chapter on Hydrogel

chapter on Hydrogel

1. HYDROGEL By:Rajesh L. Dumpala ( B.Pharm , M. Pharm.) PhD. ( Pursuing) Research Scientist, Alembic Research Centre. Vadodara E.Mail :[email protected]

2. Defination : Hydrogels   are water swollen three dimensional structures composed of primarily hydrophilic polymers. These are cross linked macro molecular networks that are insoluble but are able to swell rapidly in water or biological fluids.

3. The research on  hydrogels  is more than four decades old but there has been a tremendous growth in the recent past because of their unique bulk and surface properties. They form the basis of many novel drug delivery systems. Hydrogels can be made to respond to the environment and the extent of the response can be controlled. The environmental conditions to which a hydrogel can be made responsive pH, temperature, electric field, ionic strength, salt type, solvent, external stress, light or a combination of these. It is because of these unique properties that these classes of polymer based systems embrace numerous pharmaceutical and bio medical applications .

4. Hydrogel -forming natural polymers include proteins such as collagen and gelatin, and polysaccharides such as alginate and agarose . Synthetic polymers that form hydrogels are traditionally prepared using chemical polymerization methods. There are many approaches based on genetic engineering and biosynthetic methods to also create the unique hydrogel materials.

5. ADVANTAGES OF HYDROGELS Biocompatible. It can be injected. It is easy to modify. Timed release of growth factors and other nutrients to ensure proper tissue growth Entrapment of microbial cells within polyurethane hydrogel beads with the advantage of low toxicity. Environmentally sensitive hydrogel have the ability to sense changes of pH, temperature or the concentration of metabolite and release their load as result of such a change. Natural hydrogel materials are being investigated for tissue engineering, which include agarose , methylcellulose and other naturally derived polymers.

6. Disadvantages of hydrogelS   The main disadvantage is the high cost. Its disadvantage includes surgical risk associated with the device implantation and recovery. Hydrogels are non-adherent; they may need to be secured by a secondary dressing. Disadvantages of hydrogel in contact lenses are lens deposition, hypoxia, dehydration and red eye reaction.

7. PROPERTIES OF HYDROGELS The cross-linking of hydrogels makes their structure insoluble in water due to ionic interaction and hydrogen bonding. Tendency to absorb water or biological fluids in large amount, at least 10-20 times their molecular weight and become swollen in response to pH, temperature, electric field, ionic strength, salt type, solvent, external stress, light or a combination of these . Cross linked hydrogels have sufficient mechanical strength and physical integrity. An ideal material for use in drug delivery and immobilization of proteins, peptides, and other biological compounds. Similar physical properties as that of natural living tissue, due to high water content, soft, rubbery consistency, low interfacial tension with water and biological fluids. Hydrogels are ( swellable polymeric materials) three dimensional networks of hydrophilic polymers

8. CLASSIFICATION OF HYDROGELS Based on the method of preparation, hydrogels are classified into: Homo-polymer hydrogels Co-polymer hydrogels Multi polymer hydrogels   Based on the ionic charges hydrogels can be classified into: Neutral hydrogels Anionic hydrogels Cationic hydrogels Ampholytic hydrogels   Based on the structure hydrogels can be classified into: Amorphous hydrogels Semi-crystalline hydrogels Hydrogen bonded hydrogels  

9.   Based on the mechanism controlling the drug release they are classified into: (A) Diffusion controlled release systems Reservoir system Matrix system (B) Swelling controlled release systems (C) Chemically controlled release systems Erodible drug delivery system Pendent chain systems (D) Environment responsive systems pH sensitive hydrogel Temperature sensitive hydrogel Complexing hydrogel Sensitive to chemical or enzymatic reaction Magnetically responsive systems

10. Mechanism of Stimuli Responsive Hydrogels Stimulus Hydrogel Mechanism pH Acidic or basic hydrogel Change in pH→ swelling→ release of drug Ionic Strength Ionic hydrogel Change in ionic strength→ change in concentration of ions inside gel→ change in swelling→ release of drug Chemical Species Hydrogel containing electron accepting groups Electron donating compound→ formation of charge/transfer complex→ change in swelling→ release of drug Enzyme-substrate Hydrogel containing immobilized enzymes Substrate present→ enzymatic conversion→ product changes→ swelling of gel→ release of drug

11. Magnetic Magnetic particles dispersed in alginate microsphere Applied magnetic field→ change in pores in gel→ change in swelling→ release of drug Thermal Thermoresponsive hydrogel Change in temperature→ change in polymer-polymer and water interaction→ change in swelling→ release of drug Electrical Polyelctrolyte hydrogel Applied electric field→ membrane charging→ electrophoresis of charged drug→ change in swelling→ release of drug Ultrasound irradiation Ethylene-vinyl alcohol hydrogel Ultrasound irradiation→ temperature increase→ release of drug

12. PREPARATION METHODS OF HYDROGELS (1) Isostatic Ultra High Pressure (IUHP) In this method suspension of natural biopolymers (i.e. starch) is subjected to ultrahigh pressure of (300-700 Mpa ) for 5 to 20 minutes in a chamber which brings about changes in the morphology of the polymer (i.e. gelatinization of starch molecule 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 .

13. (2)Cross-Linking Methods (a) Cross-linking of Polymers: In this method chemically cross-linked gels are formed by radical polymerization of low molecular weight monomers or branched homopolymers or copolymers in the presence of cross-linking agent. This reaction is mostly carried out in solution for biomedical applications. ( b ) Copolymerization/Cross-linking Reactions: Copolymerization reactions are used to produce polymer gels, many hydrogels are produced in this fashion, for example poly ( hydroxyalkyl methylacrylates ).  

14. (c )Cross-linking by High Energy Radiation: High energy radiation, such as gamma and electron beam radiation can be used to polymerize unsaturated compounds. Water soluble polymers derivatized with vinyl groups can be converted into hydrogels using high energy radiation. (D) Cross-linking Using Enzymes: Recently a new method was published using an enzyme to synthesize PEG-based hydrogels . A tetrahydroxy PEG was functionalized with addition of glutaminyl groups and networks were formed by addition of transglutaminase into solution of PEG and poly (lysine- cophenylalanine ).

15. ( 3)Use of Nucleophilic Substitution Reaction Hydrogel of N-2-dimethylamino ethyl- methacrylamide (DMAEMA), a pH and temperature sensitive hydrogel has been prepared by nucleophilic substitution reaction between methacyloyl chloride and 2-dimethylamino ethylamine. (4) Use of Gelling Agent Gelling agents like glycophosphate , glycerol, 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.

16. (5) Use of Irradiation and Freeze thawing 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.

17. CHARECTERIZATION OF HYDROGELS   Morphological Evaluation This is done by instrument like stereomicroscope. Also the texture of hydrogel 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.   FTIR study Any change in the morphology of hydrogels changes their IR absorption spectra due to stretching O-H vibration. Formation of coil or helix which is indicative of cross-linking is evident by appearance of band near 1648 cm-1.  

18. In Vitro Drug Release Study 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. 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 40C by using Cone Plate type viscometer.

19. APPLICATIONS OF HYDROGELS 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:

20. (1) 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. It is however, also a very complex route, so that versatile approaches are needed to deliver drugs for effective therapy. Hydrogel -based devices can be designed to deliver drugs locally to specific sites in the GI tract. Specific antibiotic drug delivery systems for the treatment of Helicobacter pylori infection in peptic ulcer disease. These hydrogels protect the insulin in the acidic environment of the stomach before releasing the drug in the small intestine. Several hydrogels are currently being investigated as potential devices for colon-specific drug delivery. They are designed to be highly swollen or degraded in the presence of colonic enzymes or micro flora, providing colon-specificity in drug delivery.

21. (2) Rectal Delivery This route has been used to deliver many types of drugs for treatment of diseases associated with the rectum, such as hemorrhoids. This route is an ideal way to administer drugs suffering heavy first-pass metabolism . There are however, some drawbacks associated with rectal delivery. For example, due to discomfort arising from given dosage forms, there is substantial variability in patient’s acceptance of treatment. This leads to variation of availability of drugs, especially those that undergo extensive first-pass elimination. Hydrogels offer a way in which to overcome these limitations, provided that the hydrogels show bioadhesive properties. . An indomethacin poly vinyl alcohol (PVA) hydrogel used for rectal administration. Rectal administration of indomethacin hydrogels to rats yielded high indomethacin plasma concentrations, without producing a sharp peak, and a sustained-release effect. Another important issue in rectal drug delivery is to avoid rectal irritation. The products discussed above, indicated no such mucosal irritation after drug administration.

22. (3) Ocular 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. This system extended the duration of the pilocarpine to 10 hr, compared to 3 hr when pilocarpine nitrate was dosed as a solution.  In-situ forming hydrogels are attractive as an ocular drug delivery system because of their facility in dosing as a liquid, and long term retention property as a gel after dosing. 

23. (4) Wound Healing A modified polysaccharide that occurs in cartilage has been used in formation of hydrogels to treat cartilage defects has been developed. 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. 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.

24. (5) Topical drug delivery Hydrogels are having better patient compliance than conventional creams. These hydrogels have moisturizing properties therefore scaling and dryness is not expected with this drug delivery system. Antifungal formulations like cotrimazole have been developed as hydrogel formulation for vaginitis . It has shown better absorption than conventional cream formulations.

25. (6) Cosmetology For aesthetic (visual) purpose, hydrogels have been implanted into breast to accumulate them. These hydrogels swell in vivo in aqueous environment and retain water. These breast implants have silicone elastomer shell and are filled with hydroxyl propyl cellulose polysaccharide gel. (7) Protein drug delivery Interleukins which are conventionally given as injection are now given as hydrogels . These hydrogels have shown better patient compliance. The hydrogel form in situ polymeric network and release proteins slowly. These are biodegradable and biocompatible also.

26. (8) Industrial Applicability Hydrogels have been used as absorbents for industrial effluents like methylene blue dye. 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. (9) Application of Hydrogels to Fix Bone Replacements Fix bone replacements provided are orthopedic fasteners and replacements such as nails, screws, pins and knee replacements, etc., coated with hydrogels and other biocompatible/biodegradable materials which expand in the presence of liquids. Swelling of such coatings causes the fastener or replacement to be securely fixed into position once inserted into bone material.  Useful coating materials include methacrylate , hyaluronic acid esters, and crosslinked esters of hyaluronic acid resulting from the esterification of hyaluronic acid with polyhydric alcohols. Also provided is a method for fixing a bone or bone replacement in position employing such coated orthopedic fasteners or replacement.

27. (10) Hydrogel for Repairing, Regenerating Human Tissue Regenerating healthy tissue in a cancer-ridden liver, healing a biopsy site and providing wounded soldiers in battle with pain-killing, infection fighting medical treatment are among the numerous uses the scientists predict for the new technology. 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, chain-like 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.   (11 ) Miscellaneous applications Hydrogels are also used in other forms of drug delivery like pulsatile drug delivery or oral drug delivery. Injectable hydrogels are also been investigated for cancer drug delivery. In situ gel-forming hydrogels for prolonged duration have also been reported.