In-situ gel for oral drug administration: addressing polymers and stability issues

Abstract

The In-situ polymeric formulation is a drug delivery system that forms a gel upon water absorption at the site of administration. This article provides a comprehensive overview of formulation design, polymer selection, and stability challenges associated with oral In-situ gels. Despite significant advancements, key challenges persist, including premature gelation, variability in polymer performance, drug-polymer incompatibility, and drug sensitivity to physiological conditions such as pH and temperature, which may compromise formulation, stability, and reproducibility. A comparative perspective indicates that natural polymers, such as pectin, sodium alginate, and chitosan, offer superior biocompatibility but suffer from batch-to-batch variability and lower mechanical strength, whereas synthetic polymers, such as carbopol and poloxamer, provide better structural control and stability but may pose toxicity and biodegradability concerns. Semi-synthetic polymers serve as intermediate options but remain sensitive to environmental conditions. Drug selection criteria, based on the BCS classification, solubility, absorption site, and safety, are also explored to guide the development of effective formulations. Future prospects suggest that integrating nanotechnology, hybrid polymer systems, and advanced fabrication techniques such as 3D printing, along with improved standardization and real-time stability assessment, will be essential to overcoming existing limitations and enhancing the clinical applicability of oral In-situ gel systems.

Introduction

Gel is a state that lies between the liquid and solid states. Oral In-situ gels are an innovative drug delivery system that converts from a liquid to a gel upon administration, utilizing physiological conditions such as pH changes, temperature variations, or the presence of specific ions. Oral In-situ gels may be employed as solutions or suspensions and undergo rapid sol-to-gel transformations upon activation by stimuli such as pH changes, temperature modulation, solvent exchange, UV irradiation, and the presence of specific molecules or ions[1,2]. The preparation of in-situ oral gels involves various techniques, including thermal gelation, pH-triggered gelation, ionic crosslinking, and solvent exchange. Each of these methods offers distinct advantages in tailoring the gel’s properties to meet specific therapeutic needs[3]. Natural polymers are widely used in these formulations for their compatibility with biological systems and their ability to degrade naturally. Common examples of these polymers include sodium alginate, pectin, chitosan, and gellan gum. The selection of these polymers is based on their gelling properties and compatibility with the administered medication[4].

Oral In-situ gels may incorporate a diverse range of medications, including analgesics, antacids, antibiotics, and antidiabetics. The selection of suitable medications involves considering factors such as solubility, stability within the gel matrix, preferred release profiles, and the overall safety and efficacy of the substances[5]. The Biopharmaceutical Classification System (BCS) plays a vital role in evaluating the suitability of medications. For instance, BCS Class I drugs, distinguished by high solubility and permeability, are ideal candidates for this delivery approach. In contrast, Class II medications, known for poor solubility, and Class IV drugs, which exhibit both low solubility and permeability, present challenges related to absorption[6]. Challenges in formulation include achieving the ideal viscosity to facilitate smooth flow prior to gelation, reducing gelling time to enhance patient comfort, and ensuring consistent medication distribution throughout the gel matrix. Addressing stability concerns is crucial, since Environmental factors such as temperature, humidity, and pH fluctuations can compromise the structural integrity and rheological properties of the gel matrix[7]. Additionally, chemical interactions between the medication and the polymer may cause deterioration[8].

To ensure quality and effectiveness, oral In-situ gels are evaluated based on characteristics such as viscosity, gelation time, in vitro drug-release profiles, mechanical properties, and stability. This innovative combination holds promise for enhancing patient adherence and treatment outcomes in medication delivery systems[9]. Petitjean et al. emphasized the significance of pH-sensitive and thermoresponsive polymers in the advancement of oral In-situ gels. The authors highlighted the importance of employing natural and semi-synthetic polymers, such as pectin and gellan gum, due to their compatibility with biological systems. Nonetheless, the conversation also addressed the challenges of maintaining stability over extended periods, given that polymers are prone to degradation at the pH levels found in the stomach[10].

Shaikh et al. present a detailed examination of In-situ gel systems, emphasizing important polymers including gellan gum, xanthan gum, chitosan, pectin, and carrageenan. The authors explain how changes in pH and the presence of ions serve as physiological signals that initiate the sol-to-gel transition, which is essential for oral delivery. The review emphasizes the stability challenges associated with polymers, particularly the fluctuations in stomach pH that may lead to premature gelation or degradation. It also discusses how enzyme activity influences the breakdown of polymer chains and highlights batch-to-batch inconsistencies that may affect gel formation and drug release[11].

Kurniawansyah et al. conducted a comprehensive and comparative analysis of In-situ gel formulations, focusing on how physicochemical parameters such as pH, temperature, and ionic strength influence gel formation and the rate of drug release in oral delivery systems. Their research indicated that pH-sensitive polymers, such as gellan gum, together with temperature- or ion-responsive systems, could play a crucial role in the sol-to-gel transition in the gut. The review examined stability concerns, including polymer degradation at different acidic pH levels, deterioration of mechanical integrity in gastric fluid, and inconsistencies in gel strength across batches[12].

Verma et al. present a detailed examination of the polymers utilized in In-situ gel systems for oral drug delivery, emphasizing both natural components such as pectin, gellan gum, and chitosan, as well as semi-synthetic components including Carbopol, HPMC, and poloxamer. The study examines the influence of key factors, including variations in pH, temperature, and ion concentrations, on the sol-to-gel transition, a process that plays a crucial role in drug release within the gastrointestinal tract. The authors emphasize that factors such as stomach acidity, enzymatic degradation, and interactions between polymers and excipients can lead to stability challenges that may compromise the integrity and consistency of the gel[13].

The liquid formulation will be transformed into a semi-solid mucoadhesive key depot and an In-situ gel. In-situ gel is a semi-solid dosage form that is a unique approach for delivering medicines to patients and aims to achieve prolonged release of medication for the desired period. Various polymer-based delivery systems will be formulated. This may increase the residence time in the area of drug absorption. Furthermore, its ability to adhere to mucous membranes will prevent it from being removed by saliva in the oral cavity[14]. In-situ gels are a promising class of medication delivery devices because they can deliver drugs in a targeted and sustained manner within the mouth cavity. When delivered In-situ, gels convert from a liquid to a gel, which isconsistent with physiological conditions, unlike conventional dosage forms. These formulations have garnered tremendous attention in the biomedical fields, particularly in drug carriers, proteins, and cells, as well as in other applications, because of their excellent biocompatibility, solute permeability, and customizable release profiles. Their ability to store a large amount of water within their frameworks gives them the quality that distinguishes them: high water content and soft surface properties. This results in high biocompatibility of the surrounding tissues[1,15,16].

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Table 4. A application of oral In-situ gels/Other In-situ formulations.

Anuj Kumar, Phool Chandra, Anurag Verma, Sushil Bhargav, Abhinay Kumar Dwivedi, Arun Kumar, Prakhar Varshney & Neetu Sachan (05 Jun 2026): In-situ gel for oral drug administration: addressing polymers and stability issues, International Journal of Polymeric Materials and Polymeric Biomaterials, DOI: 10.1080/00914037.2026.2678950

Read also our introduction article on Alginate here: