupied by drug molecules, therefore, release studies are carried out to understand the mechanism of release over a period of application.

FTIR (Fourier Transform Infrared Spectroscopy)

Any change in the morphology of hydrogels changes their IR absorption spectra due to stretching and O-H vibration. Formation of coil or helix which is indicative of cross linking is evident by appearance of bands near 1648 cm-1.

Swelling behavior

The hydrogels are allowed to immerse in aqueous medium or medium of specific pH to know the swellability of these polymeric networks. These polymers show increase in dimensions related to swelling.

Rheology

Hydrogels are evaluated for viscosity under constant temperature of usually 4°C by using Cone Plate type viscometer ^[34].

Applications of Hydrogels in Drug Delivery

Advances in recombinant protein technology have identified several protein and peptide therapeutics for disease treatment. Thus hydrogels are primarily used for encapsulation of bioactive materials and their subsequent controlled release. Hydrogel based delivery devices can be used for oral, ocular, epidermal and subcutaneous application. These applications are discussed in detail below.

Peroral drug delivery

The pH-sensitive hydrogels have a potential use in site-specific delivery of drugs to specific regions of the GI tract. Hydrogels made of varying proportions of PAA derivatives and cross-linked PEG allowed preparing silicone microspheres, which released prednisolone in the gastric medium or showed gastroprotective property. Cross-linked dextran hydrogels with a faster swelling under high pH conditions, likewise other polysaccharides such as amidaded pectins, guar gum and inulin were investigated in order to develop a potential colon-specific drug delivery system ^[35].

Drug Delivery in the GI Tract

The ease of administration of drugs and the large surface area for absorption makes the GI tract most popular route for drug delivery. Hydrogel-based devices can be designed to deliver drugs locally to specific sites in the GI tract.

Rectal Delivery

This route has been used to deliver many types of drugs for treatment of diseases associated with the rectum, such a hemorrhoids. This route is an ideal way to administer drugs suffering heavy first-pass metabolism. An indomethacin poly vinyl alcohol (PVA) hydrogel used for rectal administration. The release of indomethacin from the PVA hydrogel agreed with the Fickian diffusion model for 10 hr. Rectal administration of indomethacin hydrogels to rats yielded high indomethacin plasma concentrations, without producing a sharp peak, and a sustained-release effect. In dogs, the indomethacin hydrogel produced a similar sustained-release effect; however, the indomethacin plasma concentration was relatively low compared with that of an indomethacin suppository ^[36].

Ocular Delivery

Drug delivery to the eye is difficult due to its protective mechanisms, such as effective tear drainage, blinking, and low permeability of the cornea. Thus, eye drops containing drug solution tends to be eliminated rapidly from the eye and the drugs show limited absorption, leading to poor ophthalmic bioavailability. Due to the short retention time, a frequent dosing regimen is necessary for required therapeutic efficacy. In hydrogel forming system can be useful in overcoming above mentioned drawbacks of liquid formulation ^[37].

Transdermal Delivery

Drug delivery to the skin has been generally used to treat skin diseases or for disinfections of the skin. In recent years, however a transdermal route for the delivery of drugs has been investigated. Swollen hydrogels can be delivered for long duration and can be easily removed. These hydrogels can also bypass hepatic first-class metabolism, and are more comfortable for the patient. The hydrogel type polyurethane (PU) foams were prepared from diisocyanate and polyol with/without hydrophilic moiety for wound dressing to protect infection from outside and to heal skin wound. Biomaterials with hydrogel properties, such as alginate and hyaluronic acid, and antimicrobial agent (silver sulfadiazine, AgSD) were also incorporated in the polyurethane foam.The PU foams have good properties such as mechanical strength, swelling ratio, and cell adhesion for applying to wound dressing ^[38].

Vaginal delivery

The vagina, in addition to being an important organ of reproductive tract, serves as a potential route for drug administration. Formulations based on a thermoplastic graft copolymer that undergo in situ gelation have been developed to provide the prolonged release of active ingredients such as nonoxynol-9, progestins, estrogens, peptides and proteins. J. Y. Chang et al. have recently reported a mucoadhesive thermosensitive gel (combination of poloxamers and polycarbophil) which exhibited increased and prolonged antifungal activity of clotrimazole in comparison with conventional PEG-based formulation ^[39].

Parenteral delivery

One of the most obvious ways to provide sustained release medication is to place the drug in a delivery system and inject or implant the system into the body tissue. Thermoreversible gels mainly prepared from poloxamers are predominantly used. The suitability of poloxamer gel alone or with the addition of hydroxypropylmethylcellulose (HPMC), sodium carboxymethylcellulose (CMC) or dextran was studied for epidural administration of drugs in vitro. Poloxamer gels were tested for intramuscular and subcutaneous administration of human growth hormone or with the aim to develop a long acting single dose injection of lidocaine. Some other thermosensitive hydrogels may also be used for parenteral administration. ReGel® (triblock copolymer PLGA-PEG-PLGA) was used as a drug delivery carrier for the continuous release of human insulin. Steady amounts of insulin secretion from the ReGel® formulations up to day 15 of the subcutaneous injections were achieved ^[40,41].

Nasal delivery

Nasal formulations of chlorpheniramine maleate and tetrahydrozoline hydrochloride were investigated. The findings suggest that liquid formulations facilitate the instillation into the nose and the hydrogel formed on the mucous membrane provide controlled drug release ^[42].

Application of hydrogel in wound healing

The use of hydrogels in the healing of wounds dates back to late seventies or early eighties. As mentioned earlier, hydrogel is a crosslinked polymer matrix which has the ability to absorb and hold water in its network structure. Hydrogels act as a moist wound dressing material and have the ability to absorb and retain the wound exudates along with the foreign bodies, such as bacteria, within its network structure. In addition to this, hydrogels have been found to promote fibroblast proliferation by reducing the fluid loss from the wound. Hydrogels help in maintaining a micro-climate for biosynthetic reactions on the wound surface necessary for cellular activities ^[43]. Fibroblast proliferation is necessary for complete epithelialisation of the wound, which starts from the edge of the wound. Since hydrogels help to keep the wound moist, keratinocytes can migrate on the surface. Hydrogels may be transparent, depending on the nature of the polymers, and provide cushioning and cooling/ soothing effects to the wound surface. The main advantage of the transparent hydrogels includes monitoring of the wound healing without removing the wound dressing. The process of angiogenesis can be initiated by using semi-occlusive hydrogel dressings, which is initiated due to temporary hypoxia. Angiogenesis of the wound ensures the growth of granulation tissue by maintaining adequate supply of oxygen and nutrients to the wound surface. Hydrogel sheets are generally applied over the wound surface with backing of fabric or polymer film and are secured at the wound surface with adhesives or with bandages ^[44].

Application of hydrogels for gene delivery

Gene delivery is defined as the incorporation of foreign DNA particles into the host cells and can be mediated by viral and non-viral methods. The delivery of gene into the host cells by utilizing a virus uses the capability of a virus to incorporate its DNA into the host cells. For the purpose retroviruses and adenoviruses have been used. These viral vectors are used as they can provide efficient transduction and high gene expression. At the same time, the use of viral vectors is quite limited as they can produce immunogenic reactions or mutagenesis of transfected cells. Hence, scientists are tuning their interest towards the available non-viral techniques, which produces less complexity. The non-viral techniques include the use of a gene gun, electroporation and sonication. Of late researchers have started the use of polymers, viz. poly-L-lysine (PLL), polyamidoamine dendrimer (PAMAM), polyethylenimmine (PEI), PGA, PLA and PLGA, for gene delivery. The use of PEG-PLGA-PEG hydrogel for the delivery of plasmid-beta 1 gene increased the wound healing process in diabetic mouse model ^[45]. Meilander- Lin and co-workers reported similar results with agarose hydrogels. They concluded that agarose gels can be useful in the wound-healing and tissue engineering application. Mageed and co-workers reported the use of recombinant silk-elastin like polymer hydrogels (SELP) for the delivery of pRL-CMV for the treatment of human breast cancers. Their results suggested an increase in the transfection efficiency when SELP hydrogels were used ^[45]. A recent study describes encapsulation of C2C12 myoblasts in a biocompatible permselective hydrogel such as alginate –poly-L–lysine- alginate (APA) to protect the cell from host immune response; while allowing diffusion of gene products ^[46].

Application of Hydrogels to Fix Bone Replacements

Provided as orthopedic fasteners and replacements such as nails, screws, pins, hip and knee replacements etc., coated with hydrogels and other biocompatible/biodegradable materials which expand in the presence of liquids. Useful coating materials include methacrylate, hyaluronic acidesters, and crosslinked esters of hyaluronic acid resulting from the esterification of hyaluronic acid with polyhydric alcohols. Replacements can be thus coated, even those made of stainless steel, metal alloys, titanium, or cobalt chromium treatment of the surfaces to improve metal-polymer adhesion ^[47].

Hydrogel for Repairing, Regenerating Human Tissue

Formulating hydrogels as delivery vehicles for cells extends the uses of these biopolymers far beyond soft-contact lenses into an intriguing realm once viewed as the domain of science fiction, including growing bones and organs to replace those that are diseased or injured. Hydrogels are formed from networks of super-absorbent, chainlike polymers. Although they are not soluble in water, they soak up large amounts of it, and their porous structure allows nutrients and cell wastes to pass right through them ^[48]

Marketed hydrogels

NANO DOX^TM HYDROGEL

Nanotherapeutics, a privately held specialty biopharmaceutical company, announced that it has submitted its first Investigational New Drug (IND) application to the FDA. NanoDOX™ is a unique formulation that holds significant promise for the millions of people suffering from diabetic ulcers. NanoDOX™ Hydrogel, the company's leading pharmaceutical product in development, is alternative topical formulation of doxycycline. Nanotherapeutics developed the product with its proprietary particle stabilization technology and formulated it to improve the topical delivery of doxycycline to increase local efficacy of the drug ^[49].

FUCOIDAN-CHITOSAN HYDROGEL^TM

Hydrogels are ideal biopolymeric pharmaceutical forms for the treatment of skin Wounds. They have low interfacial tension, high molecular and oxygen permeability, good moisturizing and mechanical properties that resemble physiological soft tissue Low gel hardness ensures that the minimum work is required for removal of gels from the container and the applicability onto the desired site. Low hardness decrease the retention time of gel formulation on the wound and therefore, a hydrogel formulation should have an appropriate hardness value for the effective treatment of wounds ^[50].

CORGEL BIOHYDROGEL^TM

The patented hyaluronan (hyaluronic acid) based biocompatible hydrogel is based on di hydroxyphenyl linkages of tyramine substituted hyaluronan. Corgel™ may be useful in surgical and transcatheter applications including vascular surgery, cardiology, ophthalmology, orthopedics, aesthetics, ENT, drug delivery, tissue engineering and regenerative medicine ^[51].

CONCLUSION:

Drug delivery has undergone a revolutionary advancement in the past few years. With the advent of novel delivery systems, various drug molecules have been revived of their therapeutic and commercial benefits. There are enough scientific evidences for the potentiality of hydrogels in delivery of drug molecules to a desired site by triggering the release through an external stimulus such as temperature, pH, glucose or light. The introduction of stimuli-responsive systems has further strengthened thelink between therapeutic need and drug delivery. These hydrogels being biocompatible and biodegradable in nature have been used in the development of nano biotechnology products and have marvelous applications in the field of controlled drug delivery as well. Different types of functional polymers have been investigated for series of drugs in vitro or in vivo. As a result, new and interesting controlled and sustained delivery strategies have become available. The fascinating properties of the stimuli-sensitive polymers seem promising in many future applications and offer possible use as the next generation of materials in biological, biomedical and pharmaceutical products.

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Received on 16.02.2012 Modified on 12.03.2012

Research J. Pharm. and Tech. 5(5): May2012; Page 561-569