Pharmaceutical Hydrogels: A Comprehensive Review

Introduction

Hydrogels are hydrophilic, three-dimensional, polymeric networks that can absorb vast volumes of water or biological fluids. They contain a lot of water and their affinity to absorb water is attributed to the presence of hydrophilic groups such as - OH, -CONH, and -SO₃H in polymers forming hydrogel structures. They resemble natural living tissues more closely than any other synthetic biomaterials due to their porosity and soft consistency. Hydrogels can either be chemically stable or they may degrade, eventually disintegrate and finally dissolve^.1-3

Both the properties of the polymers and the state and density of their network structures are important, as these structures can trap a large amount of water, especially when they are swollen.⁴ By changing their structure and properties in response to changes in pH, ionic strength, pressure, light, temperature, and electric and magnetic fields, hydrogels can be made to become environmentally sensitive. The capillarity, osmotic force, hydration capacity, and elastic retractive force of the polymer network affect the water absorption of a hydrogel. The solubility depends on the crosslink density and interplacement of the polymeric chains. Some hydrogels may exhibit responsive behaviour to external stimuli such as pH, temperature, ionic strength, light, and electric field.^5,6

The domains of biology and medicine are particularly promising for using hydrogels. Hydrogels have been thoroughly investigated for use in a variety of items, including scaffolds, contact lenses, wound care and healing, hygiene goods, drug delivery, and diagnostic tools.^7-12 Recent developments in hydrogel-based research have focused on removing constraints and issues brought on by low solubility, high crystallinity, nonbiodegradability, undesirable mechanical and thermal properties, unreacted monomers, and the toxicity of crosslinking agents. For this reason, the majority of studies have focused their research to generate biocompatible and high-mechanical strength hydrogels using renewable and biodegradable material.¹³

However, a few important issues have prevented hydrogels from being widely used in the biomedical industry. When making hydrogels, harmful polyfunctional crosslinking agents must be eliminated, which takes time and may leave behind residues. Additionally, the majority of polymers utilized are synthetic and are neither biodegradable, nor recyclable, posing a threat to their environmental sustainability. Consequently, there is a necessity for natural resources that may be easily engineered into products using biocompatible hydrogel.^14,15

Optimal criteria for selecting ingredients for hydrogel formulations

The following are list of the functional characteristics for formulation of ideal hydrogel material.^2,16

1. Must be capable of the greatest amount of swelling at equilibrium in saline or water.
2. To possess better application, and the ability of increasing the absorption (recommended particle size and porosity).
3. The maximum absorbency under load (AUL) is required.
4. Should display residual monomer and the least soluble amount.
5. Affordable price.
6. In a swelling atmosphere and while being stored, the item must have the best durability and stability possible.
7. Should not leave any toxic compounds when they are degraded.
8. Non-toxic, colourless and odourless.
9. Must have good photostability.
10. Depending on the application requirements (for example, in agricultural or hygienic applications), the hydrogel must have the ability to re-wet if necessary or to preserve the ingested solution.
11. Less than 500 Daltons should make up the molecular weight of the drug.
12. The drug must possess sufficient hydrophilicity.
13. The concentrate solutions of drug should have a pH of 5 to 9.
14. Topical administration of drugs that are very acidic or alkaline in solution is not recommended.

Classification of hydrogels

The hydrogels can be broadly categorised as follows^17,18

Alginate, chitosan, carrageenan, hyaluronan, and carboxymethyl cellulose (CMC) are examples of natural biopolymers.19 Cross-linked networks of synthetic polymers such as polyethylene oxide (PEO), polyvinyl pyrrolidone (PVP), polylactic acid (PLA), polyacrylic acid (PAA), polymethacrylate (PMA), polyethylene glycol (PEG) have also been reported. Physical crosslinking, chemical crosslinking, grafting polymerization, and radiation crosslinking are some of the preparation methods used.^20-29 These changes can enhance the viscoelasticity and mechanical qualities for use in the biomedical and pharmaceutical industries.^26,30-32 The following methods explain the mechanism involved in formulation of physical and chemical gels.

1. Physical cross-linking

Physical or reversible gels have gained popularity because of their relatively simple manufacture and the benefit of not requiring cross-linking agents. The integrity of the substances to be entrapped (such as cells, proteins, etc.) and the requirement for their removal before application are both impacted by these agents. A lot of attention is being paid to this topic right now, especially in the food business, because it can result in the development of a wide variety of gel textures when hydrocolloid type, concentration, and pH are carefully chosen.³³ The following are the numerous techniques listed in the literature for making physically cross-linked hydrogels.

Heating/cooling a polymer solution

Physically cross-linked gels are created when hot gelatine or carrageenan solutions are cooled. Helix creation, helix association, and junction zone formation, all contribute to the gel's formation.³⁴ Carrageenan is found as a random coil shape in hot solutions above the melting transition temperature. It changes into hard helical formations when it cools. Due to the sulphonic group's (SO^-3) screening of repulsion in the presence of salt (K⁺ , Na⁺ , etc.), double helices further assemble to create stable gels (Figure 3a). In some circumstances, block copolymerization-causing polymer solutions can be simply warmed to produce hydrogel. Polyethylene oxide-polypropylene oxide and polyethylene glycolpolylactic acid hydrogel are a couple of examples.^25,35

Ionic interaction

Di- or tri-valent counterions can be used to cross-link ionic polymers. The idea of gelling a polyelectrolyte solution, such as Na⁺ alginate-, with a multivalent ion with opposing charges, such as Ca²⁺⁺, 2Cl^- , is based on this technique (Figure 3b). Chitosan-polylysine, chitosan-glycerol phosphate salt, and chitosan-dextran hydrogels are some further examples.^{25, 36, 37}

Complex coacervation

A polyanion and a polycation mix can result in the formation of complex coacervate gels. According to the concentration and pH of the corresponding solutions, polymers with opposing charges will stick together and create soluble or insoluble complexes (Figure 3c). Coacervating polyanionic xanthan with polycationic chitosan is one such instance.³⁸ Positively charged proteins below their isoelectric point are more likely to bond with anionic hydrocolloids to create polyion complex hydrogels (complex coacervate).³⁹

H-bonding

By reducing the pH of an aqueous solution containing carboxyl groups polymers, H-bonded hydrogel can be produced. A network of CMC (carboxymethyl cellulose) that is hydrogen-bound is created by dispersing CMC into 0.1N HCl.⁴⁰ The technique includes adding hydrogen to the acid solution in place of sodium in CMC to encourage hydrogen bonding (Figure 3d). The creation of an elastic hydrogel is caused by the hydrogen bonds, which also cause a reduction in the solubility of CMC in water. CM-chitosan hydrogels can also be made by cross-linking the chitosan molecule in the presence of acids or multifunctional monomers. Another illustration is a hydrogel made of polyacrylic acid and polyethylene oxide (PEO-PAAc) that was created by reducing the pH of its aqueous solution to create an H-bonded gel.³⁵ When xanthan and alginate are present in a mixed environment, their molecular interactions affect the matrix's structure as a result of their intermolecular hydrogen bonds forming an insoluble hydrogel network.

Maturation (heat-induced aggregation)

Gum arabic (Acacia gums) is primarily composed of carbohydrates, although 2-3% of its composition is made of protein.⁴¹ Following fractionation by hydrophobic interaction chromatography with varied molecular weights and protein contents,⁴² three primary fractions with these characteristics have been discovered. These are glycoprotein, arabinogalactan, and arabinogalactan protein (AGP) (GP). Heat treatment causes the proteinaceous components to aggregate, increasing their molecular weight and creating a hydrogel form with improved mechanical characteristics and the ability to bind water.^43,44 The maturation process' accompanying molecular modifications show that a hydrogel can be created with precisely organized molecular dimensions. The aggregation of the proteinaceous components inside the naturally occurring gum's molecularly dispersed system is the regulating characteristic. As gum ages, the protein linked to its lower-molecular-weight components is transferred, resulting in higher concentrations of the high-molecular-weight fraction (AGP) (Figure 3e). The technique has also been used on other gums, including gum ghatti and Acacia kerensis, for denture care.⁴⁵

Freeze thawing

The mechanism entails the structure forming microcrystals as a result of freezing and thawing. Polyvinyl alcohol and xanthan gum freeze-thawed gels are examples of this form of gelation.^46,35

Chemical cross-linking

The two methods of chemical cross-linking discussed here include grafting monomers onto the polymer's backbone and using a cross-linking agent to join two polymer chains. Natural and artificial polymers can be cross-linked by reacting with cross-linkers such as aldehydes (such as glutaraldehyde and adipic acid di hydrazide) that have functional groups like OH, COOH, and NH2. There are several techniques for making chemically cross-linked persistent hydrogels that have been documented in the literature. To create chemically cross-linked permanent hydrogels, other techniques include IPN (polymerize a monomer within another solid polymer to form an interpenetrating network structure) and hydrophobic interactions (incorporate a polar hydrophilic group by hydrolysis or oxidation followed by covalent cross-linking).²⁵ The main chemical techniques that are used to create hydrogels from a variety of natural polymers, are crosslinking, grafting, and radiation in solid and/or aqueous states.

Chemical crosslinkers

The cross-linked hydrogel network of diverse synthetic and natural polymers has been produced using crosslinkers such as glutaraldehyde, epichlorohydrin, etc. To create cross-linked chains, the process primarily includes introduction of additional molecules between the polymeric chains (Figure 4a). One such instance is a hydrogel, which is made by cross-linking polyvinyl alcohol and maize starch using glutaraldehyde as a cross-linker. The produced hydrogel membrane might be employed as artificial skin while also allowing for the delivery of various nutrients, healing agents, and medications to the area of action. Additionally, 1, 3-diamino propane can be used to cross-link CMC chains, creating CMC-hydrogel that is ideal for drug delivery through pores. Another example would be hydrogel composites made of xanthan and polyvinyl alcohol that have been cross-linked with epichlorohydrin. By employing 2-acrylamide-2-methyl propane sulfonic acid to cross-link k-carrageenan and acrylic acid, biodegradable hydrogels with potential applications as innovative drug delivery systems can be created.⁴⁷

Carrageenan hydrogels hold the potential for industrial enzyme immobilization.⁴⁸ Additionally, hydrogels can be created from cellulose in NaOH/urea aqueous solutions by employing the cross-linker epichlorohydrin as well as the heating and freezing technique.^{49, 50}

Grafting

Grafting entails polymerizing a monomer on a pre-existing polymer's structural backbone. Chemical reagents or high-energy radiation treatments work to activate the polymer chains. On activated macroradicals, functional monomers proliferate, which causes branching and then cross-linking (Figure 4b).

The grafting technique mainly involves chemical grafting and radiation grafting.

Radiation cross-linking

Since it does not require chemical additives, radiation cross-linking is a frequently used technology that preserves the biocompatibility of the biopolymer. Additionally, because the alteration and sterilizing may be accomplished in a single step, the method of altering biopolymers with a specified end use in biomedicine is economical.⁵¹ The process principally relies on the polymer releasing free radicals after exposure to a highenergy source such as an electron, gamma, or x-ray beam. The polymer environment will determine how radiation (direct or indirect) will behave (i.e. dilute solution, concentrated solution, solid-state).

Radiation cross-linking involves

(1) Aqueous state radiation

(2) Radiation in paste

(3) Solid-state radiation

Test for hydrogels

1. Water vapour transmission rate

The amount of water vapour that, at a certain temperature and humidity level, flows through a unit area of film material in a given amount of time is known as the water vapour transmission rate (WVTR). For 25 hours, the water vapour transmission rate is calculated in grams per square meter. It is inversely proportional to how well a wound dressing retains moisture; hence, a wound dressing with a lower water vapour transmission rate will be able to do so. Usually, a wound dressing material that has WVTR less than 35 g/m² /hr is deemed moisture-retentive and aids in quick healing.

2. Biocompatibility test

Hydrogels are typically non-irritating and biocompatible. In this procedure, the substance whose biocompatibility needs to be assessed is placed in close proximity to the host environmental cells and then incubated at 37°C for a predetermined amount of time. In the second approach, the substance is immersed in a suitable physiological solution and incubated at 37°C for a certain amount of time to allow any leaching from the substance. The leachates that were so obtained were used to conduct the biocompatibility tests with cells present.

Evaluation of hydrogels

The physical, rheological, and antifungal activities of the gel formulations were investigated. All formulations were subjected to the skin irritation test.

1. Homogeneity

Visual inspection was used to evaluate the gels' physical characteristics, such as colour, clarity, and phase separation. They undergo testing to see if any aggregates are present.⁵²

2. Grittiness

Microscopically, any particle matter in the formulations was seen.

3. pH measurement

With the aid of a digital pH meter, gel compositions, and pH levels were determined. 100 cc of distilled water was added to one gram of gel before it was stored for two hours. Each formulation's pH was measured in triplicate, and the average values were computed and published.⁵³

4. Spreadability

On graph paper, concentric circles of varying radii were formed, and a glass plate was then glued to them. On the lower plate's center, 5 g of gel were positioned. After one minute of each addition, a 100+5 g glass plate was gently positioned on the gel, and the spread diameter was measured.

5. Extrudability

Collapsible tubes were used to hold the gel compositions. The weight required in grams to extrude a 0.5 cm ribbon of gel in 10 seconds was used to test the extrudability of gel formulations after they had been set in the containers.⁵⁴

6. Drug content

100 mL of phosphate buffer pH 5.8 was used to dissolve 1 g of gel. With the aid of phosphate buffer pH 5.8 (based on type of formulations pH may differ), suitable dilutions were created. Using a UV spectrophotometer, absorbance was measured at suitable wavelength as per the drug incorporated in gel.⁵⁵

7. In vitro drug diffusion theory

Studies on in vitro drug release were done using Franz diffusion cells. On a cellophane membrane used as a donor compartment, 0.5 g of gel was placed. The receptor compartment was filled with phosphate buffer pH 5.8 to serve as the dissolving media. The entire device was set up on a magnetic stirrer with the thermostat set at 37°C.

Samples were taken regularly, and sink conditions were preserved by replacing the old buffer solution with a fresh one. Samples were analysed using UV spectrophotometric method, High-performance liquid chromatography (HPLC) or any suitable methods.⁵⁶

8. Ex-vivo studies

Rats weighing between 200 and 250 g were decapitated. An electric razor was used to remove the rats' abdominal hair following their sacrifice using the cervical dislocation method. Adhering subcutaneous fat was meticulously cleansed after the abdomen skin was surgically removed. After giving the skin a thorough wash with regular saline, it was dried, wrapped in aluminium foil, and kept in the freezer at -20°C until needed again. The temperature of the cell was kept constant at 37°C by surrounding water in the jacket, and the medium was agitated at 100 rpm with a magnetic stirrer. The samples were obtained from the receptor compartment at predefined intervals (0, 0.5, 1, 2, 4, 8, 12, 16, 20, and 24 hours) and replaced with an equivalent volume of new receptor solution to maintain the volume constant. Samples were analysed using UV spectrophotometric method, HPLC or any suitable methods.

9. Rheology

With a cone plate type viscometer, hydrogels were tested for viscosity at a constant temperature of 4°C. The examination of viscosity can be done with this viscometer with great precision. The straightforward equation of finding the angle of repose through height and length yields the viscosity.

10. Viscosity

Using a Brookfield digital viscometer, the viscosity of the produced hydrogel was measured. Spindle number 6 was used to measure the viscosity at 10 rpm and 25°C. The suitable wide-mouth container was filled with the appropriate amount of gel. The hydrogel was poured into the wide-mouth container in a way that would allow the viscometer's spindle to dip comfortably. Before the measurements, samples of the hydrogel were given 30 minutes to settle at a constant temperature (25 +/-1 degrees Celsius).⁵⁷

8. Skin irritation

test Ten healthy male and female volunteers underwent a skin irritancy test. A 2 cm area was covered with 100 mg of gel, and any lesions or irritation/redness were checked.⁵⁸

9. Chick embryo

test This is one approach for assessing irritation caused by final formulations as well as basic components. The chick chorioallantoic membrane (CAM) is the chorioallantoic membrane, like the conjunctival tissues of a rabbit's eye. This method's irritation in this instance is comparable to the effect of the Darize test. The chorioallantoic membrane is a vascularized membrane that encircles a chick that is growing inside an egg. In this assay technique, a portion of the membrane is isolated, and the test preparation is deposited on the surface. Any alterations in the morphology of the CAM membrane, such as coagulation and hemolysis, are noted. The outcome may be influenced by several variables, including the length of incubation, humidity, breed of hen, egg age and weight, and the opening of the eggshell.⁵⁹

Applications of Hydrogel¹⁷

Drug delivery

Soon after their development, hydrogels were investigated as drug delivery systems for antibiotics and anticancer medications. Initial research focused on poly HEMA, while later research concentrated on hydrogels made of HEMA copolymers, polyacrylamide, N-vinylpyrrolidone copolymers, and polyvinyl alcohol. As a matrix for protein delivery, HEMA hydrogels have been investigated. To meet the physiological requirement, many chemical structures have been specifically designed. For instance, HPMA copolymer based hydrogels were created with encapsulated anticancer medications or with the drug (DOX) bound by a degradable oligopeptide spacer and crosslinks. A variety of organic polysaccharides were employed for drug delivery, and poly-alginate hydrogels were created to allow the co-administration of anticancer medications with various release characteristics.^1,3,17,60

The regulated and continuous release of pharmaceuticals by hydrogels makes them more appealing these days. The medications can be released at appropriate and predetermined locations.

1. Wound healing

Hydrogels are materials that are cross-linked and can contain both water and drugs. They can hold and maintain wound exudates because of their capacity to hold water.

When administered, hydrogels made of gelatin and sodium alginate can shield the site from bacterial infection.

2. Hydrogel for eye

Estimates state that 75% of the ophthalmic solution is lost as a result of lacrimal drainage, which also reduces the drug's target bioavailability. The bioavailability of drugs is also influenced by other factors, such as blinking tear drainage. These hydrogels are implanted beneath the conjunctiva and are completely safe. Pilocarpine and timolol are continuously delivered into the eye using a gel made of xyloglucan.

3. Hydrogel for transdermal drug delivery

Utilizing hydrogels topically and transdermal application has various benefits, including increasing medication efficacy and bioavailability by avoiding hepatic metabolism.

Transdermal drug delivery systems are employed to ensure continuous medication release. As they swell and resemble living tissues, hydrogels are easier to remove compared to other dose forms like patches and ointments.

Transdermal drug delivery is used to distribute medications topically and systemically, such as for the delivery of glucocorticoid budesonide transdermal hydrogels. Gentamycin contains new hydrogels based on poloxamer 407 that are more successful at treating skin infections than its parenteral administration, which can have major side effects.

4. Vaginal route

Drug formulations that are to be administered through the vaginal canal must be in the form of creams, suppositories, gels, foams, or tablets. The benefits of avoiding hepatic metabolism while administering medication via the vaginal route are numerous. The vagina's enormous surface area contributes to a rise in systemic medication absorption. Due to the vaginal epithelium, drugs with high molecular weights are permeable. The vaginal route is preferred since natural progesterone's bioavailability reduces as a result of hepatic metabolism. Bleomycin, an anticancer medication, is released over 23 hours via a flat-faced disc and is cross-linked with carbopol 934 and hydroxypropyl cellulose.

5. Oral route

The oral route has various benefits, including accessibility. For local viral and fungal infections, the oral route is employed. Additionally, this approach lowers first-pass metabolism. Magnesium stearate, hydroxypropyl cellulose, and carbopol 934 were used to create a 5 mm thickness.

6. Gastrointestinal tract

The GI tract is the most frequent and well accepted medication delivery route. Drug delivery locally also uses the gastrointestinal tract. The anti-ulcer medication famotidine has local effects. Ineffectively absorbed oral medications can have their effects and bioavailability increased with the use of sustained-release gastroretentive hydrogels.

7. Hydrogel for brain

The blood-brain barrier, like other physical barriers in the human body presents difficulties for drug delivery. Ninety-eight percent of newly synthesized medications are unable to pass this barrier. Because of this, there aren't many medications available for CNS drug administration. In rats, camptothecin loaded with Poly (lactic-co-glycolic acid) (PLGA) microspheres had a long-lasting, sustained impact. These microspheres prolong the time that rats can survive in the presence of malignant gliomas.

8. Soft contact lenses

The earliest silicon hydrogels that were sold commercially used two separate strategies. Bausch & Lomb's initial strategy was a logical progression from its creation of silicon monomers with improved compatibility in hydrogel-forming monomers. The creation of siloxy monomers with oxygen-permeable polysiloxane units and hydrophilic polyethylene oxide segments was the second Ciba vision.

9. Rectal delivery

Rectal medication distribution employs hydrogels with bioadhesive qualities. The use of xyloglucan gel with a thermal gelling property as drug delivery matrices was investigated by Miyazaki et al.

10. Subcutaneous delivery

Anticancer medications are being developed in hydrogel formulations for subcutaneous distribution; cytarabine was given a crosslinked PHEMA treatment (Ara-c). Now that the medicine has been delivered, biodegradable systems that do not require surgical removal are being developed, thanks to implantable hydrogels.

11. Novel hydrogel for controlled drug delivery

HYPAN is a brand-new hydrogel with advantageously controlled drug delivery capabilities. HYPAN hydrogels are distinct from others due to their physical network of crystalline clusters.

12. Hydrogel for gene delivery

To effectively target and distribute nucleic acids to particular cells for gene therapy, hydrogel composition must be changed. The adaptability of hydrogels has the potential to be used in the treatment of numerous inherited and/or acquired diseases and ailments.

13. Cosmetology

When inserted into breasts, hydrogels enhance them for aesthetic purposes. These implants are filled with hydroxypropyl cellulose polysaccharide gel and have a silicon elastomer shell.

14. Topical drug delivery

To distribute active ingredients like Desonide, a synthetic corticosteroid used as an anti-inflammatory for greater patient compliance, hydrogel formulations are used in place of conventional creams.

15. Protein drug delivery

Nowadays, instead of being injected, interleukins are supplied as hydrogels, which have better compliance, create in-situ polymeric networks, and release proteins gradually.

Conclusion

Hydrogel polymers have made it possible for them to be used extensively in the conventional, contemporary, and revolutionary pharmaceutical fields. The desired hydrogel material, crosslinking strategy, and processing methods can all be used to produce hydrogels for a particular application. Numerous biological applications, such as 3D cell culture, tissue engineering, diagnostics, drug delivery, and separation, are suited for hydrogels. Due to the remarkable qualities of hydrogels such as porosity, similarity to real tissues, biocompatibility, high permeability rate for oxygen and critical nutrients, variable viscoelasticity, and high water holding capacity, hydrogels have the potential to revolutionize the drug delivery industry. Still the researchers are working on nanocomposite hydrogels, nanoemulgels for enhancing the stability and to add added advantages over the conventional pharmaceutical hydrogels.

Conflicts of Interest

No