Formulation Development and Evaluation of Chitosan-Based Sustained Release Gel System of Mequinol

Abstract

The present research focuses on the formulation and comprehensive evaluation of Mequinol topical gels, with the objective of enhancing its therapeutic efficacy and stability. Eight gel formulations (B1–B8) were developed using varying concentrations of chitosan (as a mucoadhesive polymer), hydroxyethyl cellulose (HEC) (as a viscosity enhancer), and dimethyl sulfoxide (DMSO) (as a penetration enhancer). From all batches batch B6 was selected as optimized batch formulation which was subjected to a series of physicochemical evaluations, including assessments of appearance, homogeneity, pH, viscosity, spreadability, drug content uniformity, and in vitro drug diffusion. The pH values of all formulations were maintained within the dermatologically acceptable range, ensuring skin compatibility. Viscosity and spreadability studies revealed that formulations with balanced polymer concentrations exhibited optimal consistency and ease of application.

Keywords

Introduction

A drug is rarely administered in its pure form. It is always mixed with some inert chemicals called excipients. These all together form a drug delivery system (DDS). A DDS is defined as a formulation or a device that enables the introduction of a therapeutic substance in the body and improves its efficacy and safety by controlling the rate, time, and place of release of drugs in the body. Depending upon site of administration, many drug delivery systems are available from years, like oral, parenteral, topical, rectal drug delivery systems. These conventional drug delivery systems are associated with a number of limitations like slower onset of action, variable absorption patterns, patient non-compliance etc. with respect to formulation. These limitations can reduce drug efficacy. Thus, advanced drug delivery and targeted drug delivery are developed in order to optimize drug therapy and overcome those limitations. These novel drug delivery systems (NDDSs) offered many clinical benefits over conventional drug delivery systems; but they are outweighed due to their increased cost. Today many NDDSs are available like Nanoparticles, Liposomes, Floating tablets, Solid dispersion, Transdermal patches, Hydrogels, etc. NDDSs overtake conventional DDS by enhancing drug targeting specificity, lowering systemic drug toxicity, improving treatment absorption rates, and providing protection for pharmaceuticals against biochemical degradation.

Routes of drug administration

Topical Drug Delivery System

Topical drug delivery systems are localized delivery systems that are used to administer therapeutic agents via the skin to treat cutaneous disorders. These systems are most often used to treat local skin infections. The formulations are available in different forms, ranging from solid to semisolid to liquid. In the event that the drug substance in the solution exhibits a favorable lipid/water partition coefficient and is not an electrolyte, then drug absorption is enhanced via the skin. Dermatological products exhibit a range of formulations and inconsistencies in their composition. The most prevalent derma products are semisolid dosage forms.

Advantages of topical drug delivery systems

• Avoidance of primary pass metabolism
• Convenient to use and easy to apply
• Easily to terminate the medications
• Drug delivered selectively to a specific site
• The gastro-intestinal incompatibility will be avoided
• Provides drugs utilization with short biological half-life and narrow therapeutic window
• Better patient compliance
• Self-medication
• It provides effectiveness in low doses and by continuous drug input
• Avoids Fluctuation in drug levels and risks
• A large area of application compared to other route.
• Drug delivery at a specific site

Disadvantages of topical drug delivery systems

• Possibility of local skin irritation at the site of application.
• Some drugs with poor permeability are difficult to penetrate via the skin
• Drugs with larger particle sizes are difficult to penetrate
• Factors Affecting Topical drug absorption
• Some physiological factors and physicochemical factors which affects the absorption of drug through topical route.
• Thickness of skin
• PH of skin
• Temperature of skin
• Lipid content
• Hydration of skin
• Density of sweet glands
• Blood flow
• Inflammation of skin
• Partition coefficient
• Molecular weight of drug
• Degree of Ionization

Gel

The rigidity of a gel is attributed to the presence of a network formed by the interlinking of gelling agent particles. The nature of the particles and the type of force involved in the linkages determine the structure of the network and the properties of the gel. The constituent particles of hydrophilic colloids can be either spherical or an isometric aggregate of small molecules or single macromolecules.

Properties of Gels

• The gelling agent employed in pharmaceutical formulations should be inert and safe, and should not react with other formulation ingredients.
• The gelling agent incorporated into the formulation should produce a sufficient solid-like consistency during storage that can be readily fractured when subjected to shear forces generated by shaking the bottle, squeezing the tube, or during topical application.
• The substance must demonstrate adequate antimicrobial activity to impede the proliferation of microbes.
• The topical gel should not exhibit a tacky sensation upon application.
• The substance under consideration should be inert, compatible with other additives, and nontoxic.
• The object in question should be characterized by ease of handling and application.
• The object's stability during storage is paramount.
• The impact of this process should not result in any alterations to the biological nature of the drug itself. ü The optimal gelling agent for pharmaceutical or cosmetic applications must be inert and safe, and must not undergo reactions with other formulation components.
• The substance under consideration should exhibit the following properties: thixotropic, greaseless, emollient, and non-staining.

Melasma

The term "melasma" is derived from the Greek word "melas," which translates to "black." This condition is characterized as an acquired disorder of hypermelanosis. A substantial body of literature documents that women account for approximately 90% of all reported cases of melasma worldwide. In India, approximately 20-30% of middle-aged women exhibit facial melasma.

Need of Research Work

Notwithstanding considerable advances in topical drug delivery, the therapeutic potential of Mequinol, a widely utilized depigmenting agent, remains constrained by a number of significant challenges. One of the primary obstacles to the therapeutic efficacy of Mequinol is its poor skin penetration, which is due to its inability to traverse the lipid-rich stratum corneum. This reduces its bioavailability and efficacy. Furthermore, Mequinol is susceptible to oxidative degradation, which compromises its stability in conventional formulations.The current strategies to address these issues often rely on synthetic penetration enhancers or stabilizers, which, although effective, are associated with potential toxicity and skin irritation, limiting their acceptability for long-term use.

Gel have emerged as a promising drug delivery platform due to their ability to encapsulate active pharmaceutical ingredients, thereby improving their stability, protecting them from environmental degradation, and enabling controlled drug release. Although these systems have been extensively studied for various therapeutic agents, their specific application for Mequinol remains underexplored. Moreover, the majority of nanoparticle-based delivery systems lack an integrated approach to enhance dermal penetration, often focusing exclusively on controlled drug release.

Chitosan has mucoadhesive nature which helps the formulation adhere to the skin, increasing contact time. It also enhances the penetration rate and opens tight junctions in the stratum corneum, facilitating Mequinol delivery. Chitosan, provides a protective matrix for Mequinol, reducing degradation and act as stabilizer. It has pH-responsive solubility i.e. soluble in acidic conditions (pH < 6), which aligns with the stability needs of Mequinol. Despite the aforementioned potential, the incorporation of chitosan into gel system as a natural penetration enhancer specifically for Mequinol has not been the part of a systematic Research.

The absence of a unified approach that incorporates Mequinol, Gel system, and Chitosan represents a notable deficiency in the current research landscape. The combination of the protective and sustained-release capabilities of gel with the penetration-enhancing and stabilizing properties of chitosan could provide a novel and effective delivery system. The objective of this study is to address this gap by developing and evaluating a gel formulation of Mequinol, utilizing chitosan as a natural penetration enhancer. Such a system has the potential to enhance therapeutic outcomes, mitigate adverse effects, and provide a safer and more sustainable alternative to conventional dermatological treatments.

DRUG PROFILE: MEQUINOL

• Chemical Name: Mequinol
• Chemical Structure:

Figure 8: Structure of Mequinol

• Molecular Formula:      C7H8O2
• Molecular Weight:        124.14 g/mol
• Solubility: Soluble in      water, ethanol, ether and chloroform
• Melting Point: Approximately 58-62°C
• Appearance: Colorless to pale yellow powder
• Stability: Stable in a cool, dry place away from light and moisture; keep in a tightly closed container
• Half-Life: Not well-defined for topical application due to minimal systemic absorption
• Route of Administration: Topical
• Absorption: Well-absorbed through the skin; systemic absorption is minimal when applied topically
• Distribution: After topical application, it remains mostly in the epidermis with minimal distribution to systemic circulation
• Metabolism: Metabolized in the skin and liver; primary metabolic pathway involves conjugation to form sulfate and glucuronide derivatives
• Elimination: Excreted primarily through urine as metabolites
• Therapeutic Class: Methoxyphenols
• Mechanism of Action: The mechanism of action of mequinol is unknown. Although mequinol is a substrate for the enzyme tyrosinase and acts as a competitive inhibitor of the formation of melanin precursors, the clinical significance of these findings is unknown. The mechanism of action of tretinoin as a depigmenting agent also is unknown.
• Uses and Applications: Used topically for the treatment of solar lentigines (age spots) and other hyperpigmentation disorders

Evaluation of Preliminary trial batch of Mequinol-loaded sustained release mucoadhesive gel formulation

The trial batch of Mequinol gel formulation demonstrated promising formulation characteristics, including clarity, pH, viscosity, spreadability, drug content etc. These results support the feasibility of further development and optimization of the formulation for better results.

Evaluation of Mequinol-loaded sustained release mucoadhesive gel formulation

Visual Inspection for appearance and homogeneity of gel: Different formulations were verified by visual inspection for appearance and presence of mass against a black and white background. The formulations were categorized as follows: Turbid, not pleasant and non-homogeneity Opaque Pleasant and homogeneity

Determination of PH:

2 g of gel was weighed and suspended in 25 ml of distilled water. The pH was measured by using digital pH meter

Viscosity:

The viscosity of the gels was determined using a Brookfield viscometer consisting of a small sample adapter with spindle. The gel was subjected to a torque between 10 and 100%.

Spreadability analysis of gel:

It was estimated using a wooden block and glass plate apparatus. To estimate the spreadability, excess gel was placed between 2 glass plates and pressed to a uniform thickness by placing 1 kg weight for five minutes. 50 gm weight was placed on the pan. The time required to separate the two glass plates, i.e. the time in which the upper glass plate moves over the lower glass plate, was taken as the measurement of Spreadability (S). Spreadability was calculated using the following formula: 

S = Wu L/T

Where,

S = Spreadability

Wu = Weight tide to top slide

L = Length moved on the glass slide

T = Time taken to remove the plate from each other totally

Drug content:

50 mg of MQN gel was weighed and dissolved in 5 ml of methanol. The solution was then shaken on a mechanical shaker for 15 minutes and the volume was made up to 25 ml with methanol and filtered. The absorbance of the filtrate was measured at 290 nm using a UV spectrophotometer.

In vitro diffusion study

In a diffusion cell, 1.0 g of gel was placed in the donor compartment. The entire surface of the cellophane membrane was in contact with the receptor compartment containing 80 ml of pH 7.2 phosphate buffer. The receptor compartment was stirred continuously (100 rpm) using a magnetic stirrer. The temperature maintained was 37 ± 0.5°C. The study was conducted for 12 hrs with intervals of 1, 2, 4, 6, 8, 10, 12, 24 hrs. The sample was removed at the scheduled time and the same volume was replaced with fresh pH 7.2 phosphate buffer. The samples were analyzed spectrophotometrically at 290 nm to estimate Mequinol

Stability Study

The stability of the selected batch was examined at temperatures of 25 ± 2 ?C (60 ± 5% RH) and at 4 ± 2 ?C (55 ± 5% RH) for a period of three months, in accordance with the ICH guidelines. Selected optimized formulation was estimated for Description, pH variation, viscosity, spreadability and drug content.

CONCLUSION:

The study successfully developed stable Mequinol loaded sustained release mucoadhesive gel formulations with optimized physicochemical properties and enhanced drug release profiles. Among the batches, Batch B6 demonstrated the most promising characteristics, exhibiting an optimal balance between viscosity, spreadability, and sustained drug release. The formulation's stability under various storage conditions further supports its potential for clinical application. Subsequent studies, incorporating in vivo evaluations, are recommended to substantiate the therapeutic efficacy and safety of the optimized Mequinol gel formulation

ACKNOWLEDGEMENT

It gives me great pleasure to express my sincere gratitude to my guide Mr. Vinayak Mundhe, Assistant Professor, Dr Vedprakash Patil Pharmacy College, Aurangabad for his valuable suggestions, support, encouragement, and constant help throughout the entire course to execute this review work successfully. Finally, I would like to thanks to my friend Mrs. Sonali Borde mam , Atul More, Rachana Khandve, seniors for their suggestions, support and help during my work

REFERENCES

1. Krishma Kumari, Archana Kaushik, Jasmine Kaur, Bhatia, Diksha Gupta. Formulation and Evaluation of Chitosan Nanoparticles for Sustained Release of Clotrimazole. International Journal of Pharmacy and Biological Sciences. 2023; 13 (2): 162-17.
2. Archana George and Pranav S Shrivastav. Preparation and evaluation of chitosan- alginate/carrageenan hydrogel for oral drug delivery in the treatment of diabetes. Journal of Bioactive and Compatible Polymers. 2023; 38 (5): 1-14.
3. Ahmed F, Mustafa MA, Tayyab M, Sarwer MU, Khan HU, Zaheer L. Fabrication and in vitro evaluation of chitosan-based nanocomposites through ionic gelation method for the sustained release drug delivery of nicorandil. Asian J Pharm Res Health Care 2023;15:338- 46.
4. Nawaz, A.; Ullah, S.; Alnuwaiser, M.A.; Rehman, F.U.; Selim, S.; Al Jaouni, S.K.; Farid, A. Formulation and Evaluation of Chitosan-Gelatin Thermosensitive Hydrogels Containing 5FU-Alginate Nanoparticles for Skin Delivery. Gels. 2022; 8: 537.
5. M. Vishnu Prakash*, Ubaidulla U, Priyanka Sinha, R. Sivakumar, T. Sathish Kumar, Grace Rathnam. Formulation and evaluation of chitosan-based hydrogel matrix of licorice for targeting helicobacter pylori. Int. J. of Pharmacy and Analytical Research. 2021; 10(3): 271- 281.
6. Jon Keeling, Lina Cardona, Adolpho Benitez, Rachel Epstein. Mequinol 2%/tretinoin 0.01% topical solution for the treatment of melasma in men: A case series and review of the literature. Cutis, 2008; 81(2):179-83.
7. Usama Farghaly Aly, Heba A Abou-Taleb, Ahmed AH Abdellatif, Nahla Sameh Tolba. Formulation and evaluation of simvastatin polymeric nanoparticles loaded in hydrogel for optimum wound healing purpose. Drug Design, Development and Therapy, 2019;13: 1567– 1580.
8. Anam Ahsan, Muhammad Asim Farooq, and Amna Parveen. Thermosensitive Chitosan- Based Injectable Hydrogel as an Efficient Anticancer Drug Carrier. ACS Omega. 2020; 5: 20450−20460.
9. Hema A Nair, Nazia Begum. Development and Evaluation of A Poloxamer- and Chitosan- Based In Situ Gel-Forming Injectable Depot. Asian J Pharm Clin Res.2020;13 (4):36-41.
10.  Nurcan Bektas , Behiye Senel, Evrim Yenilmez, Orhan Özatik , Rana Arslan. Evaluation of wound healing effect of chitosan-based gel formulation containing vitexin. Saudi Pharmaceutical Journal. 2020; 28 (1): 87-94.
11. Kashyap Ankita, Das Asha and Ahmed Abdul Baquee. Formulation and evaluation of transdermal topical gel of ibuprofen. J Drug Delivery Thera., 2020; 10(2): 20 – 25.
12. Pradeep Kumar Bolla, Bradley A. Clark, Abhishek Juluri, Hanumanth Srikanth Cheruvu and Jwala Renukuntla. Evaluation of formulation parameters on permeation of ibuprofen from topical formulations using Strat-M® membrane. Pharmaceutics., 2020; 12: 151 – 167.
13. Rashmi D. Zode and Chakole. CM. Formulation and Evaluation of Antibacterial Gel Using Leaf Extract of Andrographis Paniculata. Indo American J Pharmaceu. Res., 2020; 10(6): 755 – 760.
14. Goh, CL, Dlova CN, A retrospective study on the clinical presentation and treatment outcome of melasma in a tertiary dermatological referral centre in Singapore, Singapore med J, 1999; 40: 455–458.
15. Gillbro JM, Olsson MJ, The melanogenesis and mechanisms of skin lightening agentsexisting and new approaches', Int J Cosmet Sci, 201
16. Blebea, N.-M.; Pus, cas,u, C.; Vlad, R.-A.; Hancu, G. Chitosan-Based Gel Development: Extraction, Gelation Mechanisms, and Biomedical Applications. Gels 2025, 11, 275
17. Blebea, N.-M.; Pus, cas,u, C.; Vlad, R.-A.; Hancu, G. Chitosan-Based Gel Development: Extraction, Gelation Mechanisms, and Biomedical Applications. Gels 2025, 11, 275.
18. Marzouk. M., El bakry. AM., El hosary. R M.,Abd El Rahman. NK. Formulation and Evaluation of Polymeric Nanoparticles Based Transdermal Hydrogel of Terbutaline Sulphate. Azhar International Journal of Pharmaceutical and Medical Sciences, 2023; 3(2):20-29.
19. Aftab, M.; Javed, F.; Haider, S.; Khan, R.; Khan, S.U.; Alam, K.; Amir, A.; Ullah, F.; Shah, N.A. Design and Characterization of Chitosan-Based Smart Injectable Hydrogel for Improved Sustained Release of Antinarcotics. Pharmaceuticals 2024, 17, 749.
20. Muhammad Suhail, I-Hui Chiu, Arif Ullah, Arshad Khan, Hamid Ullah, Noorah Saleh AlSowayan, and Pao-Chu Wu. Formulation and In Vitro Assessment of Polymeric pHResponsive Nanogels of Chitosan for Sustained Delivery of Madecassoside. ACS Omega. 2024; 9:19345−19352.
21. Parisa Javadi, Mohammad Ali Derakhshan, Reza Heidari, Hajar Ashrafi, Negar Azarpira, Mohammad Ali Shahbazi, Amir Azadi. A thermoresponsive chitosan-based in situ gel formulation incorporated with 5-FU loaded nanoerythrosomes for fibrosarcoma local chemotherapy. International Journal of Biological Macromolecules. 2024; 278. 1-16.
22. Bahareh Farasati Far, Mohsen Omrani, Mohammad Reza Naimi Jamal& Shahrzad Javanshir. Multi-responsive chitosan-based hydrogels for controlled release of vincristine. Communications Chemistry. 2023; 6:28.
23. Rajasekaran Aiyalu, Arulkumaran Govindarjan and Arivukkarasu Ramasamy. Formulation and evaluation of topical herbal gel for the treatment of arthritis in nimal model. Brazilian Journal of Pharmaceutical Sciences. 2016; 52(3): 493 – 507.
24. Doaa A. Helal, Dalia ABD EL-Rhman, Sally A. Abdel-Halim and Mohamed A. ElNabarawi. Formulation and evaluation of fluconazole topical gel. Int. J Pharmacy Pharmaceu. Sci., 2012; 4(Suppl 5): 176 – 183.
25. Japan Patel, Brijesh Patel, Hardeep Singh Banwait, Kaushal Parmar and Manish Patel. Formulation and evaluation of topical aceclofenac gel using different gelling agent. Int. J. Drug Dev. & Res., 2011; 3(1): 156 – 164.
26. https://en.wikipedia.org/wiki/Mequinol
27. https://pubchem.ncbi.nlm.nih.gov/compound/Mequinol
28. https://en.wikipedia.org/wiki/Chitosan