INTRODUCTION:

The practice of delivering drugs through the skin has long been popular. However, transdermal medication delivery systems have been offered in the pharmaceutical industry since the early 1980s.¹ Transdermal drug delivery systems are superior to other drug administration methods in a number of ways, including: a) first pass metabolism through the liver; b) easy dosage; and c) patient-controlled therapy.^2,3

Transdermal dose forms come in a variety of forms, including gels, ointments, creams, and more.⁴ Gels are a type of material that resembles jelly and can be solid, hard, or tough. Gels are described as weakly cross-linked systems without flow in a steady state.⁵ Further classifications for gels include hydrogels, xerogels, and organogels. Polymeric networks that are able to absorb significant amounts of water yet remain insoluble as a result of chemical or physical cross-linking are known as hydrogels.⁶ Three-dimensional network systems are hydrogels. Cross-linking of polymeric chains results in the formation of a system. Physical interactions, covalent bonds, hydrogen bonds, and van der wall interactions can all result in cross linking. Because of their intelligence, hydrogels can react to changes in their environment, including changes in pH, temperature, ionic strength, electrostatic field, and enzyme presence.⁷ Professor Lim and Wicht Erle of the Czech Republic created the first hydrogel in 1955. For use as a contact lens, the hydrogel was created using a synthetic poly-2-hydroxyethyl methacrylate. Hydrogels find ap plication in several fields such as biomedical sciences, contact lenses, surgical, oral, transdermal, and more.^8,9 Polymers that are synthetic or natural can be used to create hydrogels. Alginate, pectin, chondroitin sulphate, and dextran are examples of natural polymers. Conversely, synthetic polymers consist of ethylene oxide, poly (vinyl alcohol), poly (hydroxyethyl methacrylate), and poly (isopropylacrylamide). Both natural and synthetic polymers have benefits and drawbacks when used separately, but when they are combined, the physical and biocompatibility qualities, such as those of IPN and semi-IPN, improve.¹⁰ The hydrophilic functional groups that are connected to hydrogels give them their capacity to absorb water. They mimic normal tissues because they absorb 90% of the water. Hydrogels can have macroporous, microporous, or nanoporous network structures. Drug release from microporous materials occurs via the diffusion process, with sizes ranging from 0.1 to 1 micron. Microporous, with pore sizes between 100 and 1000 angstroms; medication released through convection and molecular diffusion. However, drug release from nanoporous materials with a mesh size of 10-100 angstroms occurs solely through diffusion.^11,12

CLASSIFICATION:

According to different perspectives, hydrogels can be categorized in a number of ways depending on the literature. based on phase transitions caused by chemical, physical, or physiological stimuli, such as gel-sol interactions. Temperature, electric and magnetic fields, solvent composition, light intensity, and stress are examples of physical stimulants. On the other hand, chemical stimulation refers to factors like pH, ionic strength, certain chemical compositions, and enzyme and amino acid-based biochemical stimulation. Nanogels and microgels are classified according to their pore size; homopolymers and copolymers are classified according to their polymer structure; cross-linking is classified as either chemically or physically cross-linked; degradation is classified as either biodegradable or non-degradable; sources can be classified as natural, synthetic, or hybrid; and physical properties are classified as conventional and smart. Hydrogels' adjustable characteristics, quick expandable degradation, and easy preparation make them convenient drug administration options. When it comes to delivering APIs, particularly to the skin, a hydrogel is an ideal carrier. Because of its behavior, composition, and permeability similarities to human skin, ex vivo pig ear skin is a commonly utilized model.^13,14

Figure 1. Classification of Hydrogels.

Table 1: Types of Hydrogels¹⁵

Types	Hydrogels
Depending up on nature of cross-linking reaction	Permanent hydrogels Physical hydrogels Conventional hydrogels Stimuli-responsive hydrogels
Depending upon method of preparation	Homopolymer hydrogels Copolymer hydrogels Multipolymer hydrogels Interpenetration polymeric hydrogels
Other types of hydrogels	PH sensitive hydrogels Temperature-sensitive hydrogels Complexing hydrogels Insitu hydrogels

Technical features of hydrogels:¹⁶

The technical features of hydrogels are listed as follows:

· Utmost stability and constancy in a swelling environment and during storage;

· Utmost absorption ability in brine;

· Preferred rate of absorption, particle size and porosity;

· pH-neutral, colourless, odourless and absolutely non-toxic;

· The highest absorbency under load;

· Photo stability, low soluble content and residual monomer and low price;

· Re-wetting capability — the hydrogel has to be able to give back the imbibed solution or maintain it as needed, (e.g., in agricultural or hygiene applications);

· Maximum biodegradability without formation of toxic groups.

General limitations of hydrogels:¹⁷

· High cost

· Low mechanical strength

· Can be hard to handle

· Difficult to load with drugs/nutrients

· May be difficult to sterilize

· Non-adherent

Advantages of hydrogels:¹⁸

1. Posse’s high degree of flexibility similar to natural tissues.

2. Bio compatible, bio degradable and that is why they can be injected.

3. They may be PH or temperature sensitive and release drug upon such changes.

4. Applied locally so by passing first pass metabolism.

Disadvantages of hydrogels:¹⁹

1. PNIPAAm based hydrogels are temperature sensitive hydrogels. They can cause excess or less amount of drug release in accordance with temperature stimuli.

2. They cause a sensation due to the movement of maggots.

3. In case of contact lenses cause lens deposition, hypoxia, dehydration, and eye reactions.

Methods of preparation of hydrogels:

1. Homopolymer hydrogel:

A material that absorbs water and is formed of only one kind of monomer is called a homopolymer hydrogel. It is made up of a web of interconnected polymer chains that have a high water-retention capacity. Homopolymer hydrogels have consistent chemical properties due to their homogenous structure, which makes them useful in wound treatments, medicine delivery, and agriculture.²⁰

2. Co Polymeric hydrogel:

A hydrogel made of two or more different types of monomers polymerized together is called a copolymeric hydrogel. Comparing this combination to homopolymeric hydrogels, more individualized features are possible. Copolymeric hydrogels can be engineered to possess certain mechanical strength, environmental responsiveness, and regulated swelling behavior by manipulating the kinds of monomers. Tissue engineering, drug delivery, and medical devices all make extensive use of these hydrogels.²¹

3. Semi inter penetrating networks (semi IPN):

One type of polymer system is called a semi-interpenetrating polymer network (semi-IPN), in which one polymer is crosslinked to form a network and another polymer stays linear or non-crosslinked but is woven inside the network. By combining the qualities of the two polymers, this structure improves mechanical strength, flexibility, and responsiveness. Because semi-IPNs can be utilized to fine-tune physical properties, they are frequently used in stimuli-responsive materials, drug delivery, and tissue engineering.²²

4. Inter penetrating networks (IPN):

A polymer system known as an interpenetrating polymer network (IPN) is made up of two or more polymers that are crosslinked and woven throughout one another without the need for covalent bonds. Strength, resilience, and toughness are among the mechanical qualities that are improved by this interpenetration of polymer networks. IPNs are very helpful in cutting-edge applications where specific mechanical and chemical properties are crucial, such as biomedical devices, coatings, and adhesives. They do this by combining the distinctive qualities of the various polymers.²³

Table 2: Examples of Hydrogels

Sl. No	Hydrogels	Biological activity	Reference
1	Hydrogel loaded with Moringa oleifera leaf extract	Antioxidant and Anti Microbial Activity.	24
2	Hydrogel loaded with seaweed extract	Antimicrobial Activity	25
3	Hydrogel loaded with PVA/Gelatin	Antimicrobial Activity against Skin Pathogens	26
4	Hydrogel loaded with onion peel quercetin	Antimicrobial and Anticancer Activity	27
5	Hydrogel loaded with thymol-chitosan	Antioxidant and Anti Microbial Activity.	28
6	Hydrogel loaded with Ixora coccinea leaf extract	Antimicrobial and Wound Healing Activity	29
7	Hydrogel loaded with embelin from Embelia ribes	Wound Healing Activity	30
8	Hydrogel loaded with Silver Sulfadiazine	Antimicrobial Topical Applications	31
9	Hydrogel loaded with Eupatorium glutinosum leaf extract	Antioxidant and Anti Bacterial Activity	32

Hydrogels in drug delivery:

Hydrogels now a day are more attracted because of their regulated as well as sustained release of medicines. They are able to release the medications at suitable and targeted places. There are several applications for hydrogels, which are listed below.³³

1. Wound healing:

Hydrogels are cross linked polymers that have the ability to contain water and medicine in them. Due to their water holding ability they may hold and retain wound exudates. Gelatin and sodium alginate based hydrogels when applied have the power to cover and protect the site from bacterial infection.³⁴

2. Hydrogels for eye:

The first bioadhesive-based ocular medication delivery method was created by Hui and Robinson.³⁵ An estimated 75% of the ophthalmic solution is lost as a result of nasolacrimal drainage, and the drug's intended bioavailability declines.³⁶ The blinking tear drainage is one of the additional elements that affects drug absorption. P (NIPAAM-co-dex-lactate HEMA) was the method that Mishra and colleagues used to release insulin in rat eyes. These hydrogels are implanted beneath the conjunctiva and are completely safe. For the prolonged delivery of pilocarpine and timolol in the eye, xyloglucan-based gel is utilized.³⁷

3. Hydrogels for transdermal drug delivery

Using hydrogels for topical or transderm applications has several benefits, including increased medication efficacy and bioavailability due to their ability to circumvent hepatic metabolism.³⁸ Transdermal drug delivery systems are utilized to achieve a continuous flow of medication. Hydrogels are easier to remove than other dose forms like patches and ointments because they are swollen and mimic live tissues. Drugs can be administered topically or systemically using transdermal drug administration. For example, transdermal hydrogels are created to transport gluocorticoids like budesonide.³⁹ New hydrogels based on poloxamer 407 that contain gentamycin work better to treat skin infections than gentamycin administered parenterally, which can lead to more serious conditions.⁴⁰

4. Vaginal route:

Drugs that are to be injected vaginally need to be in the form of tablets, gels, foams, suppositories, creams, or other formulations. Because vaginal drug administration bypasses the hepatic metabolism, there are numerous benefits. The vagina's enormous surface area contributes to an increase in the absorption of drugs systemically. The vaginal epithelium allows for the permeability of drugs with high molecular weights. The vaginal route is preferred since the hepatic metabolism reduces the bioavailability of natural progesterone. The anticancer medication bleomycin is released for more than 23 hours when placed on a flat-faced disk that is crosslinked with carbopol 934 and hydroxypropyl cellulose.⁴¹

5. Oral route:

One of the major benefits of the oral route is its accessibility. For localized fungal and viral infections, the oral route is employed. This path lowers the metabolism of the first pass as well. A mucosal adhesive lidocaine pill was created by mixing magnesium sterate, carbopol 934, and hydroxypropyl cellulose. tablet with a 2 mm thickness and a 1 centimeter diameter.⁴²

6. Gastro intestinal tract:

The most frequent and common method for administering drugs is the G.I. tract. Drugs are also locally delivered via the G.I. tract. Famotidine is an anti-ulcer medication with localized effects. The goal of sustained release gastro retentive hydrogels is to improve the bioavailability and therapeutic impact of oral medications that are poorly absorbed.⁴³

7. Hydrogels for brain:

Drug distribution is hampered by the blood-brain barrier, just like by other barriers in the human body. 98% of newly manufactured medications are unable to pass this threshold. As a result, there aren't many medications available for CNS drug delivery. Rats were shown to benefit from camptothecin loaded with PLGA microspheres over an extended period of time. Rats with malignant gliomas have a longer life time when exposed to these microspheres.⁴⁴

Drug Release Mechanism^45,46

Diffusion controlled:

Diffusion controlled drug release is the most popular hydrogel drug release technique. Diffusion controlled release models typically employ Fick's law of diffusion with constant or variable diffusion coefficients. Drug diffusivities are typically calculated using free volume, hydrodynamic, or obstruction-based models, or they can be determined empirically.

Chemically controlled:

Reactions taking place within a delivery matrix determine molecular release, which is referred to as chemically-controlled release. The most frequent processes that take place in hydrogel delivery systems are either reversible or irreversible interactions between the polymer network and the releaseable drug, or cleavage of polymer chains by hydrolytic or enzymatic degradation. The rate of drug release in hydrogels can be regulated by either bulk or surface erosion, depending on specific circumstances. Alternatively, the drug release rate might be determined by the binding equilibrium if the hydrogels contain drug-binding moieties.

Swelling controlled:

Controlled swelling release happens when drug diffusion happens more quickly than hydrogel swelling. In order to describe this action, shifting boundary conditions are typically used, releasing molecules at the interface between the glassy and rubbery phases of swelled Diffusion controlled drug release is the most popular hydrogel drug release technique.

Evaluation parameters of gels:

1. Swelling Ratio: This evaluates a hydrogel's capacity to absorb water. Usually, it is stated as the swelled bulk divided by the dry mass.

Evaluation Method:

Weigh the hydrogel alternately before and after it has swelled by immersing it in water.⁴⁷

2. Mechanical Properties: Elasticity: Depending on how they are used, hydrogels can be either soft or stiff. Tensile, compressive, or shear tests are frequently used to quantify elasticity. Tensile Strength: Measures the resistance to being pulled apart.

Young’s Modulus: Reflects the stiffness of the hydrogel.⁴⁸

3. Porosity: Mechanical qualities, nutrient distribution, and water retention are all impacted by the pore structure.

Evaluation Method: Porosity can be evaluated using methods like scanning electron microscopy (SEM) or mercury intrusion porosimetry.

4. Degradation Rate: In certain applications (like tissue engineering), hydrogels need to degrade at a predictable rate. This parameter is crucial for bio-compatibility.

Evaluation Method: Measure mass loss over time under simulated physiological conditions.

5. Biocompatibility: Especially important for biomedical applications. Tests are done to evaluate the interaction with cells or tissues.

Evaluation Method: Cytotoxicity assays, in vivo studies, etc.⁴⁹

6. Water Content and Retention Capacity: The ability to hold water over time is critical, especially in applications like wound dressings.

Evaluation Method: Measure the percentage of water retained over time.

7. Thermal Properties: Includes glass transition temperature and melting temperature, which influence the stability and performance of the hydrogel.

Evaluation Method: Use techniques like differential scanning calorimetry (DSC) or thermogravimetric analysis (TGA).

8. Diffusivity: This determines how substances (e.g., drugs or nutrients) can diffuse through the hydrogel matrix.

Evaluation Method: Use diffusion studies or spectroscopy to measure the movement of molecules within the hydrogel.

9. Cross-linking Density: The degree of cross-linking affects the mechanical strength and water absorption of the hydrogel.

Evaluation Method: Can be calculated from swelling experiments or estimated using techniques like rheology.

10. pH Sensitivity: Some hydrogels change their properties based on the pH of the environment, which is relevant for applications like drug delivery.

Evaluation Method: Test swelling and mechanical properties across different pH levels.⁵⁰

Polymers in Hydrogels:

Hydrogels are three-dimensional, crosslinked polymer networks that have the ability to absorb and retain significant amounts of water. The unique properties of hydrogels come from the interaction between the polymer chains and the water within the network.⁵¹

Characteristics of Polymers in Hydrogels:^52,53

1. Water Absorption and Retention: The hydrophilic nature of polymers in hydrogels allows them to absorb water, sometimes hundreds of times their own weight. This characteristic makes them suitable for applications requiring moisture control.

2. Crosslinking: The polymer chains in hydrogels are crosslinked, either chemically or physically, forming a network. Crosslinking is crucial as it prevents the polymer chains from dissolving in water and instead allows them to swell.

3. Elasticity and Softness: Due to their water content and crosslinked structure, hydrogels exhibit elasticity, making them soft and flexible. This property is essential in biomedical applications, such as contact lenses and tissue engineering.

4. Stimuli-Responsive Behavior: Some hydrogels are designed to be sensitive to environmental stimuli such as pH, temperature, or ionic strength. These stimuli-responsive hydrogels can undergo changes in swelling or other physical properties.^54,55

5. Biocompatibility: Many hydrogels are made from biocompatible polymers, making them ideal for use in medical and pharmaceutical applications. Common biocompatible polymers include polyvinyl alcohol (PVA), polyethylene glycol (PEG), and naturally occurring polymers like alginate or gelatin.

Types of Polymers in Hydrogels:

· Natural Polymers: These include biopolymers like collagen, gelatin, chitosan, alginate, and hyaluronic acid. They are biodegradable and biocompatible, commonly used in medical and tissue engineering applications.⁵⁶

· Synthetic Polymers: These include polyacrylamide (PAAm), polyethylene glycol (PEG), polyvinyl alcohol (PVA), and polylactic acid (PLA). Synthetic polymers allow for better control over hydrogel properties, such as mechanical strength and degradation rate.^57,58

Applications of Hydrogels:^59,60

1. Biomedical Applications: Hydrogels are used in wound dressings⁶¹, drug delivery systems, and tissue scaffolding due to their biocompatibility and ability to hold water, mimicking natural tissue environments.⁶²

2. Agriculture: Hydrogels are used in soil conditioners to improve water retention, especially in arid regions.⁶³

3. Contact Lenses: Many contact lenses are made from hydrogels due to their softness and ability to retain water, which keeps the eyes hydrated.⁶⁴

4. Hygiene Products: Superabsorbent polymers (SAPs) in hydrogels are used in products like diapers and sanitary pads due to their ability to absorb large amounts of liquid.⁶⁵

5. Environmental Applications: Hydrogels are being explored for applications in water purification and as smart materials for sensors.⁶⁶

CONCLUSIONS:

To sum up, hydrogels are a very adaptable family of materials with a wide range of potential uses in the pharmaceutical, environmental, and biomedical industries. Their chemical makeup and preparation process have a major impact on their special qualities, which include high water content, adjustable mechanical strength, and biocompatibility. Hydrogels can have their qualities customized for particular uses by being categorized according to their origin, structure, and reaction to stimuli. Critical insights into their performance in real-world circumstances are provided by the evaluation methods, which range from biocompatibility studies to mechanical testing. The use of hydrogels is becoming more and more widespread due to ongoing developments in the field, including the addition of nanomaterials, stimuli-responsive behaviors, and enhanced drug delivery systems. Subsequent investigations into multipurpose, sustainable hydrogels will probably strengthen their ability to tackle difficult problems in a variety of domains.

ACKNOWLEDGEMENT:

The authors thank Principal, KLE College of Pharmacy and Department of Pharmacognosy, KLE College of Pharmacy Belagavi, for all the support to complete this review.

CONFLICT OF INTEREST:

The authors declare that they have no conflict of interest.

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Received on 24.09.2024 Revised on 11.10.2024

Accepted on 26.10.2024 Published on 25.11.2024

Available online from December 27, 2024

Asian J. Research Chem. 2024; 17(6):392-398.

DOI: 10.52711/0974-4150.2024.00065