IN SITU GEL: A NOVEL DRUG DELIVERY SYSTEM

Indo American Journal of Pharmaceutical Research, 2014

ISSN NO: 2231-6876

IN SITU GEL: A NOVEL DRUG DELIVERY SYSTEM P.R. Patil*, S.S.Shaikh, K.J.Shivsharan, S.R.Shahi Department of Pharmaceutics, Government College of Pharmacy, Opposite Govt. Polytechnic, Osmanpura, Aurangabad-(431005), Maharashtra, India. ARTICLE INFO Article history Received 11/11/2014 Available online 30/11/2014

Keywords In Situ Gel, Thermally Trigged System, Ph Triggered Systems, Photo-Initiated Polymerization, Polymers, Application, Evaluation Etc.

ABSTRACT The environmental factors like change in pH, ionic concentration, temperature, osmolarity or irradiations etc physical state of formulation can change from free flowing solution to viscous gel form. This kind of phase transition from ‘sol to gel’ because of above mentioned reasons is called as in situ gelling. In situ gel is very much useful technique for improving the bioavailability of such formulations which are easily washed away from their site of administration, eg. Eye drops (in solution form) or Nasal drops. As compared to other drug delivery systems like Parenteral, Nasal, Rectal and Vaginal etc use of in-situ gel in Ophthalmic drug delivery is extensive. The intention of this new paper is to enlight the all possible areas where in-situ gel technique can be used to improve bioavailability including ophthalmic drug delivery. Therefore we have discussed here the applications of in-situ gel technique in Nasal, Oral, Rectal and Vaginal drug delivery. The most important thing required in in-situ gel is availability of suitable and compatible biodegradable polymer. Hence we have given the list of polymers (biodegradable and non-biodegradable) that may be helpful for investigators.

Copy right © 2014 This is an Open Access article distributed under the terms of the Indo American journal of Pharmaceutical Research, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Please cite this article in press as P.R.Patil et al. In Situ Gel: A Novel Drug Delivery System. Indo American Journal of Pharm Research.2014:4(11).

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Corresponding author P.R.Patil Assistant Professor, Government College of Pharmacy, Opposite Govt. Polytechnic, Osmanpura, Aurangabad (431005), Maharashtra, India [email protected]

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INTRODUCTION In situ gel formulations applied as solutions or suspensions that undergo gelation after instillation. This new concept of producing a gel in situ was suggested for the first time in the early 1970s. [12] These systems are more acceptable for the patients. They are administered into the eye as a solution and undergo an immediate gelation when in contact with the eye. Studies have shown that the precorneal residence time of some in situ gelling for several hours. The in situ gelation has been the most attractive feature of these systems. Various polymeric combinations have been successfully used for fabrication. [1] Hence, they are promising means for overcoming the limitation of conventional topical ophthalmic dosage forms like eye drops, suspensions and ointments. In situ activated gel forming systems are those which are when exposed to physiological conditions will shift to a gel phase. Gelation occurs via the cross-linking of polymer chains that can be achieved by covalent bond formation (chemical cross-linking) or non-covalent bond formation (physical cross-linking).The progress that has been made in gel technology is in the development of a droppable gel. [2] In situ gel-forming systems can be described as low viscosity solutions that undergo phase transition to form viscoelastic gels due to conformational changes of polymers in response to the physiological environment. The rate of in situ gel formation is important because between instillation in the eye and before a strong gel is formed; the solution or weak gel is produced by the fluid mechanism of the eye. [21] ADVANTAGES 1. Generally more comfortable than insoluble or soluble insertion. Less blurred vision as compared to ointment. 2. Increased bioavailability due to increased precorneal residence time. 3. Decreased naso-lacrimal drainage of the drug which causes undesirable side effects arising due to systemic absorption of the drug through naso-lacrimal duct is reduced. 4. Drug effect is prolonged hence frequent instillation of drug is not required. 5. The principle advantage of this formulation is the possibility of administering accurate and reproducible quantities, in contrast to already gelled formulations and moreover promoting precorneal retention. [4] METHODS OF DRUG DELIVERY : Physiological Stimuli: [1,3,5] Thermally Trigged System : Temperature-sensitive hydrogels are probably the most commonly studied class of environment-sensitive polymer systems in drug delivery research. The use of biomaterial whose transitions from ‘sol to 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 and no external source other than that of body heat is required to trigger gelation. A useful system should be endurable to account for small differences in local temperature, such as it might be encountered in appendages in the oral cavity. Three main strategies are exists in engineering of thermoresponsive sol to gel polymeric system. For convenience, temperature-sensitive hydrogels are classified as fallows. Table 1: Classification of Hydrogels (Thermally Trigged System). Types of Hydrogels

Characteristics

Negatively Thermosensitive

Have Lower Critical Temperature (LCST) and Contract upon heating above the LCST.

Positively Thermosensitive

Have Upper Critical Temperature (UCST) and Contract upon cooling below UCST.

Thermally Reversible

Polymer solution is a free flowing liquid at ambient temperature and gels at body temperature. When injected as a solution into the body, the material forms a firm, stable gel within minutes.

Polymers Poly-(N-isopropylacrylamide) (PNIPAAm). PNIPAAm is a water soluble polymer at its low LCST, but hydrophobic above LCST, which result on precipitation of PNIPAAm from the solution at the LCST. Poly-(acrylic acid) (PAA) and Polyacrylamide (PAAm) or Poly-(acrylamide-co-butyl methacrylate). They have positive temperature dependence of swelling.

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pH Triggered Systems : The second approach of in situ gel formation is based on Change in pH. Certain polymers such as PAA (Carbopol®, carbomer) or its derivatives, polyvinylacetal diethylaminoacetate (AEA), Mixtures of poly (methacrylic acid) (PMA) and poly (ethylene glycol) (PEG) shows change from sol to gel with change of pH. Swelling of hydrogel increases as the external pH increases in the case of weakly acidic (anionic) groups, but decreases if polymer contains weakly basic (cationic) groups.

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Poly-(ethylene oxide)-b-poly (propylene oxide)-b-poly (ethylene oxide) (Pluronics®, Tetronics®, poloxamer).

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Chemical Reactions : [1,7,12] Ionic cross-linking : Certain ion sensitive natural polysaccharides such as Carrageenan, Gellan gum, Pectin, Sodium alginate undergo phase transition in presence of various ions such as K+, Ca2+, Mg2+, Na+ eg. Alginic acid undergoes gelation in presence of divalent/polyvalent cations e.g. Ca2+ due to the interaction with glucoronic acid block in alginate chains. Enzymatic cross-linking : Certain natural enzymes operate efficiently under physiologic conditions without need for potentially harmful chemicals such as monomers and initiators. They provide a convenient mechanism for controlling the rate of gel formation, which allows the mixtures to be injected before in situ gel formation. Physical Changes In Biomaterials : [1,9,14] Swelling : In situ formation may also occur when material absorbs water from surrounding environment and expand. 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. It has some bioadhesive properties and can be degraded in vivo by enzymatic action. Diffusion : This method involves the diffusion of solvent from polymer solution into surrounding tissue and results in precipitation or solidification of polymer matrix. N-methyl- pyrrolidone (NMP) has been shown to be useful solvent for such system. Photo-Initiated Polymerization : [1,11,13] A solution of monomers such as acrylate or other polymerizable functional groups and initiator such as 2,2 dimethoxy-2phenyl acetophenone, camphorquinone and ethyl eosin can be injected into a tissues site and the application of electromagnetic radiation used to form gel designed readily to be degraded by chemical or enzymatic processes or can be designed for long term persistence in vivo. Typically long wavelength ultraviolet and visible wavelengths are used. A photopolymerizable, biodegradable hydrogel as a tissue contacting material and controlled release carrier is reported by Sawhney.

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POLYMERS: Ideal Characteristics [1]:  It should be biocompatible.  It should have pseudo plastic behavior.  It should have good tolerance.  It should be capable of adherence to mucus.  Polymer should be capable of decreasing viscosity with increasing shear rate there by lowering viscosity during blinking.

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Table 2: Examples of Polymer. Polymers Carbopol-934, Chitosan, Gellan gum, Gum karaya, HPMC, Hyaluronic acid esters, MC, Methylpyrrolidinone Chitosan, Pectin, Poloxamer, Pluronic F-127, SodiumAlginate, Trimethyl Chitosan, Xyloglucan, etc.

2) Nasal

Acacia, Carbomer, Carbopol-934, Carrageenan, Chitosan, CMC, Gellan gum, Gum karaya, HEC, HPMC, Pectin, PEG, Poloxamer, PVA, PVP, Sodium-Alginate, Tragacanth, etc.

3) Ocular

Carbomer, Carbopol-940, Carrageenan, Chitosan, Gelatin, Gellan gum, HPMC, HEC, Sodium-Alginate, Pluronic F-127, Poloxamer, PVA, PVP, Xanthan gum, Xyloglucan, etc.

4) Rectal and Vaginal

Carbopol, Chitosan, Gelatin, HEC, HPC, HPMC, MC, PEG, Pluronic F-127, Poloxamer, Polycarbophil, PVP, SodiumAlginate, Sodium-CMC, Starch, etc.

5) Parenteral

Cellulose acetate, Chitosan, Gelatin, PEG, Poloxamer, Sodium-Alginate, SodiumHyaluronate, etc.

Drugs Ambroxol, Articaine HCl, Benzydamine HCl, Cimetidine, Indomethacin, Paracetamol, Theophylline, etc. Acetaminophen, Chloramphenicol, Insulin, Ketorolac, Melatonin, Metaclopramide, Midazolam, Oxymetazoline, Oxytocin, Salbutamol, Zolmitripan, etc. Aceclofenac, Ciprofloxacin, Diclofenac, Dorzolamide, Fluconazole, Indomethacin, Methazolamide, Ofloxacin, Pilocarpine, Timolol, Voriconazole, etc. Acetaminophen, Acyclovir, Chloramphenicol, Clotrimazole, Doxorubicin, 5-Flurouracil, Insulin, Metronidazole, Nimesulide, Oxybutynin, Oxytocin, Quinine, etc. Doxorubicin, 5-Flurouracil, Palcitaxel, etc.

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Type of Drug Delivery 1) Oral

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Carbopol Cellulose derivatives Chitosan Gelatin Gellan gum Hyaluronic acid derivatives Pectin PEG Pluronic F-127 Poloxamer PVA PVP

Sodium alginate Tragacanth Oral

Nasal

Ocular

Rectal and Vaginal

Parenteral

Xanthan gum

Figure 1: Plot of polymers in different kind of drug delivery: APPLICATIONS IN DRUG DELIVERY :

Oral : 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. [1]

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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 sensitized rats was observed. In-situ gel was found to inhibit the increase in nasal symptoms as compared to marketed formulation nasonex (mometasone furoate suspension 0.05%). 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.Wu et al. designed a new thermosensitive hydrogel by simply mixing N-[(2-hydroxy-3-methyltrimethylammonium) propyl] chitosan chloride and poly (ethylene glycol) with a small amount of α-βglycerophosphate; for nasal delivery of insulin. The formulation was in solution form at room temperature that transformed to a gel form when kept at 37o C. Animal experiments demonstrated hydrogel formulation to decrease the blood-glucose concentration by 40-

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Nasal :

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50% of the initial values for 4-5 h after administration with no apparent cytotoxicity.Therefore, these types of systems are suitable for protein and peptide drug delivery through nasal route. [1, 16]

Ocular : For in situ gels 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. Conventional delivery systems often result in poor bioavailability and therapeutic response because high tear fluids turn over and dynamics cause rapid elimination of the drug from the eye. So, to overcome bioavailability problems, ophthalmic in situ gels were developed much of the interest in the pharmaceutical application of gellan gum has concentrated on its application for ophthalmic drug deliver. Drug release from these in situ gels is prolonged due to longer precorneal contact times of the viscous gels compared with conventional eye drops. Miyazaki et al. attempted to formulate in situ gels for ocular delivery using Xyloglucan (1.5%w/w) as the natural polymer. These in situ forming polymeric systems were observed to show a significant mitotic response for a period of 4 h when instilled into lower cul-de-sac of rabbit eye. The formulation and evaluation of an ophthalmic delivery system for indomethacin for the treatment of uveitis was carried out. A sustained release of indomethacin was observed for a period of 8 h in-vitro thus considering this system as an excellent candidate with the water- soluble Carbopol system has been reported. [1, 17]

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Parenteral : The development of injectable in-situ forming drug delivery systems has received a considerable interest over the last decade. A novel, injectable, thermosensitive in situ gelling hydrogel was developed for tumor treatment. This hydrogel consisted of drug loaded chitosan solution neutralized with β-glycerophosphate. Local delivery of paclitaxel from the formulation injected intratumorally was investigated using EMT-6 tumors implanted subcutaneously on albino mice. Ito et al. designed and synthesized injectable hydrogels that are formed in situ by cross-linking of hydrazide modified hyaluronic acid with aldehyde modified versions of cellulose derivatives such as carboxymethylcellulose, hydroxypropylmethylcellulose and methylcellulose. These in situ forming gels were used for preventing postoperative peritoneal adhesions thus avoiding pelvic pain, bowel obstructions and infertility. For a better

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Rectal And Vaginal : 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-β-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. [1, 18]

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therapeutic efficacy and patient compliance, mucoadhesive, thermosensitive, prolonged release vaginal gel incorporating clotrimazoleβ-cyclodextrin complex was formulated for the treatment of vaginitis. [1, 13] EVALUATION AND CHARACTERIZATION : Sol to gel Transition Temperature and Gelling Time: For in situ gel forming systems, the sol to gel transition temperature and pH should be determined. Gelling time is the time required for first detection of gelation of in situ gelling system. Thermosensitive in situ gel should be checked for in situ gelling at body temperature. [1,2] Clarity: The clarity of formulated solutions can be determined by visual inspection against black and white background. [1,3] Texture Analysis: The firmness, consistency and cohesiveness of formulation are assessed using texture analyzer which mainly indicates the syringeability of sol so the formulation can be easily administered in-vivo. Higher values of adhesiveness of gels are needed to maintain an intimate contact with surfaces like tissues. [1,2,4] Gel Strength: A specified amount of gel is prepared in a beaker, from the sol form. This gel containing beaker is raised at a certain rate, so pushing a probe of rheometer slowly through the gel. The changes in the load on the probe can be measured as a function of depth of immersion of the probe below the gel surface. [1,9,25] Viscosity and Rheology: This is an important parameter for the in situ gels, to be evaluated. The viscosity and rheological properties of the polymeric formulations, either in solution or in gel made with artificial tissue fluid (depending upon the route of administrations) were determined with different viscometer. The viscosity of these formulations should be such that it should be patient complient. [1,2,7] Fourier Transform Infra-Red Spectroscopy and Thermal Analysis: Fourier transform infra-red spectroscopy is performed to study compatibility if ingredients. Differential scanning calorimetry is used to observe if there are any changes in thermograms as compared with the pure ingredients used thus indicating the interactions. [1,4,12]

Drug Content: Uniform distribution of drug is important to get good bioavailability. The content of drug is estimated by simultaneous method by UV-Visible spectrophotometer. Method involves dilution of 1 ml of formulation with 100 ml of ATF solution pH 7.4. Aliquot of 1 ml was withdrawn and further diluted to 10 ml of ATF solution. Then concentration is determined by UV-Visible spectrophotometer. [1,5,22] In-Vitro Drug Release Studies: The drug release studies are carried out by using the plastic dialysis cell. The cell is made up of two half cells, donor compartment and a receptor compartment. Both half cells are separated with the help of cellulose membrane. The sol form of the formulation is placed in the donor compartment. The assembled cell is then shaken horizontally in an incubator. The total volume of the receptor solution can be removed at intervals and replaced with the fresh media. This receptor solution is analyzed for the drug release using analytical technique. [1,12,26]

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Accelerated stability Studies: Formulations are placed in ambient colour vials and sealed with aluminium foil for a short term accelerated stability study at 40±2°C and 75±5% RH as per International Conference on Harmonization (ICH) states Guidelines. Samples are analyzed every month for clarity, pH, gelling capacity, drug content, rheological evaluation, and in vitro dissolution. [1,6,10]

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Histopathological Studies: Two mucosa tissue pieces (3 cm2) were mounted on in vitro diffusion cells. One mucosa was used as control (0.6 mL water) and the other was processed with 0.6 mL of optimized organogel (conditions similar to in vitro diffusion). The mucosa tissues were fixed in 10% neutral carbonate formalin (24 hours), and the vertical sections were dehydrated using graded solutions of ethanol. The subdivided tissues were stained with haematoxylin and eosin. The sections under microscope were photographed at original magnification ×100. The microscopic observations indicate that the organogel has no significant effect on the microscopic structure of the mucosa. The surface epithelium lining and the granular cellular structure of the nasal mucosa were totally intact. No major changes in the ultra structure of mucosa morphology could be seen and the epithelial cells appeared mostly unchanged. [1,13,23]

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Ocular irritancy test: The Draize irritancy test was designed for the ocular irritation potential of the ophthalmic product prior to marketing. According to the Draize test, the amount of substance applied to the eye is normally 100μl placed into the lower cul-de-sac with observation of the various criteria made at a designed required time interval of 1hr, 24hrs, 48 hrs, 72hrs, and 1week after administration. Three rabbits (male) weighing 1.5 to 2kg are used for the study. The sterile formulation is instilled twice a day for a period of 7 days, and a cross over study is carried out (a 3 day washing period with saline was carried out before the crossover study). Rabbits are observed periodically for redness, swelling, watering of the eye. [1,7,24] Table 3: Some Examples of Marketed Formulations: Sr. No 1)

Type of Drug Delivery Oral

Name of Drug Betamethasone

2)

Nasal

3)

Occular

4)

Rectal & Vaginal

Fluconazole Zinc gluconate, Zinc acetate Ganciclovir Lidocaine Loteprednol etabonate Pilocarpine Timolol Diazepam Dinoprostin Metronidazole Nonoxynol-9

5)

Parenteral

Oxyquinoline sulphate, Ricinolic acid Progesterone Ganciclovir Doxycycline Leuprolide acetate

Marketed Formulation Celestone® , Celestone soluspan® Diflucan® Zicam® Zirgan® Akten® Lotemax Gel® Pilostat®, Carpine® Timoptic® Diastat® Prostin E® Metrogel Vaginal® Advantage S® Conceptrol® Gynol II® Acid jelly® Crinone® Vitrasert® Atridox® Atrisorb D® Eligard® Lupron depot®

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REFERENCES 1. Nirmal H. B. et al, In-Situ Gel: New Trend in Controlled and Sustained Drug Delivery System, International Journal of PharmTech Research, 2010, 2, 1398-1408. 2. Lekhraj Verma et al, Development Of Phase Change Solutions For Ophthalmic Drug Delivery Based On Ion Activated And Ph Induced Polymers, International Journal Of Pharma Professional’s Research, 2010, 1, 137-144. 3. Zarikar Nitin Et al, Ophthalmic In-Situ Drug Delivery System, International Journal of Pharmaceutical Research and Development, 2013, 5, 48-55. 4. J. Padma Preetha et al, Formulation And Evaluation of In-Situ Ophthalmic Gels of Diclofenac Sodium, Journal of Chemical and Pharmaceutical Research, 2010, 2, 528-535. 5. Demiana I. Nesseem et al, Evaluation of Two In-Situ Gelling System Foe Ocular Delivery of Moxifloxacin: In Vitro and in Vivo Studies, Journal of Chemical and Pharmaceutical Research, 2011, 3, 66-79. 6. I.D. Rupenthal et al, Comparison Of Ion-Activated In Situ Gelling System For Ocular Drug Delivery, International Journal Of Pharmaceutics, 2011, 78-85. 7. Mahesh N. Mali et al, In Situ Gel Forming System for Sustained Ocular Drug Delivery, European Industrial Pharmacy, February 2010, 17-20. 8. Chandra Mohan Eaga et al, In-Situ Gels – A Novel Approach For Ocular Drug Delivery, Scholars Research Library Journal, 1, 21-33. 9. Rajoria et al, In-Situ Gelling System – A Novel Approach for Ocular Drug Delivery, American Journal of PharmTech Research, 2012, 2, 24-53.

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CONCLUSION In situ gels are wonderful amalgamation of two pharmaceutical forms one solution and second gel. Both have their own advantages like solution provide ease of handling and administration while gel helps to increase the contact period with targeted tissue. This not only improves the bioavailability but also reduces the frequency of dosing which ultimately leads to patient compliance. Use of biodegradable polymer will help to improve the utility of in-situ gel. Due to flexible nature of in-situ gel, formulator can play with its release properties. Formulator can mold it into controlled, sustained or prolong release as per the needs.

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10. Shweta Gupta et al, Ophthalmic Drug Delivery Systems with Emphasis on In-Situ Hydrogels, Pharmagene, 1, 80-87. 11. Rathod Hetangi et al, In Situ Gel As A Novel Approach Of Gastro retentive Drug Delivery, International Journal Of Pharmacy & Life Sciences, 2010, 1, 440-447. 12. Lalit Kumar et al, In Situ Gel: A Novel System for Occular Drug Delivery, International Journal of Pharmaceutical Sciences Review and Research, 2011, 9, 83-91. 13. Dr. S. L. Harikumar et al, Injectable In-Situ Gelling Controlled Release Drug Delivery System, International Journal Of Drug Development & Research, 2012, 4, 56-69. 14. Pandya et al, Ophthalmic In-Situ Gelling System, International Journal of Pharmacy & Life Sciences, 2011, 2, 730-738. 15. M. Jothi et al, In-Situ Ophthalmic Gels for the Treatment of Eye Diseases, International Journal of Pharmaceutical Sciences and Research, 2012, 3, 1891-1904. 16. Patil et al, A Novel Ophthalmic Drug Delivery System: In-Situ Gel, International Journal of Pharmaceutical Sciences and Research, 2012, 3, 2938-2946. 17. Huang Y. et al, Molecular Aspects of Muck and Bioadhesion: Tethered Structures and Site Specific Surfaces, Journal of Controlled Release65, 2000, 63-71. 18. Monika Prajapati et al, Gastro retentive floating in Situ Gel of- An Overview, The Global Journal of Pharmaceutical Research, 2012, 1, 1309-1321. 19. Sudipta Ganguly et al, A Novel in Situ Gel for Sustained Drug Delivery and Targeting, International Journal Of Pharmaceutics276, 2004, 83-92. 20. Waphare K. B. et al, Gastro retentive In-Situ Gel: A Review, International Journal of Universal Pharmacy and Life Sciences, 2013, 53-71. 21. Subimol S et al, Fabrication of Ophthalmic in Situ Gel of Diclofenac Potassium and Its evaluation, Scholars Academic Journal of Pharmacy, 2013, 2, 101-106. 22. Indu P. K. et al, Formulation and Evaluation of Ophthalmic Preparation of Acetazolamide, International Journal of Pharmacy, 2000, 199, 119-127. 23. Banker and Rhodes, Drug and Pharmaceutical Science: Modern Pharmaceutics, Marcel Dekker, 2 nded, Vol 40, 568-594. 24. Sasaki H. et al, Different Effects of Absorption Promoter on Corneal and Conjuctival Penetration of Ophthalmic Beta Blocker, Pharmaceutical Research, 1995, 12, 1146-1150. 25. Miyazaki S. et al, Thermally Reversible Xyloglucan Gels for Rectal Drug Delivery, Journal of Control Release, 1998, 56, 75-83. 26. Mitan R. et al, A pH Triggered in-situ Forming Ophthalmic Drug Delivery System for Tropicamide, Drug Delivery Technology, 2007, 5, 44-49.

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