In Situ Gelling System: A Comprehensive Review
Khemnar Ashwini*, Kote Rupali Balasaheb, Jadhav Ravindra S., Mule Asmita, Jinat Maniyar, Khetmalis Aditya, Monika Magar, Nikita Borse
Department of Pharmaceutics, Pravara Rural Education Society's Institute of Pharmacy, Loni, M.S., India.
*Corresponding Author E-mail:
ABSTRACT:
In situ gelling systems are an innovative class of drug delivery formulations that undergo a sol-to-gel phase transition under physiological conditions, such as temperature, pH, or ionic strength, at the site of administration. These systems are administered as low-viscosity liquids, which transform into semi-solid gels upon exposure to specific stimuli, thereby providing prolonged residence time, sustained drug release, and enhanced bioavailability. This unique property makes them particularly suitable for ocular, nasal, oral, buccal, vaginal, rectal, dermal, and injectable routes, where conventional dosage forms often suffer from rapid clearance, low absorption, or poor patient compliance. Various stimuli-responsive polymers, including thermosensitive, pH-sensitive, and ion-activated polymers, enable precise gel formation and controlled drug release. Preparation methods include temperature-triggered, pH-triggered, ion-activated, enzyme-responsive, dual/multi-stimuli responsive systems, and techniques such as spray-drying or freeze-drying. Evaluation parameters for these systems include visual clarity, pH, gelling capacity, viscosity, rheology, drug release, permeability, irritation, histological safety, sterility, and stability. Marketed formulations like Timoptic-XE®, Pilopine HS® Gel, and NasoGel® demonstrate their clinical utility. Recent advances focus on biodegradable polymers, nanocarrier integration, and tissue engineering applications. In situ gelling systems offer a versatile, patient-friendly platform for localized and systemic drug delivery, representing a promising approach to enhance therapeutic efficacy, reduce dosing frequency, and improve overall patient compliance in modern pharmaceutics.
KEYWORDS: Sol to Gel, InSitu Gelling, Thermosensitive, Occular, Sustained release
Drug delivery is a rapidly evolving field that focuses on the development of formulations capable of delivering therapeutic agents effectively, safely, and conveniently to achieve optimal therapeutic outcomes.1 Among the various novel drug delivery approaches, in situ gelling systems have gained significant attention due to their unique ability to undergo a sol-to-gel phase transition under physiological conditions at the site of administration.
This transition results in the formation of a gel that sustains drug release, prolongs the residence time of the formulation, and improves bioavailability and patient compliance.2 These systems have emerged as promising platforms for controlled, localized, and sustained drug delivery across a wide range of administration routes including ocular, nasal, oral, vaginal, rectal, and injectable routes.3-5
The term “in situ” means “in its original place” or
“on-site.” Therefore, an in situ gelling system refers to a formulation that is
administered as a solution or sol but converts to a gel when it encounters
specific physiological conditions such as body temperature, pH, or ionic
concentration.6-9 This conversion occurs through physicochemical
changes within the polymeric system that lead to cross-linking and formation of
a semi-solid gel network.10 The gel formed acts as a drug reservoir,
releasing the therapeutic agent in a controlled or sustained manner, thereby
enhancing its therapeutic efficacy and reducing the frequency of
administration.11
Need for In Situ Gelling Systems:
Conventional dosage forms such as eye drops, nasal sprays, or oral liquids often suffer from limitations such as poor retention time, rapid clearance from the site of action, and low bioavailability. For instance, in ophthalmic delivery, conventional eye drops show less than 5% drug absorption due to drainage through the nasolacrimal duct, tear turnover, and poor corneal permeability. Similarly, in nasal delivery, mucociliary clearance limits the contact time of drugs with the nasal mucosa, thereby reducing absorption. To overcome these limitations, researchers developed in situ gelling systems that can form gels upon administration and remain in contact with the mucosa or tissue for extended periods.12
The in situ gelling approach ensures that the formulation remains a low-viscosity liquid during administration, allowing for easy handling and precise dosing. Once it comes into contact with the body environment, it transforms into a high-viscosity gel due to a change in temperature, pH, or ionic concentration.13-15 This dual behavior offers a combination of convenience during administration and prolonged therapeutic action afterward, making it an ideal platform for sustained release formulations.16
The concept of in situ gelling systems evolved from early gel formulations that had limitations such as poor residence time and patient discomfort. In the 1980s, the emergence of “smart polymers” capable of sol-to-gel transitions based on environmental changes marked the foundation of in situ gel systems. By the 1990s, ocular delivery applications were established, with gellan gum-based systems improving drug retention in the eye. During the 2000s, applications expanded to nasal, oral, rectal, and injectable routes. The 2010s saw advances in biodegradable and mucoadhesive polymers, while the 2020s have focused on precision, patient-specific formulations using 3D printing and biopolymers.17
ADVANTAGES:
1. Ease of administration: The liquid form allows for convenient and pain-free administration.
2. Prolonged retention: The gel formed increases the residence time at the site of action.
3. Controlled drug release: The gel matrix acts as a barrier, enabling sustained or controlled release.
4. Improved bioavailability: Prolonged contact enhances drug absorption and bioavailability.
5. Reduced dosing frequency: Sustained release minimizes the need for repeated administration.18-20
DISADVANTAGES:
1. Formulation complexity:
Precise optimization of polymer concentration and trigger conditions (pH, temperature, ions) is required to ensure reproducible gelation.
2. Variable gelation behavior:
Differences in physiological conditions among patients (e.g., tear pH, temperature, ion content) may lead to inconsistent gel formation.
3. Limited drug loading capacity:
High polymer viscosity or network density can restrict drug incorporation and diffusion.
4. Initial burst release:
A rapid drug release may occur before complete gelation, affecting controlled-release profiles.
5. Viscosity-related discomfort:
Highly viscous gels can cause blurred vision (in ocular use), irritation, or difficulty in application.
6. Potential local irritation or toxicity:
Some polymers or cross-linking agents may irritate mucosal tissues or cause allergic reactions.
7. Sterilization difficulties:
Heat-sensitive polymers may degrade during autoclaving, complicating sterilization procedures.
8. Stability issues:
Long-term storage may alter polymer properties, viscosity, and drug release behavior.
9. Scale-up challenges:
Maintaining uniform gelation and polymer consistency at industrial scale can be difficult.
10. Limited mechanical strength:
Some in situ gels may exhibit weak gel structure, leading to premature erosion or leakage.
11. Drug-polymer compatibility:
Interactions between active ingredients and polymers may affect stability or therapeutic efficacy.21-22
PREPARATION METHODS OF IN SITU GELLING SYSTEM:
1. Temperature-Triggered Gelation:
Thermosensitive polymers remain in a sol state at low temperatures and form gels at body temperature (around 37°C). Polymers such as Poloxamers (Pluronics), poly(N-isopropyl acrylamide) (PNIPAAm), and methylcellulose exhibit this property. When these formulations are administered, they undergo micellar rearrangement or polymer network formation due to hydrophobic interactions, leading to gel formation.23
Figure 1: Temperature-Triggered Gelation
2. pH-Triggered Gelation:
pH-sensitive polymers respond to changes in the environmental pH by ionization or neutralization of their functional groups, resulting in sol-to-gel transition. For example, Carbopol forms a gel when the pH increases from acidic (formulation pH) to near-neutral values (physiological pH). Chitosan, a natural polymer, gels in slightly basic environments due to the deprotonation of its amino groups.
Figure 2: pH-Triggered Gelation
3. Ion-Activated Gelation:
Ionic-sensitive systems form gels upon contact with multivalent cations such as Na⁺, Ca²⁺, or Mg²⁺ present in physiological fluids. Polymers like gellan gum (Gelrite®) and sodium alginate exhibit ion-induced gelation. In ocular applications, for instance, the presence of tear fluid ions induces gelation of the formulation upon instillation.24
Figure 3: Ion-Activated Gelation
4. Enzyme-Triggered Gels:
Combine polymers with enzyme substrates that respond to specific tissue enzymes (e.g., transglutaminase with gelatin).Gelation occurs at the site where target enzymes are present, forming a local depot.
5. Dual or Multi-Stimuli Responsive Gels:
Combine polymers responsive to two or more stimuli (e.g., temperature + pH, pH + ions).Gelation occurs only when both conditions are met, enhancing site-specificity and control over release.
6. Spray-Drying and Freeze-Drying Methods (Optional for Solid Formulations):
Polymers and drugs are dissolved or dispersed, then dried to form powders. Rehydration in physiological fluids leads to gel formation.25
1. Ocular Drug Delivery:
Used to enhance ocular residence time and bioavailability by forming gels in contact with tear fluid.
2. Nasal Drug Delivery:
Facilitates brain-targeted and systemic delivery by prolonging nasal mucosal contact time.
3. Oral Drug Delivery:
Enables controlled and sustained drug release through gelation in the gastrointestinal tract.
4. Buccal Drug Delivery:
Provides rapid systemic absorption and avoids hepatic first-pass metabolism via buccal mucosa adhesion.
5. Vaginal Drug Delivery:
Ensures localized, prolonged release of antifungal or contraceptive drugs with improved patient compliance.
6. Rectal Drug Delivery:
Offers sustained and leakage-free local or systemic delivery, suitable for pediatric and geriatric patients.
7. Parenteral (Injectable) Drug Delivery:
Forms depot-type gels post-injection for long-term, controlled systemic or localized drug release.
8. Dermal and Transdermal Delivery:
Delivers drugs through the skin for wound healing, pain relief, or anti-inflammatory therapy.
9. Periodontal Drug Delivery:
Provides localized, sustained antibiotic release directly into periodontal pockets for infection control.
10. Biomedical and Tissue Engineering Applications:
Used as injectable scaffolds for tissue regeneration, wound healing, and localized therapeutic delivery 26
1. Visual Appearance and Clarity: Ensures the formulation is clear, transparent, and free from particulate matter.
2. pH Measurement: Confirms the pH is within physiological range to avoid irritation and maintain stability.
3. Gelling Capacity: Evaluates the ability of the sol to form a stable gel under physiological conditions.
4. Isotonicity: Checks osmotic balance to prevent irritation of ocular or nasal tissues.
5. Viscosity and Rheology: Assesses flow behavior before and after gelation to ensure suitable consistency.
6. Texture Analysis: Determines gel firmness, spreadability, and patient acceptability.
7. In Vitro Drug Release: Measures the rate and extent of drug diffusion through the gel matrix.
8. Gel Strength: Evaluates the mechanical strength and structural integrity of the formed gel.
9. Drug Content Uniformity: Ensures even drug distribution throughout the formulation.
10. Transcorneal or Mucosal Permeability: Determines drug diffusion across biological membranes for absorption prediction.
11. Ocular Irritation Studies: Assesses eye safety using tests like HET-CAM or Draize methods.
12. Histopathological Examination: Examines tissue sections to confirm biocompatibility and absence of damage.
13. Sterility Testing: Verifies that the formulation is free from microbial contamination.
14. Stability Studies: Determines product stability and shelf life under ICH-specified conditions.
15. Scintigraphy or Gamma Scintigraphy: Tracks in vivo residence time and gel localization using radiolabeled formulations.27-28
Examples include Timoptic-XE® (timolol maleate), Pilopine HS® Gel (pilocarpine), NasoGel®, Ciprodex®, and Lacrisert®, which utilize various gelling triggers to achieve sustained release and improved patient compliance.29
Recent studies highlight applications in ocular delivery, bone tissue engineering, and cancer therapy. Thermosensitive and biodegradable hydrogels are used for localized and sustained drug release, tissue regeneration, and targeted cancer therapy. Integration of nanocarriers, biodegradable polymers, and dual-trigger systems represents the next generation of in situ gelling technologies.
In situ gelling systems represent a significant step forward in controlled and patient-friendly drug delivery. Their ability to transition from sol to gel in response to physiological stimuli enables localized and sustained therapy, enhancing drug efficacy and compliance. Continued research into smart polymers, biodegradable materials, and nanotechnology integration will further expand their therapeutic potential in modern pharmaceutical science.
REFERENCES:
1. Bhagat BV, Hapse SA, Mane AR, Pagar HJ, Wagh VS. Development of ophthalmic in situ gelling formulation of ciprofloxacin hydrochloride using gellan gum. Research Journal of Pharmacy and Technology. 2011; 4(11):1742-1745.
2. Jayant D, Shah B, Anil B. Design and development of pH-monitored in situ gel of lomefloxacin. Journal of Pharmaceutical Science and Bioscientific Research. 2013; 3(2):10-15.
3. Harsha Vardhani Kondepati, Girish Pai Kulyadi, Vamshi Krishna Tippavajhala. A Review on In Situ gel forming ophthalmic drug delivery systems. Research J. Pharm. and Tech. 2018; 11(1): 380-386.
4. Choudhary NG, Syed AM, Kale VV, Avari JG. Oral sustained release in situ gel forming polymeric drug delivery systems. Research Journal of Pharmacy and Technology. 2010; 3 (3): 682-687.
5. Swapnil D, Sonawane, Swaroop L. Design and evaluation of ion induced in situ gel formulation for levofloxacin hemihydrateocular delivery. International Journal of Pharmaceutical Science Invention. 2014; 3(3):38-43.
6. Prerana V, Asmita S, Sudha R. Microspheric in-situ gel for ocular drug delivery system of bromfenac sodium. International Journal of Pharmaceutical Sciences and Research. 2014; 5(3):179-185.
7. Shinde, G. S., Jadhav, R., Vikhe, D., & Kote, R. B.Development and evaluation of herbal fast disintegrating tablet of Achyranthes aspera linn root extract. Asian Journal of Pharmacy and Technology, 2024:14(2), 119-122.
8. Shinde GS, Rao PS, Jadhav RS, Kolhe P, Athare D. A review on chromatography and advancement in paper chromatography technique. Asian Journal of Pharmaceutical Analysis. 2021; 11(1):45-8
9. Nisha G Shetty and Charyulu RN. Phase transition ocular drug delivery system for antazoline phosphate. International Journal of Drug Formulation and Research. 2012; 3(1); 27-39.
10. Baladaniya M, Vadgama N, Patel P. Gastro retentive in situ floating gel formulation – an overview. Research Journal of Pharmaceutical Dosage Forms and Technology.2014; 6(2):140-145.
11. Tanvi PP, Moin KM, Vishnu MP. Sustained ophthalmic delivery of ciprofloxacin hydrochloride from an ion-activated in situ gelling system. Der Pharmacia Lettre. 2011; 3(4):404-410.
12. Shinde G, Godage RK, Jadhav RS, Manoj B, Aniket B. A Review on Advances in UV Spectroscopy. Research Journal of Science and Technology. 2020; 12(1):47-51.
13. Godge RK, Shinde GS, Joshi S. Simultaneous Estimation and Validation of Dapagliflozin and Saxagliptin in Bulk Drug and Dosage Form by RP-HPLC. Research Journal of Science and Technology. 2019; 11(1):59-63.
14. NS Malekar, SB Gondkar, RB Saudagar. In- situ nasal gel: a review. Research Journal of Pharmaceutical Dosage Forms and Technology. 2015; 7(4): 285-293.
15. Prasanth VV, Della GT, Shashi R. Formulation and evaluation of in situ ocular gel of levofloxacin. Journal of Drug Delivery and Therapeutics. 2017; 7(4):68-73.
16. Mahdi ZH, Maraie NK, Amer ZA. Application of liquisolid technology to enhance the dissolution of cefixime from its oral capsules. International Journal of Applied Pharmaceutics. 2018; 10(5): 214-219.
17. Gupta SK, Singhvi IJ. In situ gelling system and other possible innovative approach for ocular disease: a review. Research Journal of Pharmacy and Technology. 2011; 4(6): 872-882.
18. Sandeep DS, Narayana CR, Anoop NV. Smart in situ gels for glaucoma- an overview. International Journal of Pharmaceutical Sciences Review and Research. 2018; 50(4):94-100.
19. Mahdi ZH, Maraie NK. Overview on nanoemulsion as a recently developed approach in drug nanoformulation. Research Journal of Pharmacy and Technology. 2019; 12(11): 1-7.
20. Shinde GS, Jadhav RS, Kote RB, Kadam AJ, Bankar AA. Bioanalytical Method Development and Validation of UV Spectrophotometric Method for Estimation of Metformin Hydrochloride in Urine Sample. Asian J Res Chem. 2024; 17(2):93–6. doi: 10.52711/0974-4150.2024.00019
21. Shinde, G. S , Jadhav R S, Tambe V B , Kote R B .RP-HPLC Method Development and Validation of Lamivudine, Zidovudine and Nevirapine in Bulk and Dosage form using UV Detector." Research Journal of Pharmacy and Technology 17.10 (2024): 5011-5015
22. Makwana SB, Patel VA, Parmar SJ. Development and characterization of in-situ gel for ophthalmic formulation containing ciprofloxacin hydrochloride. Results in Pharma Sciences. 2016; 6(2):1-6.
23. Reeshanteni B, Abdullah K, Rajermani T. Formulation of in-situ gelling system for ophthalmic delivery of erythromycin. International Journal of Students Research in Technology and Management. 2017; 5(1):1-8.
24. Mundhada DR, Chandewar AV. An overview on in-situ gel. Research Journal of Pharmaceutical Dosage Forms and Technology. 2015; 7(4): 261-265.
25. Sonjoy M, Manjunath KM, Thimmasetty J, Prabhushankar GL, Geetha MS. Formulation and evaluation of an in situ gel-forming ophthalmic formulation of moxifloxacin hydrochloride. International Journal of Pharmaceutical Investigation. 2012; 2(2): 78-82.
26. Gupta SK, Singhvi IJ. Sustained ophthalmic delivery of moxifloxacin hydrochloride from a pH triggered in situ gelling system. Research Journal of Pharmacy and Technology. 2012; 5(12):1538-1542.
27. Nagesh C, Manish P, Chandrashekhara S, Rahul S. A novel in situ gel for sustained ophthalmic delivery of ciprofloxacin hydrochloride and dexamethasone- design and characterization. Der Pharmacia Lettre. 2012; 4(3): 821-827.
28. Vazir AA, Shiv Kumar HG, Paranjothy KLK, Mohd K. Ophthalmic drug delivery of diclofenac potassium from different polymer formulations: in situ sol gels. Research Journal of Pharmaceutical Dosage Forms and Technology. 2009; 1(2): 158-161.
29. S wadghane, Rohit Bhor, Shinde Ganesh.A review on some biological activities of Hyantion Derivative.2023; 13(1):173-178
|
Received on 23.10.2025 Revised on 19.11.2025 Accepted on 10.12.2025 Published on 20.01.2026 Available online from January 27, 2026 Asian J. Pharm. Tech. 2026; 16(1):105-109. DOI: 10.52711/2231-5713.2026.00015 ©Asian Pharma Press All Right Reserved
|
|
|
This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License. Creative Commons License. |
|