CHARACTERISTIC OF HYDROGEL

Depending on the nature and composition of the hydrogel the next step is the disintegration and/or dissolution if the network chain or cross-links are degradable. Biodegradable hydrogels, containing labile bonds, are therefore advantageous in applications such as tissue engineering, wound healing and drug delivery. These bonds can be present either in the polymer backbone or in the cross-links used to prepare the hydrogel. The labile bonds can be broken under physiological conditions either enzymatically or chemically, in most of the cases by hydrolysis.^[5]

Biocompatibility is the third most important characteristic property required by the hydrogel. Biocompatibility calls for compatibility with the immune system of the hydrogel and its degradation products formed, which also should not be toxic. Ideally they should be metabolized into harmless products or can be excreted by the renal filtration process. Generally, hydrogels possess a good biocompatibility since their hydrophilic surface has a low interfacial free energy when in contact with body fluids, which results in a low tendency for proteins and cells to adhere to these surfaces. Moreover, the soft and rubbery nature of hydrogels minimizes irritation to surrounding tissue. ^[6]

The cross-links between the different polymer chains results in viscoelastic and sometimes pure elastic behavior and give a gel its structure (hardness), elasticity and contribute to stickiness. Hydrogel, due to their significant water content possess a degree of flexibility similar to natural tissue. It is possible to change the chemistry of the hydrogel by controlling their polarity, surface properties, mechanical properties, and swelling behavior.

Generally hydrogel 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 hydrogel 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 swell ability 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.

POLYMERS INVOLVED IN HYDROGEL

Pectin

Pectin is a family of polysaccharides, in which the polymer backbone mainly comprises a-(1-4)-D-galacturonic acid residues. Although the gelation of pectin will occur in the presence of H+ ions, a source of divalent ions, generally calcium ions is required to produce the gels that are suitable as vehicles for drug delivery.

Xyloglucan

Xyloglucan is a polysaccharide derived from tamarind seeds and is composed of a (1-4)-b-D-glucan backbone chain, which has (1-6)-a-D xylose branches that are partially substituted by (1-2)-b-D-galactoxylose.

Xanthum gum

Xanthum gum is a high molecular weight extra cellular polysaccharide produced by the fermentation of the gram-negative bacterium Xanthomonas campestris. Cellulose derivative contains a cellulosic backbone (b-D-glucose residues) and a trisaccharide side chain of b-D-mannose-b-D-glucuronic acid-a-D-mannose attached with alternate glucose residues of the main chain.

Gellan gum

Gellan gum is an anionic deacetylated exocellular polysaccharide secreted by Pseudomonas elodea with a tetrasaccharide repeating unit of one a-L-rhamnose, one b-D-glucuronic acid, and two b-D-glucuronic acid residues.

Chitosan

Chitosan is a biodegradable, thermo-sensitive, polycationic polymer obtained by alkaline deacetylation of chitin, a natural component of shrimp and crab shell. Chitosan is a biocompatible pH-dependent cationic polymer, which remains dissolved in aqueous solutions up to a pH of 6.2.^[7][8]

Carbopol

Carbopol is a well-known pH-dependent polymer, which stays in solution form at acidic pH but forms a low viscosity gel at alkaline pH. HPMC is used in combination with carbopol to impart the viscosity to carbopol solution, while reducing the acidity of the solution.

HYDROGELS: SWELLING- CONTROLLED DRUG DELIVERY SYSTEM-

A hydrogel is considered to be a polymeric material that has the ability to absorb >20% of its weight of water and still maintain a distinct 3D structure. The hydrophilicity of the polymer imparts water-attracting properties to the system. Their characteristic water-insoluble behavior is attributed to the presence of chemical or physical cross-links, which provide a network structure and physical integrity to the system. Hydrogels are elastic in nature because of the presence of a memorized reference configuration to which they return even after being deformed for a long time. ^[9] In a true sense, hydrogels consist of polymers combined with water to create a solid with certain water like properties, such as permeability for many water-soluble substances. Hydrogels are available in various structural and chemical forms, on which basis they have been broadly classified in the literature. ^[10]Traditionally, controlled release polymeric systems have been classified into ‘matrix’ and ‘reservoir’ types. ^[11] Matrix systems are most commonly employed because of their ease in development, cost-effectiveness and better performance. However, these systems tend to follow Higuchi’s model, wherein drug release is proportional to the square root of time (t½). This leads to non-uniform release rates, continuously decreasing in the beginning and more rapidly thereafter. The key benefit of hydrogels for controlled drug delivery lies in the near constant release rates. ^[12]Various stimuli that have been explored for modulating drug delivery are represented in Fig.2

Figure no.2: Stimuli responsive swelling of hydrogels (Hydrogels: from controlled release to pH-responsive drug delivery Piyush Gupta, Kavita Vermani and Sanjay Garg , research focus, Vol. 7, 2002)

PH-RESPONSIVE HYDROGELS-

Variations in pH are known to occur at several body sites, such as the gastrointestinal tract, vagina and blood vessels, and these can provide a suitable base for pH-responsive drug release. In addition, local pH changes in response to specific substrates can be generated and used for modulating drug release. The pH-responsive drug delivery systems have been targeted for per oral controlled drug delivery, taste-masking of bitter drugs and intravascular drug release during elevated blood pH in certain cardiovascular defects. ^[13]

FORMULATION ASPECTS-

Preparation of hydrogel-based drug product involves either cross-linking of linear polymers or simultaneous polymerization of monofunctional monomers and cross-linking with polyfunctional monomers . Further, the mechanical strength of poorly cross-linked hydrogels can be adequately enhanced by various methods. Polymers from natural, synthetic or semi-synthetic sources can be used for synthesizing hydrogels. Usually, polymers containing hydroxyl, amine, amide, ether, carboxylate and sulfonate as functional groups in their side chains are used.^[14] A detailed list of various monomers and cross-linkers is available in the literature.^[15]A stepwise methodology shown in Fig no.3. The preparation of hydrogel-based drug delivery systems is following -

a. Isostatic ultra high pressure (IUHP)

Here the suspension of natural biopolymers like starch, are subjected to ultrahigh pressure of 300-700 MPa for 5 or 20 min in a chamber which brings about changes in the morphology of the polymer (i.e. gelatinization of starch molecules occur). It is different from heat-induced gelatinization where a change in ordered state of polymer occurs. Usually the temperature within the chamber varies from 40 to 52°C.

b. Use of cross linkers

Since hydrogels are the polymers which swell in presence of water and they entrap drug within their pores; therefore, to impart sufficient mechanical strength to these polymers, cross linkers are incorporated like glutaraldehyde, calcium chloride and oxidized konjac glucomannan (DAK). These cross linkers prevent burst release of the medicaments. Hydrogels of gelatin has been prepared with DAK. Some researchers have reported in situ hydrogel formation by incorporating lactose along with sodium azide that results in formation of azide groups along with amino groups in polymers like chitosan and thus a photo cross linkable chitosan (Az-Ch-LA) is formed which has desired integrity.

c. Use of water and critical conditions of drying

Aerogels of carbon have been prepared by super critically controlling the drying conditions. Aerogels of resorcinol formaldehyde hydrogels have also been prepared by using water as solvent and sodium carbonate as pH regulator. The final texture of hydrogel is governed by molar ratio of resorcinol to sodium carbonate. This method of preparation leads to porous hydrogels with no shrinkage during drying process. The method is expensive but leads to formation of xerogels with sufficient mechanical strength.

d. Use of nucleophilic substitution reaction

Hydrogels of N-2-dimethylamino ethyl-methacryalmide (DMAEMA), a pH and temperature sensitive hydrogel has been prepared by nucleophilic substitution reaction between methacyloyl chloride and 2-dimethylamino ethylamine. The synthesized hydrogel was characterized for its swelling behavior.

e. Use of gelling agents-

Gelling agents like glycophosphate, 1-2 propanediol, glycerol, trehalose, mannitol, etc, have been used in formation of hydrogels. Usually the problem of turbidity and presence of negative charged moieties which are associated with this method pose problem of interaction with the drug.

f. Use of irradiation and freeze thawing-

Hydrogels prepared by chemical methods (i.e. use of crosslinkers, gelling agents or reaction initiators) are having problems of removal of residue or unnecessary charged moieties present. Irradiation method is suitable and convenient but the processing is costly. The mechanical strength of such hydrogels is less. However with freeze thawing method, the hydrogels so formed have sufficient mechanical strength and stability but are opaque in appearance with a little swelling capacity. However, hydrogels prepared by microwave irradiation are more porous than conventional methods.^[16]

Figure no. 3: Schematic representation of the steps involved in preparation of a hydrogel based drug delivery system. (Hydrogels: from controlled release to pH-responsive drug delivery Piyush Gupta, Kavita Vermani and Sanjay Garg , research focus, Vol. 7, 2002)

EVALUATION STUDY

Swelling studies-

The results indicate that with an increase in pH, a considerable increase in swelling was observed for all the hydrogel formulations, which may be due to the dissociation of the ‐COOH groups of acrylic acid, thereby increasing the osmotic pressure ^[17][18]

Spreadability

It indicates the extent of area to which gel readily spreads on application to skin or affected part. The therapeutic potency of a formulation also depends upon its spreading value. Spreadability is expressed in terms of time in seconds taken by two slides to slip off from gel which is placed in between the slides under the direction of certain load. Lesser the time taken for the separation of two slides, better the spreadability. It is calculated by using following formula,

S = M. L / T

Where, M = wt. tied to upper slide L = length of glass slides T = time taken to separate the slides

Viscosity study

The measurement of viscosity of the prepared gel was done with a Brookfield Viscometer. The gels were rotated at 0.3, 0.6 and 1.5 rotations per minute. At each speed, the corresponding dial reading was noted. The viscosity of the gel was obtained by multiplication of the dial reading with factor given in the Brookfield Viscometer catalogues

Drug content

1 g of the prepared gel was mixed with 100ml of suitable solvent. Aliquots of different concentration were prepared by suitable dilutions after filtering the stock solution and absorbance was measured. Drug content was calculated using the equation, which was obtained by linear regression analysis of calibration curve.

Measurement of pH

The pH of various gel formulations was determined by using digital pH meter. One gram of gel was dissolved in 100 ml distilled water and stored for two hours. The measurement of pH of each formulation was done in triplicate and average values are calculated

Skin irritation study

Guinea pigs (400-500 g) of either sex were used for testing of skin irritation. The animals were maintained on standard animal feed and had free access to water. The animals were kept under standard conditions. Hair was shaved from back of guinea pigs and area of 4 cm² was marked on both the sides, one side served as control while the other side was test gel was applied (500 mg / guinea pig) twice a day for 7 days and the site was observed for any sensitivity and the reaction if any, was graded as 0, 1, 2, 3 for no reaction, slight patchy erythema, slight but confluent or moderate but patchy erythema and severe erythema with or without edema, respectively.

Stability

The stability studies were carried out for all the gel formulation by freeze - thaw cycling. here, by subjecting the product to a temperature of 4° C for 1 month, then at 25°C for 1 month and then at 40°C for 1month, syneresis was observed. After this, the gel is exposed to ambient room temperature and liquid exudate separating is noted.

In vitro drug release study-

In the HCl buffer, the percentage drug release was found to be low in all the cases; this can be attributed to the fact that the hydrogel swells less in the acidic medium. When the dissolution medium was changed to phosphate buffer the release was found to increase with time^.[17][18]

PHARMACEUTICAL APPLICATIONS OF HYDROGELS

To provide sustained or controlled drug delivery into systems, the hydrogels are designed, modulated and characterized for the expected in-vivo results. These hydrogels have gained existence in drug delivery through parenteral, ocular, rectal, vaginal, dermal and nasal routes. ^[19]Some of the important pharmaceutical applications of hydrogels are discussed below.

Wound healing

A modified polysaccharide that occurs in cartilage has been used in formation of hydrogels to treat cartilage defects has been developed.^[20]The polysaccharide is functionalized with methacrylate and aldehyde group which react with proteins of skin tissues, while the methacrylate cross links with back bone of disaccharide chondroitin; thus, a network is formed from where the chondrocytes cells are released.^[21] Honey hydrogels have been used for prompt wound healing. These hydrogels have matrix in which honey is cross-linked and most acceptable, easily peeled, and transparent system. ^[22] The hydrogel of gelatin and PVA (polyvinyl alcohol) along with blood coagulant have been formulated. The cell adhesive hydrogel ensured better effect than corresponding gel or ointment in controlling blood coagulation. ^[23]

Colon specific drug delivery

Colon specific hydrogels of polysaccharides have been specifically designed because of presence of high concentration of polysaccharidase enzymes in the colon region of GI (gastrointestinal) tract. Drugs loaded in such hydrogels show tissue specificity and change in the pH or enzymatic actions that cause liberation of drug. Controlled delivery of Ibuprofen to colon has been achieved through hydrogel of guargum cross linked with glutaraldehyde as cross linker. ^[24]

Cosmetology

For aesthetic purpose, hydrogels have been implanted into breast to accentuate them. These hydrogels swell invivo in aqueous environment and retain water. These breast implants have silicone elastomer shell and are filled with hydroxyl propyl cellulose polysaccharide gel. ^[25]

Topical drug delivery

Hydrogels have been used to deliver active component like Desonide which is a synthetic corticosteroid usually used as an anti-inflammatory. Instead of conventional creams, the hydrogels have been formulated for better patient compliance. These hydrogels have moisturizing properties therefore scaling and dryness is not expected with this drug delivery system. ^[26] Antifungal formulations like cotrimazole have been developed as hydrogel formulation for vaginitis. It has shown better absorption than conventional cream formulations. ^[27]

Ocular drug delivery-

For ocular drug delivery of pilocarpine and timolol, the polymers which form gel such as xyloglucan have been used for sustained drug delivery. Hydrogels of poly hydroxyethyl methacrylamide (pHEMA), N, N-dimethyl acrylamide (DMAAm) and 2-(N-ethyl per fluorooctane sulfonamide) ethylacrylate (FOSA) have been used for ocular delivery to have complete absorption through cornea. Drugs like diclofenac and phenaramine maleate have been successfully delivered through hydrogels. ^[28]

Industrial applicability-

Hydrogels have been used as absorbents for industrial effluents like methylene blue dye. ^[29] The other example is the adsorption of dioxins by hydrogel beads. The DNA of Salmon milt adsorbs dioxins which produce health hazards like carcinogenicity, immunotoxicity or endocrine disruption.

Modified dosage forms-

An interesting research in this field of drug delivery is of bio-macromolecules like insulin delivered to the site of absorption with hydrogels of poly (methacrylamide –co-N- vinyl- 2- Pyrrolidone co- itaconic acid). The insulin entrapped in this matrix showed release at the desired interval. The swelling behavior was analyzed in medium containing pepsin which degrades insulin. Thus when an optimized concentration of cross linkers like N, N’ –methylene bisacrylamide are used then maximum entrapment efficiency is observed. Thus the release and unwanted degradation of drugs like insulin can be prevented by hydrogel based drug delivery devices. ^[30]

Tissue engineering-

The micronized hydrogels (micro gels) have been used to deliver macromolecules like phagosomes into cytoplasm of antigen-presenting cells. The release is because of acidic conditions. ^[31] Such hydrogels mold themselves to the pattern of membranes of the tissues and have sufficient mechanical strength. This property of hydrogels is also used in cartilage repairing. ^[32]

Protein drug delivery-

Interleukins which are conventionally given as injection are now given as hydrogels. These hydrogels have shown better patient compliance. The hydrogels form in situ polymeric network and release proteins slowly. These are biodegradable and biocompatible also. ^[33]

Miscellaneous applications-

Hydrogels are also used in other forms of drug delivery like pulsatile drug delivery or oral drug delivery. ^[34] Injectable hydrogels are also been investigated for cancer drug delivery. In situ gel-forming hydrogels for prolonged duration have also been reported. ^[35]

CONCLUSION:

The primary requirement of a successful controlled release product focuses on increasing patient compliance, good stability, and biocompatibility characteristics. Drug delivery has undergone a revolutionary advancement in the past few years. With the advantage of novel delivery systems, various drug molecules have been revived of their therapeutic and commercial benefits. A lot of research is ongoing in various laboratories to explore stimuli-responsive hydrogels as drug delivery systems for better patient care. From the hydrogel, drug molecule was deliver is trigger by the external stimulus such as temperature, PH, light or glucose. It is used in nano biotechnology produt because of its biodegradable and biocompatible in nature. It is excellent type of controlled drug delivery system. There is a need for continued improvement in the delivery of not only hydrophobic molecules, but also the delivery of more sensitive molecules such as proteins, antibodies, or nucleic acids. In this paper, we present a exhaustive note on ph based hydrogel. The aspects of our project focused on development of novel hydrogel for drug delivery system. It is used as site specific controlled drug delivery system. With this compilation we assure that the content of the article would be a useful tool to understand the in-depth knowledge of this subject concern.

ACKNOWLEDGEMENT:

Authors want to acknowledge the facilities provided by the Rungta College of Pharmaceutical Sciences and Research, Kohka, Kurud Road, Bhilai, Chhattisgarh, India. The authors are also grateful to the e-library of Pt. Ravishankar Shukla University, Raipur, Chhattisgarh, India, 490001 for providing UGC-INFLIBNET facility. The authors acknowledge Chhattisgarh Council of Science and Technology (CGCOST) for providing financial assistance under mini research project (MRP) vide letter no. 1124/CCOST/MRP/2015; Dated: September 4, 2015 and 1115/CCOST/MRP/2015; Dated: September 4, 2015.

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Received on 05.02.2017 Modified on 27.03.2017

Research J. Pharm. and Tech. 2017; 10(4): 1261-1268.

DOI: 10.5958/0974-360X.2017.00224.4