INTRODUCTION:

In situ geletion is a process of gel formation at the side of action after the formulation has been applied at the site. In situ gel phenomenon based upon liquid solution off drug formulation and converted into semi solid mucoadhesive key depot. In situ derived latin which means “In its original place or in position”. It is help for the sustained control release of the drug improve patient compliance & comfort by its special characteristic future of ‘Sol to Gel’ transition. In situ forming delivery system such as administration and reduced frequency of administration. In prove patient compliance and comfort. In situ geling systems are liquid room temperature but undergo gelation when it contact with body fluids or change in PH. In converts to very strong gels.

At the site of drug absorption they swell to form a strong gel that is capable of prolong the residence time of the active substance. Natural and synthetic polymers used for the production of in situ gels. Gel formation occurs on or combination of different stimuli like PH change, temperature modulation and ironic crosslinking. In situ gel administrated by oral, ocular, rectal, vaginal, injectable and intraperitoneal routes. Recent advance in In Situ Gel have made it possible to exploit the changes in physiological uniqueness. In different regions of the GI tract for the improve drug absorption as well as patient’s convenience and compliance. In situ gel made an irreplaceable space because of their unique characteristics. It helps for the reduced frequency of drug administration of the drug in the body. Low doses of the drug is required & there will be no drug accumulation and no side effects. The bioavailability of the drug will be more. There will be increase residence time of the drug due to gel formation. The in Situ gel system decreases wastage of the drug. Liquid dosage form that can sustain drug release and remain in contact with cornea of eye for entended period of time is ideal. Reduced systemic absorption of drug drained through the nanolacrimal duct may result in some undesirable side effects. In situ gel system has emerged as one of the best novel drug delivery system. In situ geling system helps for the sustained and controlled release of the drugs. In situ geling system are used pectin, gellan gum, chitosan, alginic acid, guar gum, carbopal, xyloglucon, xantham gum, HPMC, polaxomer etc. The above mentioned properties ‘sol to gel transition’ can be widely used for sustained delivery vehicle preparation of bioactive molecules. Ophthalmic preparation always been challenging because it shows seviour side effects.

eg.

1) Lactrimation,

2) Tear,

3) Non productive absorption of drugs to cornea.

The development of in situ gel systems has received considerable attention over the past few years owing to the several advantages offered by this polymeric system, such as ease of administration and reduced frequency of administration, improved patient compliance and comfort. In situ gel formation occurs due to one or combination of different stimuli like pH change, temperature modulation and solvent exchange.^1,12,13,17

ADVANTAGES:

Ÿ Ease of administration, comfort

Ÿ Reduced frequency of administration further

Ÿ Improved patient compliance

Ÿ Can be administered to unconscious patients.

Ÿ Drug gets released in a sustained and controlled manner

Ÿ Natural polymers have inherent properties of biocompatibility, biodegradability, and biologically recognizable moieties that support cellular activities.

Ÿ Synthetic polymers usually have well-defined structures that can be modified to yield tailorable degradability and functionality.

Ÿ In situ gels can also be engineered to exhibit bioadhesiveness to facilitate drug targeting, especially through mucus membranes, for non-invasive drug administration.

Ÿ In situ gels offer an important “stealth” characteristic in vivo, owing to their hydrophilicity which increases the in vivo circulation time of the delivery device by evading the host immune response and decreasing phagocytic activities.

Ø It show local action and side specificity by acting directly targeted site.

Ø It show less adverse effects as compared to other pharmacological dosage forms.^[1,3]

OPHTHALMIC DIFFERENT ROUTS AND DOGES FORMS:

Table No. 1.⁷

Sr. No.	Route	Dosage Forms	Benefits	Constraints
1	Topical	Solutions,	Ease of administration	Poor bioavailability, suitable only for anterior segment, blurring vision.
		Suspensions	Patient compliance. Best for drug with slow dissolution.	Drug properties decide Performance. Loss of both solution & Suspended solid.
		Ointments	Flexibility in drug choice. Improved drug stability. Resistance to nasolacrimal drainage Inhibition of dilution by tears.	Sticking of eyelids. Blurred vision. Poor patient compliance. Drug choice limited by partition coefficient.
		Emulsions	Prolonged release of drug from vehicle	Blurred vision. Patient‟s non-compliance. Possible oil entrapment.
		Gels	Comfortable. Less blurred vision	Matted eyelids after use. No rate control on diffusion
2	Subconjunctival	Injectables	Delivery of large molecular size drugs, sustained release of drug	Patient non-compliance, suitable for only water soluble drugs
3	Retrobulbar	Injectables (used For anesthetization)	-	Perforation of globe, patient non- compliance
4	Peribulbular	Injectables (used For anesthetization)	Avoidance of perforation of globe	Non-compliance in pediatrics patients and patient with mental disorders
5	Intracameral	Injectables	Sustained delivery to aqueous humor	Patient non-compliance.
6	Intraviteral	Injectables	Sustained delivery of drug to posterior segment of the eye	Patient non-compliance.

PREPARATION OF IN SITU GEL

· The polymeric solution was prepared by dispersing required quantity of sodium alginate as a main polymer and HPMC – E50 LV, HPMC – K4M as co – polymer in water using magnetic stirrer and polymers completely dissolve.

· Aqueous solution of moxifloxacin hydrochloride add in polymeric solution with continuous stirring.

· Buffering and osmalacity against were added then result solution along with benzokanium chloride.

· PH adjust to 6.5 and using 0.1 N NaOH/0.1 N HCL

Fig.1 synthesis of performed gel.^{14, 16}

PHYSICAL PARAMETERS:

The formulated in situ gel solution was tested for:

Clarity:

The clarity of the formulations before and after gelling will be determined by visual inspection of the formulations under fluorescent light, alternatively against white and black backgrounds.

pH:

The pH of the prepared in situ gelling system after addition of all the ingredients will be measured using pH meter.

Gelling capacity:

The gelling ability of the prepared formulations will be determined either visually or by SEM.

By visual inspection- The gelling capacity is determined by pouring a drop of the solution in a vial containing 2 ml of artificial tear fluid which should be freshly prepared and equilibrated at 37°C, and both the time of gelation and the time taken for the gel formed to dissolve will be noted. The composition of the artificial tear fluid.

Dose:

Dose greater than 400mg is given in two divided dose. Present Study: oflaxacin of liquid formation comprising a dilute aqueous solution of sodium alginate designed to form gels in situ in acidic environment of the stomach.

Mode of action of moxifloxacin hydro-chloride in vitro drug release study of formulation:

In vitro release rate of the moxifloxacin hydrochloride from the sol to gel system for the carneal drug availability was determined by diffusion processes.^7,
15

METHODS:

Chemicals:

Moxifloxacin hydrochloride supplied as a gift sample by Cipla Pharmaceuticals Ltd, Baddi.Ophthalmic solution (Mosi) was purchased from Indian market, containing Moxifloxacin Hydrochloride 5mg/mL.

Instrumentation:

A UV-Visible spectrophotometer (2450 Shimadzu, software UV Probe 2.21) with spectral bandwidth 1 nm was employed for all spectroscopic measurements, using a pair of 10 mm was employed for all.

Selection of common solvent:

Double Reversed Osmosis (R.O.) water was selected as common solvent for developing spectral characteristics of MOX. The selection was made after evaluating the solubility of MOX in different solvents.

Preparation of Stock standard solution and selection of wavelengths:

A stock standard solution of MOX was prepared by dissolving 10 mg in 100 mL methanol to obtain concentrations 100 μg/mL. After proper dilutions, 10 μg/mL MOX was scanned in the UV-region i.e. 400 - 200 nm. MOX showed maximum absorbance at 288.2 nm. In Zero order UV –Spectrophotometric method (Method I), two wavelengths 279.0 nm to 296.4 nm were selected for determination of Area Under Curve [AUC] (Figure I). In method II, the zero order spectrum was derivatized into first order derivative (Δ λ = 2 nm, scaling factor 2) using UV Probe software 2.21 and two wavelengths 289.4 nm to 305.6 nm were selected for determination of AUC.^7,
15

Zero order spectrum of MOX showing wavelength selection between 279.0 and 296.4 nm.

Fig.2 First derivative spectrum of MOX showing trough wavelength selection between 289.4 and 305.6

Fig. 3

Study of linearity curves:

Examine the linearity of the assay, the calibration curve for MOX at a concentration ranged from 2 – 12 μg/mL in water was prepared by putting an aliquot portions 0.2 - 1.2 mL into series of six separate 10 mL volumetric flasks and volume was adjusted to mark with water. The AUC between the selected wavelengths were determined and calibration curves were constructed by plotting concentration versus AUC between the selected wavelengths. The optical characteristic and statistical data is shown in table.^7,
15

Analysis of marketed formulation:

An accurately measured volume of ophthalmic solution equivalent to 10 mg of MOX was transfer into 100 mL volumetric flask and volume was made up to the mark with water, filtered through 0.45 μm Whatmann filter paper. A suitable volume of solution was further diluted with water to obtain concentration 8 μg/mL of MOX. AUC were recorded in between the selected wavelengths and the concentrations were determined using respective linear regression equations. The analysis procedure was repeated for six times with ophthalmic solution. ⁸

MECHANISM OF OCCULAR IN SITU GEL

Polymers used

Reversible phase transition (sol to gel)

Pseudo plastic behavior to minimized interference with blinking

Liquid dosages form formulated

Exposure to physiological condition change

To the gel phase

Increase precorneal residence time^{8, 9}

DRUG USED:

1) Levofloxacin eye drops (prolong ocular retension)¹¹

2) Sodium alginate

3) Plain eye drops.

4) Hydrogels (Controling ocular hypertension)

5) Bringzolamide (Gellan gum)

Figure. 4: Model showing precorneal and intraocular events following topical ocular administration of the drug⁷

Study of linearity curves:

To examine the linearity of the assay, the calibration curve for MOX at a concentration ranged from 2 – 12 μg/mL in water was prepared by putting an aliquot portions 0.2 - 1.2 mL into series of six separate 10 mL volumetric flasks and volume was adjusted to mark with water. The AUC between the selected wavelengths were determined and calibration curves were constructed by plotting concentration versus AUC between the selected wavelengths. The optical characteristic and statistical data is shown in table.^{7, 15}

Analysis of marketed formulation:

MECHANISM OF OCCULAR IN SITU GEL:

Polymers used

Reversible phase transition (sol to gel)

Pseudo plastic behavior to minimized interference with blinking

Liquid dosages form formulated

Exposure to physiological condition change

To the gel phase

Increase precorneal residence time^{8, 9}

DRUG USED

1) Levofloxacin eye drops (prolong ocular retension)¹¹

2) Sodium alginate

3) Plain eye drops.

4) Hydrogels (Controling ocular hypertension)

5) Bringzolamide (Gellan gum)

MECHANISM OF IN SITU GEL IN GLUCOMA:

The In situ gel system’s formation is done by two mechanisms such as physical mechanism and chemical mechanism.

Physical Mechanism:

In situ formation based on physical mechanism consists of the following:

Diffusion:

Diffusion17 is a type physical approach that is used in in-situ gel formulation. In this method involves the diffusion of solvent from polymer solution into surrounding tissue which results in formation of precipitation or solidification of polymer matrix. N-methyl pyrrolidone (NMP) has been commonly used polymer in formation of in-situ gelling system.¹⁰

Swelling:

Swelling is a type of physical approach that is used in in-situ formulation. In this method the polymer are surrounding the polymer imbibe and the fluids that are present in exterior environment and swell from out to inside and drug releases slowly. Myverol (glycerol mono-oleate) is a substance which is used as polar lipid that swells in water to form Lyotropic liquid crystalline phase structures. This substance has some bioadhesive properties and it can degrade in vivo by enzymatic action.¹⁰

Fig. 6^{15, 16} Fig 7^15,

Chemical Mechanism:

In situ gelling formation based on chemical reactions mechanism. Chemical reactions that results in situ gelation may involve the following processes.¹⁰

Drugs used:

Fig. 8: Eye drops of anti glaucoma drugs.¹⁰

EVOLUTION PARAMETER:

General appearance and clarity:

Visual appearance and clarity of prepared in situ formulation is checked for the presence of any particulate matter under fluorescent light against a white and black background.³

pH:

pH affects both solubility as well as the stability of the drug in ophthalmic formulations. It should be such that the formulation will remain stable at that pH at the same time there would no irritation to the patient upon administration. It is measured by digital pH meter. The pH of ophthalmic in situ gelling formulations should be in the range of 7-7.4 which is the desired pH range of eye.^3,4,5,6

Viscosity and Rheology:

This is an important parameter for the In situ gels, to be evaluated. Viscosity and rheological properties of in situ forming drug delivery systems may be assessed using Brookfield rheometer or some other type of viscometers such as Ostwald's viscometer. The viscosity of these formulations should be such that no difficulties are envisaged during their administration by the patient, especially during parenteral and ocular administration^{3,4, 5}

Gelation Temperature:

This parameter is necessary for the ophthalmic in situ gels prepared by temperature triggered mechanism using poloxamers as temperature dependent polymers. The sol-gel phase transition temperature (gelation temperature) is determined for formulations by taking 2 ml of refrigerated sample to a test tube sealed with a parafilm. Then these test tubes were placed in the water bath to heat. The temperature is increased in steps of 10°C/minute. Gel formation is indicated by a lack of movement of the meniscus on tilting the tube. The temperature was allowed to increase with constant rate until the gel again comes in liquid form to measure sol temperature.^{3, 4, 5}

Mechanism of temperature sensitive system:

Gel strength:

This parameter can be evaluated using a rheometer. Depending on the mechanism of the gelling of gelling agent used, 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 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.^{5, 6}

Gelling Capacity:

The gelling capacity was determined by placing one drop of the formulation in a vial containing 2 ml of freshly prepared artificial tear fluid and observing the time required to form gelation of formulation and also time taken for the gel re-dissolve; the composition of artificial tear fluid used is a composition of NaCl- 0.670 g, sodium bicarbonate- 0.200 g, calcium chloride- 2H2O 0.008 g, in 100 ml of purified water. The grading of gelling capacity is based on the time taken to form gel and time taken to dissolve the gel in simulated tear fluid. Formulations with good gelling capacity should show gelation remaining for longer periods once gelation occurs. ⁵

Texture analysis:

The consistency, firmness, and cohesiveness of in situ gel are assessed by using texture profile analyzer which mainly indicated gel strength and easiness in administration in vivo. Higher values of adhesiveness of gels are needed to maintain an intimate contact with the mucous surface. Texture analysis provides information on mechanical properties of samples, namely hardness, compressibility, and adhesiveness. These properties can be directly correlated with sensory parameters in vivo and, therefore, are valuable in the development of a product with desirable attributes that contribute to patient acceptability and compliance. A formulation designed for ophthalmic use should be, for example, easily removed from the package, present a good spreadability on the corneal surface and adhere to the mucous layer without disintegrating, in order to prolong retention time.⁵

Isotonicity Evaluation:

Isotonicity is an important characteristic of the ophthalmic preparations. Isotonicity has to be maintained to prevent tissue damage or irritation of the eye. All ophthalmic preparations are subjected to isotonicity testing, since they exhibited good release characteristics and gelling capacity and the requisite viscosity. Formulations are mixed with few drops of blood and observed under a microscope at 45X magnification and compared with standard marketed ophthalmic formulation.^{5, 6}

In vitro drug release study:

In vitro drug release study is done by using Franz diffusion cell. In receptor compartment freshly prepared simulated tear fluid is placed. The dialysis membrane is placed in between receptor and donor compartments. The whole assembly is kept on the thermostatically controlled magnetic stirrer to simulate in vivo conditions and temperature of the medium is maintained at 37°C ± 0.5°C. Medium is continuously stirred at 20 rpm. 1ml of the formulation is placed in donor compartment. Sample (0.5ml) is withdrawn at a predetermined time interval and same is replaced by ATF. Samples are analyzed either on UV spectrophotometer or HPLC.⁵

Ex vivo drug release studies:

Goat corneas are used to study the permeation across the corneal membrane. The cornea is carefully removed along with a 5-6 mm of surrounding scleral tissue and washed with cold saline. The washed corneas are kept in cold freshly prepared solution of tear buffer of pH 7.4. The study is carried out by using the Franz-diffusion cell in such a way that corneum side continuously remains in an intimate contact with the formulation in the donor compartment.

The receptor compartment is filled with STF pH 7.4 at 34°C ± 0.5°C. The receptor medium is stirred on a magnetic stirrer. The samples are withdrawn at different time intervals and analyzed for drug content. Receptor phase is replenished with an equal volume of STF (pH 7.4) at each time interval.^{3, 5}

Sterility testing:

Sterility testing is performed by aseptically transferring 2ml of the formulation into 20ml thioglycolate medium and soya bean - casein digest medium in two separate test tubes. The inoculated media are incubated at 30 to 35°C (thioglycolate medium) and 20 to 25˚C (soya bean - casein digest medium) for 14 days and observed for turbidity and microbial growth.^{3, 5, 6}

Drug Content:

Tests for drug content will be carried out for all the prepared gel formulations. 1 ml of the formulation is taken in 50 ml volumetric flask, dissolved in phosphate buffer pH 7.4 with gentle stirring and final volume was adjusted to obtain concentration 25 μg/ ml respectively. The absorbance was measured at measure wavelength of particular drug using phosphate buffer pH 7.4 as blank using UV spectrophotometer.^{3, 5, 6}

DEPEND ON VARIOUS FACTOR:

Temperature:

Temperature is the most widely used stimulus in environmentally responsive polymer systems in in-situ gelling formulation. The change of temperature used in easy to control, and also easily applicable both in vitro and in vivo. In this system, gelation is caused due to body temperature and no need of external heat. 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. There are three types of temperature induced systems. They are negatively thermo sensitive type Eg: Poly (Nisopropylacrylamide) positively thermo sensitive type Eg: polyacrylic acid thermally reversible type Eg: poloxamer, pluronics, Tetronics.^5,
6

Change PH:

pH sensitive in situ gels Gelling of the solution is triggered by a change in the pH. Eg: Cellulose acetate phthalate (CAP). All pH-sensitive polymers contain pendant acidic or basic groups that either accept or release protons in response to changes in environmental pH. The polymers with a large number of ionizable groups are known as polyelectrolytes. 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.¹⁵

Solvent exchange:

Solvent exchange in situ forming gel is a drug delivery system which is in sol from before administration. When it contacts with the body fluid, then the water miscible organic solvent dissipates & water penetrates into the system leading the polymer preparation as in situ.

U.V. Radiation:

A source of radiant energy is selected on the basis of nature of work, stability, wide range and operating temperature. The associated optical system including the selection of device for obtaining monochromatic radiations is best upon sensitivity sophistication and cost of instrument. The detector and galvanometer for readout are now days developed with wide sensitivity and digital reading with recording device. For the visible region tungsten lamb is commonly employed in an instrument. It emites continuous, incandescent radiations.

Presences of specific molecules or ions.:

Polymers may undergo phase transition in presence of various ions. Some of the polysaccharides fall into the class of ion-sensitive ones. While k-carrageenan forms rigid, brittle gels in reply of small amount of K+, icarrageenan forms elastic gels mainly in the presence of Ca2+. Gellan gum commercially available as Gelrite® is an anionic polysaccharide that undergoes in situ gelling in the presence of mono and divalent cations, including Ca2+, Mg2+, K+ and Na+. Gelation of the low-methoxy pectins can be caused by divalent cations, especially Ca2+. Likewise, alginic acid undergoes gelation in presence of divalent/polyvalent cations. Gellan gum (Gelrite) is a linear, anionic hetero polysaccharide secreted by the microbe Sphingomonas elodea (formerly known as Pseudomonas elodea). The polysaccharide can be produced by aerobic fermentation and then isolated from the fermentation broth by alcohol precipitation. The polymer backbone consists of glucose, glucuronic acid, and rhamnose in the molar ratio 2:1:1. These are linked together to give a tetra saccharide repeat unit. The native polysaccharide is partially esterified with L-glycerate and acetate, but the commercial product Gelrite has been completely deesterified by alkali treatment. Gelrite® (deacetylated gellan gum) is one of the most interesting in situ gelling polymers that has been tested since it seems to perform very well in humans. Gelrite has been granted regulatory approval as pharmaceutical excipient and is marketed by Merck in a controlled-release glaucoma formulation called Blocarden® Depot (Timoptic®). Formulations with the Gelrite can be administered to ocular mucosa as a low viscosity solution. On contact with cations in tear fluid the formulation will form a clear gel. This is caused by cross linking of the negatively charged polysaccharide helices by monovalent and divalent cations (Na+, K+, Ca+). Several models have been presented to explain gellan gum gelation.¹⁵

Fig.12

APPROACHES OF IN-SITU GELING SYSTEM:

Various approaches for in-situ gelling system

Stimuli Responsive In-Situ Gelling System:

Physical or chemical changes in response to small external changes in the environmental conditions,

Temperature induced in-situ gel system:

Temperature is Temperature is the most widely used stimulus in environmentally responsive polymer systems. The change of temperature is not only relatively easy to control, but also easily applicable both in-vivo and in-vitro. These hydrogels are liquid at room temperature (20˚-25˚C) and undergoes gelation when in contact with body fluids (35˚-37˚C), due to increase in temperature. The polymers which show temperature induced gelation are poloxamers or pluronics, cellulose derivatives (methyl cellulose).^{2, 7}

PH inducing in-situ gelling system:

Polymers containing acidic or alkaline functional groups that respond to changes in pH are called pH sensitive polymers. The pH is an important signal, which can be addressed through pH-responsive materials. Gelling of the solution is triggered by change in pH. At pH 4.4 the formulation is free from is a free running solution which undergoes coagulation when the pH is raised by the body fluid to pH 7.4. The polymers which shows pH induced gelation are cellulose and its derivatives polyvinyl acetate, polyethylene glycol^{2, 7}

Osmotically Induced In-Situ Gelling System:

In this method, gelling of the solution instilled is triggered by changes in the ionic strength. It is assumed that the rate of gelation depend on the osmotic gradient across the surface of the gel. The aqueous polymer solution forms a clear solution forms a clear gel in the presence of the mono or divalent cations. The polymer which shows osmotically induced gelation is gellan gum, alginates.^2,7

Chemically Induced In-Situ Gelling System:

The chemical reaction which forms in-situ gel systems are ionic crosslinking, enzymatic cross linking and photo-polymerization^{2, 7}

Ionic cross linking:

Ion sensitive polysaccharides such as carragenan, gellan gum, pectin, sodium alginate undergo phase transition in presence of various ions such as k+, Ca2+, Na+. These polysaccharides fall into the class of ion-sensitive ones. For example, Alginic acid undergoes gelation in presence of divalent cations example-Ca2+ due to the interaction with guluronic acid block in alginate chains.^2,7

Enzymatic cross linking:

In-Situ formation catalyzed by natural enzymes has not been investigated widely but seems to have some advantages over chemical and physicochemical approaches. For example an enzymatic process operates efficiently under physiologic conditions without need for potentially harmful chemicals such as monomers and initiators.^{2, 7}

Photo polymerization:

Photo polymerizable systems when introduced to the desired site via injection get photo cured in-situ with the help of fiber optic cables and then release the drug for prolonged period of time. A photo polymerization, biodegradable hydro gels as a tissue contacting material and controlled release carrier.^{2, 7}

POLYMER USED IN-SITU GEL:

1. The polymers and its degradation products should be nontoxic and non-absorbable from the gastrointestinal tract.

2. It should adhere quickly to moist tissue and should possess some site specificity.

3. It should be a non-irritant to the mucous membranes.

4. It should possess a wide margin of safety both locally and systemically.

5. The cost of the polymer should be not too high, so that prepared dosage form remains Competitive.

CONCLUSION:

In situ gels offer the primary requirement of a successful controlled release product that is increasing patient compliance. Exploitation of polymeric in-situ gels for controlled release of various drugs provides a number of advantages over conventional dosage forms. Sustained and prolonged release of the drug, good stability and biocompatibility characteristics make the in situ gel dosage forms very reliable. Over the last decades, an impressive number of novel temperature, pH, and ion induced in-situ forming solutions have been described in the literature. Each system has its own advantages and drawbacks. The choice of particular hydrogels depends on its intrinsic properties and investigated therapeutic use.

REFERENCE:

1. K, Sarada, S. Firoz, K. Padmini. ‘In Situ Gelling ‘Sree Vidyanikethan college of pharmacy, Sree Sainath Nagar, Chandragiri (M), Tiruapti, Andhara Pradesh, India. 15 May 2014, ISSN-0976-822X. Page No.- 76-79.

2. Chand Pallavi, Pratibha, Katiyal Preeti. ‘Indian Journal of Pharmaceutical and Biological Resarch’ (IJPBR) Pharmaceutical Sciences, S.G.R.R.I.T.S., Patel Nagar Dehradun, Uttarakhand, India. 30 Jun 2016, ISSN-2320-9267. Page No.- 11-13.

3. Nikode Snehal, Dixit Gauri and Upadhya Kanchan, ‘In Situ Gel’ Application and Uses of Polymers. Department of Pharmaceutic’s, Priyadarshini JL College of Pharmacy, Hingna Road, Nagpur, Maharashtra, India. 29 June 2016, ISSN-2278-4357. Page No.-1638-1658.

4. Mhanty Dibyalochan ‘On in Situ Gel’ (Novel Drug Delivery System) Associate Profrssor, Department of Pharmaceutic’s, Anurag Group of Institution, Hyderabad, Telangana, India. 12 May 2018, ISSN-0976-044X. Page No.-175-180.

5. Bakshi Dr. Vasudha. ‘On In Situ Gel’(ANDDS) Profrssor and Dean, Anurag Group of Institutions, Hyderabad Telangana, India. 12 May 2018, ISSN-0976-044X. Page No.-175-180.

6. Sahoo Keshaei Chinmaya ’On In Situ’(ANDDS) Assistant Professor, Department of Pharmaceutic’s, Malla Reddy College of Pharmacy (Offiliated to Osmania University), Maisammaguda, Secundarabad, Telanganna, India. 30 Apri 2018, ISSN-0976-044X. Page No. 175-180.

7. Dabir d. Priyanka, Shahi Dr. S. R. and Deore V. Swati; Opthalmic In Situ Gel’ Department of Pharmaceutic’s, Government College of Pharmacy, opp. Government Polytechnique, Osmanpura, Aurangabad, Maharashtra, India. 26 March 2016, ISSN-2394-3211.Page No.-205-203.

8. Mesharam Sarika, ’Ocular in Situ Gel’ Development, Evaluation and Advancements, TATA Consultancy service, Hinjewadi, Pune, India. 2015, ISSN-2320-4206.Page No.-340-345.

9. Thorat Santosh ‘Ocular in Situ Gel’ Development, Evaluation and Advancements Lupin Research Park, Hinjewadi, Pune, India. 4Jul 2015, ISSN-2347-9531. Page No. 340-345.

10. Ds Sandeep, Charyulu R. Narayana, Narayana V Anoop. ‘Smart In Situ Gels For Glucoma’ Department of Pharmaceutic’s, NGSM Institute of Pharmaceutical Sciences, Nitte (Deemed to be University) paneer, Deralakatte, mangalore, Karnataka, india. May-June 2018, ISSN-0976-044X. Page No.94-99.

11. Gupta Himanshu, Khar R. K., Ali Asgar, Bhatnagar Aseem, Mittal Gaueav, Aqil M ‘Nanoparticles Loden In Situ Gel of Levofloxacin For Enhanced Ocular Retention Department of Pharmaceutics, Faculty of Pharmacy, Jamia Hamdard, New Delhi, India. 2013, ISSN-1071-7544. Page No. -306-309.

12. Indian Pharmacopoeia 1996, Government of India Ministry of Health and Family Welfare, Published The Controller of Publication Delhi. Volume I-II.

13. British Pharmacopoeia 2007, Introduction General Notice Monograph Medicinal and Pharmaceutical Substance. Volume I, II, III, IV, V.

14. Rajendran Swaminath, Kumar K. Sathesh, Ramesh S., Rao Ranga Suresh. ‘Thermoreversible In Situ Gel for Sub Gingival delivery of Simvastatin Treatment of Peritonal Disease. Department of Periodontology, Faculty of Dental Science, Shri Ramachandra University, Chennai, Tamilnadu, India. 24-July-2017. Page No. 101-106.

15. Rajas Jayprakash Nittur, Kunchu Kavitha, Tamijh Mani, Theetta Gounder, ‘In Situ Ophthalmic Gels’ Department of Pharmaceutics, Bharti College of Pharmacy, Bharatinagar Mandya, Karnataka, India. 22-Feb-2011, ISSN – 0976-044X. Page No. 8-12.

16. Baajun Bai, ‘Performed Partical Gel for conformance control’ SPE, University of Missouri-Rolla, Liangxiong Li, SPE, New Mexico Institute of Mining and Technology, Page No. 415-421.

17. Madan R. Jyatsana, Adokar R. Bhushan, Duakamal. ‘Development and Evalution of In Situ Gel of Pregabalin’ Department of Pharmaceutics Sinhgad Technical Education Society, Smt. Kashibai Navale College of Pharmacy Pune, Maharashtra India. 28 September 2016. Page No. 226-230.

Received on 25.04.2019 Modified on 20.05.2019

Res. J. Pharma. Dosage Forms and Tech.2019; 11(3):217-226.

DOI: 10.5958/0975-4377.2019.00037.5