Transdermal Drug Delivery using Nanogels:

Methods of Preparation and Evaluation Techniques

 

Nupoor Sunil Erram, Jameel Ahmed S. Mulla*

Department of Pharmaceutics, Shree Santkrupa College of Pharmacy, Ghogaon - Karad, Maharashtra, India.

*Corresponding Author E-mail: jameelahmed5@gmail.com

 

ABSTRACT:

Nanogels have emerged as a promising platform for transdermal drug delivery due to their unique physicochemical properties, such as high-water content, tunable size, and responsive behavior. This review highlights the recent advancements in nanogel-based transdermal drug delivery systems, focusing on methods of preparation and evaluation techniques. Various preparation methods, including oil in water (o/w) emulsion solvent diffusion method, inverse (mini) emulsion polymerization technique, membrane emulsification technique, spray drying/cross linking reversible addition-fragmentation chain transfer (RAFT) polymerization, are discussed in detail. Furthermore, critical evaluation parameters such as particle size measurement, drug content, zeta potential, entrapment efficiency, rheological evaluation, SEM analysis, TEM analysis, in vitro drug release, skin irritation studies and skin permeation studies are explored to assess nanogel effectiveness. The ability of nanogels to enhance drug permeation through the skin barrier, provide controlled release, and improve patient compliance underscores their potential in modern therapeutics. This review aims to provide comprehensive insights into the design, development, and evaluation of nanogels for efficient transdermal drug delivery, highlighting future challenges and opportunities in the field.

 

KEYWORDS: Nanogels, Transdermal Drug Delivery, Controlled Release, Skin Permeation, Drug Encapsulation, Crosslinking Techniques, In vitro Evaluation, In vivo Studies.

 

 

INTRODUCTION:

Nanogel engineering in case of cancer therapies are widely studied in current trends1. For the transdermal drug delivery systems nanogel are promising carriers now-a-days2. Nanogels are three-dimensional network formed by cross-linked chain of polymer. Nanogel occurs in size ranging from 100 to 200nm3. Nanogels is the strategy used for treatment of the disease and any dysfunction by using as a vehicle for drug delivery capable of finding the way across by challenging the physiological barriers present in human body4,5.

 

Nanogels can be synthetic or in combination of two, possessing the highest degree of adaptability in terms of size, shape, surface characteristics and degradation mechanisms6. These are the most productive formulations as compared to conventional and macro sized dosage formulations for drug delivery7. Nanogels possess the properties of solid and liquid at same time. It consists of solid segments combined with polymers distributed in large volume of fluid in which the solid particles are arranged in three-dimensional (3-D) structures having the nanoscale structures8-13. Nanogel can be formulated on a large scale, and the raw resources are readily available having highly economical cost benefit ratio14. For the preparation of nanogel formulations there are mainly two approaches used commonly i.e. 1) Interactive polymer self-assembly in physical form; 2) chemically joining pre-made polymers15. Transdermal administration removes pulsed entry into the systemic circulation, which frequently results in unwanted side effects, and permits continuous input of medications with short biological half-lives. It also offers controlled, continuous drug administration16-22.

 

Nanogel formulations helps to overcome the disadvantages of nanoparticles and hydrogels and helps to demonstrate the traits and attributes of hydrogel and nanoparticles separately possess simultaneously. The Drug release pattern from nanogel is explained in Fig. 1.

 

 

Figure 1: Drug Release Mechanism from Nanogel

 

On the basis of structures nanogels are classified as

·       Simple nanogel

·       Hollow nanogel

·       Core shell nanogel

·       Hairy nanogel

·       Multilayer nanogel

·       Functionalized nanogel23

 

Nanogels can be administered by following routes

·       Oral

·       Pulmonary

·       Nasal

·       Parenteral

·       Intra-Ocular

·       Topical

 

Advantages:

1.     Nanogels are highly biocompatible and biodegradable.

2.     Nanogels are highly effective at loading drugs..

3.     They possess the capacity to enter the tiniest capillary channels.

4.     Drug with hydrophilic and hydrophobic nature can be used in the formulation.

5.     Controlled and sustained release of drug at target site can be achieved.

6.     Pre-mature leakage of drug from solution can be prevented24,25.

 

Methods of Preparation of Nanogels:

Polymers used in the nanogel preparation:

There are many polymers used in nanogel formulations based upon the method of preparation but the common polymers used are Carbopol 934, Locust bean gum, tamarind seed gum and many more are the commonly used gelling agents used in the gel formation.

 

Oil in Water (O/W) Emulsion Solvent Diffusion Method:

This method includes preparation of emulsion by solvent diffusion process. The required amount of API is added to mixture of oil and surfactant which is called oily phase. Then required amount of gelling agent is added in sufficient amount of water and mixed well to obtain gel like consistency with the help of sonication and heating. The oil phase is mixed with the aqueous phase with help of homogenization to form an emulsion. The nanogel of desired particle size can be obtained with further homogenization18.

 

Inverse (Mini) Emulsion Polymerization Technique:

This process involves water in oil polymerization technique in which aqueous droplets act as the internal phase which are dispersed uniformly in a continuous phase using surfactant having oil solubility providing system stability. A mechanical stirrer is used in this process for a stable emulsion.

 

Table 1: Review of reported nanogel formulations of various categories

Sr. No.

Drug

Category

Method of Preparation

Reference

1

Curcumin

Anticancer

Encapsulating nanogel

26

2

Beta sitosterol

Cholesterol lowering agent

Nanoparticles loaded nanogel

27

3

Cotimoxazole

Antibacterial

High speed homogenization (solvent diffusion)

28

4

Itraconazole

Antifungal

Nanoparticles loaded nanogel

29

5

Lovastatin

Cholesterol lowering agents

Solid lipid nanoparticles loaded nanogel (Solvent emulsification)

30

6

Monteleukast

Asthma

Nanogel loaded with Niosomes

31

7

Ketoprofen

Analgesic, Anti-inflammatory

Nanoemulsion

32

8

Aceclofenac

NSAID

Nano dispersion by modified emulsification diffusion

33

9

Methotrexate

Anticancer

MTX-loaded Nanostructured lipid carriers

34

10

Diclofenac sodium

NSAID

Nanoemulsion

8

11

SpantideII Ketoprofen

Anti-inflammatory

Nanoparticles loaded nanogel

35

12

Acetazolamide

Glaucoma

Nanovesicles loaded nanogel

11

13

Terconazole

Antifungal

lecithin-integrated liquid crystalline

36

14

5-florouracil

Anticancer

Synthesis of polymer by micro emulsion and drug loading by solvent evaporation

37

15

Pullulan

Antifungal

Self-assembled nanogels

38

 

Centrifugation is used for purification at the final step of the process. To control the particle size there are various factors need to observed such as amount of surfactants and cross linking polymers added in formulation for a stable emulsion39,40.

 

Membrane Emulsification Technique:

This process involves a membrane of uniform pore size from which the dispersed phase and the external phase are passed through the membrane with specific morphology (i.e. particle of desired size). The prepared nanogel are collected the desired container having desired morphology. Various types of the emulsion can be prepared by using this method by controlling various parameters41.

 

Spray Drying/Cross Linking:

Electro sprayers are used to produce small droplets with the help of nebulizers. This process involves use of volatile solvents which rapidly evaporates from the solution to give the product of various particle size. Various parameters are taken into consideration for adjustment. The drug with polymer is added to a volatile solvent and then left for formation of droplets. Rapid evaporation helps in formation of encapsulated drug with the polymer. The precursor dissolved in solvent is allowed to spray with the equipment to obtain final product42-44.

 

Reversible Addition-Fragmentation Chain Transfer (RAFT) Polymerization:

By adding dithioester chemicals during the radical polymerization process, a polymer experiences a number of chemical reactions. Reversible addition, reversible compound degradation, chain transfer reactions, and other processes are examples of the reactions. By changing the length, configuration, and characteristics of the polymers employed in the formulation, the RAFT approach can change the micelle structure of amphiphilic polymers45.

 

Micellar Nanogels:

These types of nanogels can be prepared using polymeric micelles. The method is very simple and laboratory based.The micelles are generally prepared for the API being badly soluble, or falling within BCS class II. The excipient are selected according to the nature of API and prepared using a magnetic stirrer. The gelling agent is added to the resulting formulation to form a nanogel. The nanogels prepared by this method are also called as Micellar loaded nanogels46.

 

Evaluation of Prepared Nanogels:

Particle size measurement:

Particle Size Analyzers (PSA) are machines that quantify particle size utilizing a variety of technologies, including high definition image processing, Brownian motion analysis, particle gravitational settling, and particle light scattering37. The particle size of the nanogel formulation is to be measured using the apparatus. The prepared nanogel formulation is diluted with double distilled water and further subjected to examination. The mean particle size is determined from the results obtained and is determined using a range48-55.

 

 

Figure 2: Working of Particle Size Analyser

 

Drug Content:

The amount of nanogel used for analysis is to be transferred into flask and then is diluted to certain point. The resulting mixture was further subjected for centrifugation. Then the solution is filtered and the filtrate is subjected for further dilutions and the samples were analysed using UV-Visible spectrophotometer using blank solution. Drug content is to be calculated using the formula48,49.

 

                           Actual Drug Content

Drug content = ––––––––––––––––––––– × 100

                          Theoritical Drug Content

 

Zeta potential:

The electrical potential at the sliding plane is known as the zeta potential. This plane serves as the interface between fluid that is mobile and fluid that is fixed to the surface.


 

 

 

Figure 3: Working of Zeta Potential Analyser

The scientific word for electrokinetic potential is zeta potential47. For detecting the electric charge present on particles surface, zeta potential is used. Also helps in detecting physical stability of colloidal formulation which is an important tool in evaluation of charge present in the formulation58-60.

 

Entrapment Efficiency:

Firstly the prepared nanogel is subjected to centrifugation at a suitable speed. The supernatant is obtained after the process is to be collected in beaker which is followed by dilutions with a suitable solvent. After dilutions the samples were analysed using UV-Visible spectrophotometer using a blank and the total (%EE) is calculated using the formula48,61-64.

 

              amount of API added in formulation –

                           amount of API in supernatant

%EE = ––––––––––––––––––––––––––––––––––  × 100

              Amount of API added in formulation

 

Rheological Evaluation:

The fluid layer in contact with the pipe's sides or the object's surface tends to be in the same state of motion as the object it is in contact with when a fluid or solid object is moving through a pipe; that is, While the fluid layer in contact with the moving object is at rest, the fluid layer along the pipe's side is  carried along at the same velocity as the object. If there is not a significant velocity differential between the fluid at the pipe's core and its sides, or between the fluids that an object is traveling through and the fluid it is traveling through, known as laminar flow51.

 

Determination of viscosity is done by brook-field viscometer. The nanogel is weighed in spate quantities and is to be dispersed in solvent for hydration. The resulting mixture is kept overnight at room temperature and the following evaluation is carried out. The results are carried out in triplicate48,49,67.

 

SEM Analysis:

Like their optical equivalents, scanning electron microscopes photograph the object and extract structural and compositional details by using a concentrated electron beam rather than light. With the help of a positive electrical potential, A beam of electrons is produced by the electron source and aimed at the specimen. The electron beam is limited and focused into a narrow, monochromatic beam by using magnetic lenses and metal apertures. The interaction between the atoms in the specimen and the electrons in the beam results in signals that provide information about the composition, surface topography, and other electrical properties of the specimen. An image is created by identifying and transforming these interactions and effects52.

The structural features of any active pharmaceutical ingredient can be determined using scanning electron microscope (SEM). At a higher magnification the smallest particle present in the formulation can be studied59,69,70.

 

 

Figure 4: Brookfield’s Viscometer

 

 

Figure 5: Working of Scanning Electron Microscope

 

TEM Analysis:

Light and transmission electron microscopes (TEMs) are comparable. The primary distinction is that TEM targets the specimen with an electron beam, whereas light microscopes employ light rays to target and create an image to produce an image. When the electron highlights the specimen, the resolution power increases which results in increasing the wavelength of the electron transmission53.

 

Shape and morphology of the formulation can be examined by TEM method. A drop of formulation is to be placed on carbon coated copper grid and suitable stain is added to impart colour to the formulation and allowed to dry for a specific time. The images were captured for the resulting formulation34,54,71,72.

 

In Vitro Drug Release:

The release of any drug from nanogel formulation is to be carried out using Franz diffusion cell apparatus. Nanogel to be analysed are evenly distributed on the surface of cellophane membrane. The whole assembly is to be setup in such a way that one end of the membrane is dispersed in the medium approx (1 to 2 mm). The assembly is to set up on hot plate with thermostat and magnetic stirrer facility. The sample is to be withdrawn at specific intervals and further subjected to dilutions, finally analysed using UV-Visible          spectrophotometer56, 48,76.

 

Skin Irritation Studies:

According to the OECD Guidelines, the acute dermal irritation research must be carried out. A section of the rabbit's trunk, about 5cm by 5cm, was shaved for the experiment. A test area measuring 2.5cm by 2.5cm has been chosen. To prepare the drug for cutaneous application, combine it with as little oil as possible (2 mg/kg). During the application, the animals need to be fitted with Elizabethan collars. The skin should be covered with the paste for four hours, and then the wrappings should be taken off. Following patch removal, the skin's reactions were noted after three minutes, one hour, and four hours. The findings are recorded, and the test needs to be run three times57,78.

 

Skin Permeation Studies:

Franz diffusion cell apparatus can be used for skin penetration tests of a medication from its formulation. The formulations to be examined are dispersed equally across the cellophane membrane's surface. The entire assembly must be set up so that the membrane's one end is around 1 to 2mm scattered throughout the medium. The assembly needs to be placed on a hot plate with a magnetic stirrer and thermostat. The sample must be removed at predetermined intervals, exposed to additional dilutions, and then examined with a UV-visible spectrophotometer49,79.

 

CONCLUSION:

Nanogel formulations are most widely studied formulations in today’s pharmaceutical field the reason being is formulation of nanogel is not tedious but very simple to formulate. The formulation serves many advantages over many primary formulations like gels, creams, ointment etc. There are also many ways and options for the formulation and evaluation of nanogel formulation. Nanogel formulations can also be formulated on industrial scale which is an advantage due to wide availability of chemicals and simple process to manufacture

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Received on 20.03.2025      Revised on 13.08.2025

Accepted on 07.11.2025      Published on 10.04.2026

Available online from April 13, 2026

Asian J. Res. Pharm. Sci. 2026; 16(2):147-153.

DOI: 10.52711/2231-5659.2026.00023

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