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In situ gelling polymeric drug delivery system

Dr Pradnya Palekar Shanbhag, Associate Professor in Pharmaceutics, Department of Pharmaceutics and Prajal P. Pandhare, Vivekanand Education Society’s College of Pharmacy talk about in situ gel forming systems and how these are used in various biomedical applications including drug delivery

Dr Pradnya Palekar Shanbhag Prajal P. Pandhare

In the past few years, increasing number of in situ gel forming systems have been investigated and many patents for their use in various biomedical applications including drug delivery have been reported. This interest has been sparked by the advantages shown by in situ forming polymeric delivery systems such as ease of administration and reduced frequency of administration, improved patient compliance and comfort, also capable of releasing the drug in a sustained manner maintaining relatively constant plasma profile. These systems are liquid at room temperature but undergo gelation once administered. These have a characteristic property of temperature dependence, pH dependence and cation induced gelation. In situ gels are administered by oral, ocular, rectal, vaginal, injectable and intra-peritoneal routes. Both natural and synthetic polymers can be used for the production of in situ gels. Recent advances in in situ gels have made it possible to exploit the changes in physiological uniqueness in different regions of the GI tract for the improved drug absorption as well as patient’s convenience and compliance.

Approaches for in situ gelling polymeric drug delivery system

1) Physiological stimuli approach

  1. Temperature induced in situ gel system: The use of biomaterial whose transitions from sol-gel is triggered by increase in temperature is an attractive way to approach in situ formation. The ideal critical temperature range for such system is ambient and physiologic temperature. In this system, gelling of the solution is triggered by change in temperature, thus sustaining the drug release. These hydrogels are liquid at room temperature (20 –25°C) and undergo gelation when in contact with body fluids (35 – 37°C), due to an increase in temperature.
  2. pH induced in situ gel systems: Another formation of in situ gel based on physiologic stimuli is formation of gel is induced by pH changes. All the pH-sensitive polymers contain acidic or basic groups that either accept or release protons in response to changes in environmental pH. Swelling of polymer increases as the external pH increases in the case of weakly acidic (anionic) groups also known as polyacids, but decreases if polymer contains weakly basic (cationic) groups termed as polybases.

2) Physical change in biomaterial approach

  1. Swelling mechanism: In situ formation may also occur when material absorbs water from surrounding environment and expand to occur desired space. One such substance is myverol 18-99 (glycerol mono-oleate), which is polar lipid that swells in water to form lyotropic liquid crystalline phase structures.
  2. Diffusion mechanism: This method involves the diffusion of solvent from polymer solution into surrounding tissue and results in precipitation or solidification of polymer matrix. N- methylpyrrolidone (NMP), dimethyl sulfoxide (DMSO), tertahydrofuran, 2-pyrrolidone and triacetin has been shown to be useful solvents for such system.

3) Chemical reaction approach

  1. Ionic crosslinking: Certain ion sensitive polysaccharides such as carrageenan, gellan gum (Gelrite), pectin, sodium alginate undergo phase transition in presence of various ions such as K+, Ca2+, Mg2+, Na+. These polysaccharides fall into the class of ion-sensitive ones.
  2. Photo-polymerisation: A solution of monomers or reactive macromer and initiator can be injected into a tissues site and application of electromagnetic radiation used to form gel. Acrylate or similar polymerizable functional groups are typically used as the polymerizable groups on the individual monomers and macromers because they rapidly undergo photopolymerisation in the presence of suitable photo initiator. Photopolymerizable systems when introduced to the desired site via injection get photocured in situ with the help of fibre optic cables and then release the drug for prolonged period of time.
  3. Enzymatic cross-linking: In situ formation catalysed by natural enzymes has not been investigated widely but seems to have some advantages over chemical and photochemical approaches. For example, an enzymatic process operates efficiently under physiologic conditions without need for potentially harmful chemicals such as monomers and initiators. Intelligent stimuli-responsive delivery systems using hydrogels that can release insulin have been investigated.
Marketed product Active ingredient Use
Atridox 8.5% doxycycline Periodontal treatment with subgingival delivery
Atrisorb D 4% doxycycline Periodontal tissue regeneration
Eligard Leuprolide acetate Treatment of Prostate cancer
Sandostatin Octreotide Treatment of Acromegaly

Polymers for In Situ gelling polymeric drug delivery system

  • Thermosensitive polymers: Cellulose derivatives, Poloxamer, Poly(ethylene oxide) / Poly(D, L-lactic acid -coglycolic acid)
  • pH sensitive polymers: Carbopol, Cellulose acetophalate latex
  • Ionic crosslinking polymers: Pectin, Alginic acid, Gellan gum


1) In situ forming drug delivery system for parenteral administration

Controlled parenteral systems used in drug delivery are implants, microspheres and liposomes. These suffer from limitations such as implants need surgical implantation, microspheres for parenteral delivery have complex manufacturing process and on other hand liposomes have high production cost and drug leakage is a problem.

Injectable in situ gel forming drug delivery system represents an attractive alternative to microspheres and implants as parenteral depot systems and has following advantages over conventional parenteral system:

  • Less invasive technique: The application is less invasive and less painful compared to implants.
  • Direct delivery to a target area: This helps in achieving higher drug concentration at the desired site of action to minimise systemic side effects.
  • Biodegradable and biocompatible: Injectable in situ system is made of biodegradable polymers and biocompatible solvents and therefore do not require removal.
  • Economic factors: Operating expenses for the production of in situ forming applications are marginal, thus lowering investment and manufacturing costs.

Atrigel system

The formulation of these systems includes dissolution of water insoluble biodegradable polymer into a biocompatible solvent. The drug is then added to the solution where it dissolves or forms a suspension. This drug and polymer mixture is then easily and conveniently injected into the body where it forms a solid implant inside the tissue. Most commonly used polymers are poly (dl-lactide), lactide/glycolide copolymers and lactide / caprolactone copolymers because of their degradation characteristics. The solvents employed in the Atrigel system includes dimethyl sulfoxide, N-methyl-2-pyrrolidone (NMP), tetraglycol and glycolfurol to more hydrophobic solvents such as propylene carbonate, triacetin, ethyl acetate. When this formulation is injected into the body the water miscible organic solvent dissipates and water penetrates into the organic phase. This leads to phase separation and precipitation of the polymer forming a depot at the site of injection.

2) In situ forming drug delivery system for ocular administration

Conventional ocular drug delivery systems used are eye drops, eye gels, eye ointments suffer from poor bioavailability due to tear production, transient residence time, impermeability of corneal epithelium, binding to the lachrymal proteins and problem like blurring of vision.

The poor bioavailability  and therapeutic response  exhibited by conventional ophthalmic solutions due to rapid precorneal elimination of the drug may be overcome by the use of a gel system instilled as drops  into the eye and undergo a sol-gel transition in the cul­de­sac. For in situ gel based ocular delivery, natural polymers such as gellan gum, alginic acid and xyloglucan are most commonly used polymers. Local ophthalmic drug delivery has been used for various compounds such as antimicrobial agents, anti-inflammatory agents and autonomic drugs used to relieve intraocular tension in glaucoma.

Case studies

1) In situ forming drug delivery system for oral administration

Pectin, xyloglucan and gellan gum are the natural polymers used for in situ forming oral drug delivery systems. The potential of an orally administered in situ gelling pectin formulation for the sustained delivery of paracetamol has been reported. The main advantage of using pectin for these formulations is that it is water soluble, so organic solvents are not necessary in the formulation. In situ gelling gellan formulation as vehicle for oral delivery of theophylline is reported. The formulation consisted of gellan solution with calcium chloride and sodium citrate complex. When administered orally, the calcium ions are released in acidic environment of stomach leading to gelation of gellan thus forming a gel in situ. An increased bioavailability with sustained drug release profile of theophylline in rats and rabbits was observed from gellan formulations as compared to the commercial sustained release liquid dosage form.

2) In situ forming drug delivery system for nasal administration

An in situ gel system for nasal delivery of mometasone furoate was developed and evaluated for its efficacy for the treatment of allergic rhinitis. Gellan gum and xanthan gum were used as in situ gel forming polymers. Animal studies were conducted using an allergic rhinitis model and the effect of in situ gel on antigen induced nasal symptoms in sensitised rats was observed. In situ gel was found to inhibit the increase in nasal symptoms as compared to marketed formulation nasonex (mometasonefuroate suspension 0.05 per cent). Intact ciliated respiratory epithelium and normal goblet cell appearance indicated from histopathology of rat nasal cavity proved that these formulations were safe for nasal administration. Thermoreversible gel formulations of flunarizine hydrochloride for improved drug residence time in the nasal cavity have been investigated. The formulations so prepared were in the liquid state at 4°C but turned into a gel at the temperature of the nasal cavity. Poloxamer 407 was used as the polymer which exhibited the phase transition behaviour. Inclusion complexes using ß-cyclodextrin were prepared for increasing the solubility of flunarizine in nasal secretion. The prepared formulations were characterised for drug loading, content uniformity, in vitro drug diffusion, bioadhesion strength, gel strength, viscosity and gelation point. The formulations exhibited drastic increase in the viscosity at the temperature of 37°C indicating their possible use as in situ gelling systems. Out of all the formulations studied, the ß-cyclodextrin formulations shows the fastest release, possibly due to increase in the solubility and dissolution rate of flunarizine hydrochloride.

3) In situ forming drug delivery system for rectal and vaginal administration

In situ gels also possess a potential application for drug delivery by rectal and vaginal route. Miyazaki et al. investigated the use of xyloglucan based thermoreversible gels for rectal drug delivery of indomethacin. Administration of indomethacin loaded xyloglucan based systems to rabbits indicated broad drug absorption peak and a longer drug residence time as compared to that resulting after the administration of commercial suppository. For a better therapeutic efficacy and patient compliance, mucoadhesive, thermosensitive, prolonged release vaginal gel incorporating clotrimazole-ß-cyclodextrin complex was formulated for the treatment of vaginitis. In addition, a significant reduction of drug Cmax was observed after administration of in situ polymeric system thus indicating the avoidance of adverse effects of indomethacin on nervous system.

Marketed products of Ocular In Situ gelling system

  • Timoptic-XE: Timolol maleate ophthalmic gel formulation of Merck and Co Inc, supplied as a sterile, isotonic, buffered, aqueous gel forming solution of timolol maleate.
  • AzaSite: Marketed product of InSite Vision. AzaSite is a topical ophthalmic solution of azithromycin formulated in DuraSite (polycarbophil, edetate disodium, sodium chloride).
  • Akten: HPMC based gel of lidocaine hydrochloride for ocular surface anesthesia. Akten also contains hypromellose, sodium chloride, and purified water as inactive ingredients.


With the advent of novel delivery systems, various drug molecules have been revived of their therapeutic and commercial benefits. The introduction of in situ gelling systems has further strengthened the link between therapeutic need and drug delivery. The primary requirement of a successful controlled release product focuses on increasing patient compliance which the in situ gels offer. Sustained and prolonged release of the drug, good stability and biocompatibility characteristics make the in situ gel dosage forms very reliable. Use of biodegradable and water soluble polymers for the in situ gel formulations can make them more acceptable and excellent drug delivery systems. Moreover in situ gels have ease of commercialisation which is added advantage from industrial point of view.


  1. Nirmal H.B, Bakliwal S.R, Pawar S.P; In Situ gel: New Trend in Controlled and Sustained Drug Delivery System, International Journal of Pharm Tech Research April-June 2010 Vol. 2 Pg. 1398-1408.
  2. Vyas Jigar et al; A Review On In Situ Polymeric Drug Delivery System, International Journal Of Pharmaceutical Research And Development (IJPRD), July 2011 Vol. 3(5) pg.53-59.
  3. Madan, et al In Situ Forming Polymeric Drug Delivery Systems; Indian Journal of Pharmaceutical Sciences May-June 2009 pg. 242-251.
  4. Aman Kant et al, In situ Gelling system-An Overview, Pharmacology online 2011 pg. 28-44.
  5. Kulkarni S.S, Aloorkar N.H; Smart polymers in drug delivery: An overview, Journal of Pharmacy Research Vol. 3 January 2010 pg 100-108.
  6. M. R. Aguilar et al, Smart Polymers and Their Applications as Biomaterials, Topics in Tissue Engineering Vol. 3, 2007, pg 1- 22.
  7. Shaikh R G et al; A Review on Polymers Used in In Situ Drug Delivery Systems, International Journal for Pharmaceutical Research Scholars, Vol.1 2012 Pg.17-31.
  8. Eve Ruel-Gariepy, Jean-Christophe Leroux; In Situ forming hydrogels-review of temperature sensitive systems, European Journal of Pharmaceutics and Biopharmaceutics, 2004 pg. 409-426.
  9. C.B. Packhaeuseret al; In Situ forming parenteral drug delivery system: An overview, European Journal of Pharmaceutics and Biopharmaceutics, 2004 pg 445-455.
  10. Kullwany Singh, S.L Harikumar; Injectable In situ gelling controlled release drug delivery system, International Journal of Drug Delivery And Research Vol. 4 April-June 2012 pg 56-69.
  11. N G N Swamy, Zaheer Abbas; Mucoadhesive In Situ gel as nasal drug delivery system: an overview, Asian Journal of Pharmaceutical Sciences 2012(3) pg 168-180.
  12. K S Rathore; In Situ Gelling Ophthalmic Drug Delivery system: An Overview, International Journal of Pharmacy and Pharmaceutical Sciences Vol. 2, 2010, pg 30-34.
  13. Madhugiri P et al; In situ Gels Based Drug Delivery, Current drug Therapy 2011 Vol. 6 (3) pg 213-222.


#2 pinky 2013-10-30 20:28
#1 Zeinab Rahmani 2013-06-21 17:13
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