Application of hydrogel

Dharmendra singh*,Versha shrivastava, Shrikant Nirwan, K. C. Samanta

*Department of pharmaceutics (Assist. Professor ), Gyan Vihar School of Pharmacy,
Suresh Gyan Vihar University Jaipur.

ABSTRACT

Hydrogel is a network of polymer chains that are water-insoluble, sometimes found as a colloidal gel in which water is the dispersion medium. Hydrogels are crosslinked polymer networks that absorb substantial amounts of aqueous solutions. Several techniques have been reported for the synthesis of hydrogels. The first approach involves co polymerization/crosslinking of co-monomers using multifunctional co-monomer, which acts as crosslinking agent. Chemical initiator initiates the polymerization reaction. Some applications are used in hydrogels in pharmacy. Nanotherapeutics Files Investigational New Drug Application for NanoDOX™ Hydrogel to Treat Lower Extremity Diabetic Ulcers. Skin Oxygenation After Topical Application of Liposome-Entrapped Benzyl Nicotinate as Measured by EPR Oximetry in vivo: Influence of Composition and Size.
Starch Based Hydrogel with Potential Biomedical Application as Artificial Skin.
Some environmental variables, such as low pH and elevated temperatures, are found in the body. For this reason, either pH-sensitive and/or temperature sensitive hydrogels can be used for site-specific controlled drug delivery. Hydrogels that are responsive to specific molecules, such as glucose or antigens, can be used as biosensors as well as drug delivery systems. New synthetic methods have been used to prepare homo- and co-polymeric hydrogels for a wide range of drugs, peptides, and protein delivery applications

Keywords: Hydrogels, NanoDOX™, Polyvinyl Alcohol; Starch, hypan.

INTRODUCTION-

DEFINATION: - Hydrogel is a network of polymer chains that are water-insoluble, sometimes found as a colloidal gel in which water is the dispersion medium. Hydrogels are superabsorbent (they can contain over 99% water) natural or synthetic polymers. Hydrogels also possess a degree of flexibility very similar to natural tissue, due to their significant water content. Hydrogels are crosslinked polymer networks that absorb substantial amounts of aqueous solutions. [1], [2].

CLASSIFICATION OF HYDROGEL: Hydrogels can be divided into two categories based on the. : -
 Chemical crosslinked networks
 Physical crosslinked networks

Hydrogels can also be separated into two groups based on: -
 Natural hydrogel polymers
 Synthetic hydrogel polymers

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. Approaches using genetic engineering and biosynthetic methods to create unique Hydrogel materials. [3]

METHOD OF PREPARATION OF HYDROGELS: - Several techniques have been reported for the synthesis of hydrogels

 The first method involves co polymerization of co-monomers using multifunctional co-monomer, which acts as crosslinking agent. Chemical initiator initiates the polymerization reaction. 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. 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.

The monomers and the crosslinking agents used in the preparation of hydrogels.
 Solution polymerization/crosslinking
 Suspension polymerization [4]

COMMON USES FOR HYDROGELS:-
• currently used as scaffolds in tissue engineering. When used as scaffolds, hydrogels may contain human cells in order to repair tissue.
• environmentally sensitive hydrogels. These hydrogels have the ability to sense changes of pH, temperature, or the concentration of metabolite and release their load as result of such a change.
• as sustained-release delivery systems
• provide absorption, desloughing and debriding capacities of necrotics and fibrotic tissue.
• hydrogels that are responsive to specific molecules, such as glucose or antigens can be used as biosensors as well as in DDS.
• used in disposable diapers where they "capture" urine, or in sanitary napkins
• contact lenses (silicone hydrogels, polyacrylamides)
OTHER ,LESS COMMON USES INCLUDE:-
• breast implants
• granules for holding soil moisture in arid areas
• dressings for healing of burn or other hard-to-heal wounds. Wound gels are excellent for helping to create or maintain a moist environment.
• reservoirs in topical drug deliver; particularly ionic drugs, delivered by iontophoresis (see ion exchange resin)
Common ingredients are e.g. polyvinyl alcohol, sodium polyacrylate, acrylate polymers and copolymers with an abundance of hydrophilic groups.Natural hydrogel materials are being investigated for tissue engineering, these materials include agarose, methylcellulose, hylaronan, and other naturally derived polymers.
ADVANTAGES: -
 Entrapment of microbial cells within polyurethane hydrogel beads with the advantage of low toxicity
 Hydrogel is more elastic and stronger than available hydrogels of similar softness. Poly (methyl acrylate-co-hydroxyethyl acrylate) hydrogel implant material of strength and softness.
 Hydrogel-based microvalves have a number of advantages over conventional microvalves, including relatively simple fabrication, no external power requirement, no integrated electronics, large displacement (185 μm), and large force generation (22 mN).
 Environmentally sensitive hydrogels. These hydrogels 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, these materials include agarose, methylcellulose, hylaronan, and other naturally derived polymers[23][24]

DISADVANTAGES :-

 The main disadvantages are the high cost and the sensation felt by movement of the maggots.
 Its disadvantage include thrombosis at anastomosis sites and the surgical risk associated with the device implantation and reterieval.
 Hydrogels are nonadherent; they may need to be secured by a secondary dressing.
 Disadvantages of hydrogel in contact lenses are lens deposition, hypoxia, dehydration and red eye reactions.[25],[24]

APPLICATIONS OF HYDROGELS-

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: -[5]

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 harsh, acidic environment of the stomach before releasing the drug in the small intestine. Comparison to that 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.

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. . The polymeric compounds tested were polycarbophil and sodium alginate. Miyazaki et al. investigated the potential application of xyloglucan gels with a thermal gelling property as matrices for drug delivery. Another important issue in rectal drug delivery is to avoid rectal irritation. The products discussed above, indicated no such mucosal irritation after drug administration

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.
This system extended the duration of the pilocarpine to 10 hr, compared to 3 hr when pilocarpine nitrate was dosed as a solution. Chetoni et al. reported silicone rubber hydrogel composite ophthalmic inserts. . 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. Cohen et al developed an in-situ gelling system of alginate with high gluronic acid contents for the ophthalmic delivery of pilocarpine.

Figure 1.1 Tissue locations applicable for hydrogel based drug delivery systems

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.
These hydrogels can be used as controlled release devices in the field of wound dressing. Current research in this field is now focused on electrically assisted delivery using iontophoresis and electroporation. Hydrogel-based formulations are being looked at fortransdermal iontophoresis to obtain enhanced permeation of products in question such as, hormones and nicotine.

SUBCUTANEOUS DELIVERY:-Among the varied possible pharmaceutical applications of hydrogels, the most substantial application is probably in implantable therapeutics. Leading to inflammation, Carcinogenicity and immunogenicity. They have high water content, environment similar to biological tissue, making them relatively biocompatible.
Thus hydrogels are an ideal material to be used for delivery of proteins and peptides. Hydrogel formulations for subcutaneous delivery of anticancer drugs have been proposed. For example, crosslinked PHEMA was applied to cyratabine (Ara-C) Current studies on implantable hydrogels are leading towards the development of biodegradable systems, which don’t require surgical removal once the drug has been administered. [5], [6], [7], [8]. [23], [25].

APPLICATION FOR NANO DOXTM HYDROGEL TO TREAT LOWER EXTREMITY DIABETICULCERS:- Nanotherapeutics, a privately held specialty biopharmaceutical company, announced that it has submitted its first Investigational New Drug (IND) application to the FDA. a topical doxycycline hydrogel for chronic wounds. The randomized double-blind study will assess the safety and efficacy of the product on the healing rates of non-infected diabetic ulcers of the lower extremity. "Diabetic ulcers are the primary cause of amputations of the leg, foot, or toe. Two-thirds of all lower extremity .We believe that NanoDOX™ is a unique formulation that holds significant promise for the millions of people suffering from diabetic ulcers," said Weaver H. Gaines, Chairman of the Board. "
NanoDOX™ Hydrogel, the company's leading pharmaceutical product in development, is an 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.
NanoDOX™ 1% Doxycycline Monohydrate Hydrogel NanoDOX™ Hydrogel is a topical hydrogel applied directly to the entire surface of the wound. A gauze dressing or a non-adhering dressing is applied to cover the hydrogel and wound NanoDOX™ Hydrogel is composed of doxycycline monohydrate

FIG.1.Destroyed tumor cells. Anti-5t4 antibodies recognize tumor cells.

Lower Extremity Diabetic Ulcers Foot and lower leg ulcers are the primary cause of the approximately 80,000 amputations of toes, feet, and lower legs each year. It is estimated that up to 30% of diabetics with foot ulcers will eventually require amputation. (National Institutes of Health and CDC data)
NanotherapeuticsNanotherapeutics is a privately held specialty biopharmaceutical company with full product development and cGMP manufacturing capabilities and a proprietary pipeline. . Nanotherapeutics is focused on drug development, not early-stage discovery an injectable bone graft for orthopedic applications. [8]. [9].

SKIN OXYGENATION AFTER TOPICAL APPLICATION OF LIPOSOMES:-
Improved skin oxygenation has a positive effect on the treatment of ischaemic diseases. It stimulates the healing process of damaged skin and increases the effectiveness of radiotherapy in skin cancer treatment. Topical application of vasodilators that increase skin oxygenation could therefore enhance the effect of radiation on tumors.
Liposomes are drug carriers for dermal therapy, which can considerably improve the effectiveness of drugs and at the same time diminish their side effects. Although there is general agreement that liposome as drug carriers enhance the penetration of drugs through the skin, little is known about the actual mechanisms of interaction among liposomes, drug molecules, and the stratum corneum. The mechanism by which liposomes affect the penetration of drugs into the skin is not completely understood.
 After repeated application of liposomes, the pO2 baseline increased and the response of the skin tissue was faster.
 The penetration through the skin of nicotinates incorporated in different formulations has been studied by various physical methods. However, they do not yield quantitative results because they are not able to correlate directly the blood flow characteristics with oxygen levels in skin. [10], [11], [12].
FUCOIDAN-CHITOSAN HYDROGEL- As Burn Healing Accelerator
Hydrogels are ideal biopolymeric pharmaceutical forms for the treatment of skin Wounds.

Fig.2.The scheme of the microscopic evaluation of the wound area. A-the eschar area
Of the wound, B-the wound epithelial elongation, C-non-burned epithelial area, Dwound
epithelium thickness (the healing area of the wound) E-the eschar thickness of
the wound, F-non-burned epithelium thickness, G- the papillary structures as called
rete pegs or finger like projections. [14]
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. [13] [14].

NEW TYPE OF HYDROGEL FOR CONTROLLED DRUG DELIVERY:-

The new type of hydrogel system HYPAN (which is known under the trademark HYPANTM) is described in some detail here, emphasizing its grades and those properties potentially useful in controlled drug delivery systems.

 A physical network of crystalline clusters, which fully replace the covalent network typical of other hydrogels, distinguishes HYPAN hydrogels. As a result, HYPAN hydrogels can be processed by a number of methods unusual for hydrogels, such as extrusion, injection molding and the like.15,16

APPLICATION OF HYDROGELS TO FIX BONE REPLACEMENTS
Provided are 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. 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.
It is another object of the present invention to provide the fastener of the present invention for use in fixing a bone or bone replacement in position. The fixing method comprises the steps of:
(a) Providing a hole in existing bone to accommodate a fastener;
(b) Locating a bone or bone replacement adjacent to said existing bone, said bone or bone replacement having a hole therein to accommodate a fastener;
(c) Providing a fastener according to claim 1; and
(d) Inserting said fastener of step (c) into the holes in said existing bone and said bone or bone replacement such that said coating absorbs fluid and swells, thereby securely fixing said bone or bone replacement in position.

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. [17][18][19].

FIG.3. Repairing, Regenerating Human Tissue. [22].

HYDROGEL FORREPAIRING, 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 myriad uses the scientists foresee 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.
Peptides are short chains of amino acids, the building blocks of proteins. Different amino acids are bonded together to form chains, which then fold up into more compact shapes with specific functions
"Although we have currently only demonstrated this capacity of our gels using simple models, we envision that when injected into the body, the cells encapsulated in the gel can go about their business in restructuring the tissue,"

 “It has the ability to regenerate itself quite easily”.
 We want to use the hydrogels to deliver hepatocytes to the liver,

 “It's been a very successful collaboration”, “A whole host of terrific students and other”.

 These could be used to beef up the liver's function prior to surgery if, for example, someone had hepatitis, or drank a lot, factors that would normally limit the amount of cancerous liver that can be removed. People on- and off-campus have helped this come to fruition. [20], [21], [22].

SUMMARY & CONCLUSION: -

Recent developments in the field of polymer science and technology has led to the development of various stimuli sensitive hydrogels like pH, temperature sensitive, which are used for the targeted delivery of proteins to colon, and chemotherapeutic agents to tumors. Some environmental variables, such as low pH and elevated temperatures, are found in the body. For this reason, either pH-sensitive and/or temperature sensitive hydrogels can be used for site-specific controlled drug delivery. Hydrogels that are responsive to specific molecules, such as glucose or antigens, can be used as biosensors as well as drug delivery systems. The liposomal drug delivery system developed here enables controlled release of vasodilator and would allow an appropriate time for beginning irradiation treatment to be defined. Thus, the fucoidan-chitosan hydrogels may be suitable as a wound substitutes and can be used in wound healing. New synthetic methods have been used to prepare homo- and co-polymeric hydrogels for a wide range of drugs, peptides, and protein delivery applications. Hydrogels are also used in regenerating human tissue cells.

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