INTRODUCTION:

Oral drug delivery is the most desirable route for the drug administration. Whenever systemic effects are indented but oral bioavailability of some compounds has promoted the search of more effective route for the systemic delivery. Tran mucosal route of drug delivery (i.e. the mucosal lining of the nasal, rectal, vaginal, ocular, oral cavity) nasal mucosa is the major route of administration to achieve faster and higher level of drug absorption ^[1].Therapy through intranasal administration has been an accepted form of treatment in the Ayurvedic system of Indian medicine.

In recent years many drugs have been shown to achieve better systemic bioavailability through nasal route by an oral administration. Nasal mucosa has been considered as potential administration route to achieve faster and higher level of drug absorption because it is permeable to more compound than gastrointestinal tract due to lack of pancreatic and enzymatic activity, neutral pH of nasal mucous.^[2] The history of nasal drug delivery dates back to earlier topical applications drugs intended for local effects. Nasal therapy also called ‘Nasya karma’ has been recognized form of treatment in the Ayurvedic system of Indian medicines .^[3] In addition, intranasal drug delivery enables dose reduction, rapid attainment of therapeutic blood levels, quicker onset of pharmacological activity, and fewer side effects .^[4] Smart polymeric systems represent promising means of delivering the drugs, these polymers undergoes sol-gel transition, once administered. These systems are injectible fluids that can be introduce into body in a minimal invasive manner prior to solidifying or gelling within the desired or nasal cavity.^[5] In -situ gel formulation offers an interesting alternative for achieving systemic drug effects of parenteral routes , which can be convenient, which can result unacceptability, low bioavailability and passes first-effect. Majority of products available are used for treatment of allergic rhinitis, migraine, cold, pain etc. The various formulations given by nasal route includes nasal gel, spray, powders etc. Thus nasal route is the promising alternative for other drug delivery systems.^[6]

Nasal drug delivery^[2]

Intranasal route is considered for the drugs that are ineffective orally and are used chronically where rapid entry into the circulation is desired and they require small doses. The absorption of drugs from the nasal mucosa most probably takes place via the aqueous channels of the membrane. Therefore, as long as the drug is in the form of solution and molecular size is small, the drug will be absorbed rapidly via the aqueous path of membrane. The absorption from the nasal cavity decrease.

Advantages of intranasal drug delivery:^[7,8]

§ Rapid drug absorption via highly vascularizedmucosa

§ Ease of administration, non-invasive

§ Improved bioavailability

§ Improved convenience and compliance

§ Self-administration

§ Avoidance first-pass metabolism

§ Rapid onset of action

§ Lower side effects

§ Convenient route when compared with parenteral route for long term therapy.

§ Bioavailability of larger drug molecules can be improved by means of absorption

§ enhancer or other approach

Disadvantages of intranasal drug delivery

§ Some drug may cause irritation to the nasal mucosa.

§ Nasal congestion due to cold or allergies may interfere with absorption of drug.

§ Drug delivery is expected to decrease with increasing molecular weight.

§ The amount of drug reaches to different regions of the brain and spinal cord varies with each agent.

§ Frequency use of this route leads to mucosal damage.

Anatomy and physiology of nose:

The nasal cavity is divided into two halves by the nasal septum and extends posterior to the nasopharynx, while the most anterior part of the nasal cavity, the nasal vestibule, opens to the face through the nostril Breathing and olfaction are the major function of human nose. But is also functioned as filtration and humidification of inhaled air before reaching in lowest airway. Nasal cavity has mucus layer and hairs, those helpful in filtration of particles trapped in inhaled air. Additionally metabolism of endogenous substances, mucociliary clearance also functions of nose. The human nasal cavity has a total volume of about 16-19ml and total surface area of about 180cm2 and is divided into two nasal cavities via septum. The volume of each cavity is approximately 7.5ml having surfaced around 75cm2.^[9]

Fig. 1 Structure of the Nose

Three region can be distinguished in each part

1) The Respiratory region

The respiratory region is the largest having the highest degree of vascularity, and is mainly responsible for systemic drug absorption. The respiratory epithelium is composed of four types of cells namely-non ciliated, ciliated columnar cells, basal cells, goblet cells. These cells facilitate active transport processes such as the exchange of water and ions between cells and motility of cilia. ^(10,11)

2) The Olfactory region:

It is of about 10 cm2 in surface area and it plays a vital role in transportation of drugs to the brain and the CSF. The olfactory region is located on the roof of the nasal cavities, just below the cribriform plate of the ethmoid bone, which separates the nasal cavities from the cranial cavity. The olfactory tissue is often yellow in color, in contrast to the surrounding pink tissue. The olfactory epithelial layer predominantly contains three cell types: the olfactory neural cells, the subtentacula cells and the basal cells. ^[12,13]

3) The Vestibular region:

It is anterior part of nasal cavity. Surface area is is 0.6 cm ² .Nasal portion is covered by a stratified squamous keratinized epithelial with sebaceous gland. It is located at the opening of nasal passages and is responsible for filtering out the air borne particles. Drug absorption is very difficult in this region but it afforded high resistance against toxic environment. ^[14,15]

Mechanism of drug absorption by nasal route:

The absorbed drugs from the nasal cavity must pass through the mucous layer. It is the first step in absorption. Small, unchanged drugs easily pass through this layer but large, charged drugs are difficult to cross it. The principle protein of the mucous is mucin has the tendency to bind to the solute, hindering diffusion. ^[16]

The three mechanism are as follows:

1) First mechanism- Also known as paracellular transport this utilizes the aqueous route of transport and is slow and passive. . There is an inverse log-log correlation between intranasal absorption and the molecular weight of water soluble compounds. The molecular weight greater than 1000 Daltons show poor bioavailability .^[15]

2) second mechanism- also known as trancellular route which utilizes the lipoidal route for transport of lipophilic drugs.

3) Drugs also cross cell membrane by an active transport routevia carrier mediated or transport through the opening of tight junction.

In-Situ Gelling System:

a) Gel:

Gel is the state which exists between solid and liquid phase. The solid component comprises a three dimensional network of interlinked molecules which immobilizes the liquid - In-situ gelation is a process of gel formation at the site of action after the phase .^[16]

b) In–situ delivery system:

Formulation has been applied at the site. In-situ gel phenomenon based upon liquid solution of drug formulation and converted into semi- solid mucoadhesive key depot. It permits the drug must be delivered in a liquid form or solution form.^[17]

In-Situ gelation is a process of gel formation at the site of application after the composition or formulation has been applied to the site. In the field of human and animal medicine, the sites, topical application sites, surgical sites and other agents are brought into contact with tissues or body fluids. As a drug delivery agent, the in-situ gel has an advantage related to the gel being formed in-situ providing sustained release of the drug. At the same time, it permits the drug to be delivered in liquid form. This new concept of production a gel in –situ was suggested first time in early 1980s. In-situ means a Latin word at the place. Both natural and synthetic polymers are used for production of in-situ gels. In-situ gel forming drug delivery system are principle, capable of releasing drug in sustained manner maintaining relatively plasma profiles. ^[18]

Principle of gelling system:

The principle involving the In-situ gelling of nasal formulation is that the formulation imbibe in the nasal fluid after administration and forms gel into the nasal cavity. In the nose, the mucous lower layer comes and goes around the cilia, forwarding the propulsion phase, backward in the preparatory phase, cilia extremity scrapes the upper layer of mucous penetrating it almost 0.5 mm. Ciliary situated backwards help to remove any obstacle if there is any interference in the propulsion phase. After the formulation of the gel, dissolution occurs and the mucociliary removal towards the nasopharynx occurs. ^[6]

Ideal drug candidate:^[19,20]

· Appropriate nasal absorption properties.

· The drug should not cause nasal irritation.

· Low dose. Generally, ≤ 25 mg per dose.

· The drug must not possess toxic nasal metabolites.

· No offensive odours/aroma associated with the drug.

· The drug has aqueous solubility to provide to the desired in a 25-150μl volume of formulation administered per nostril.

· Suitable stability characteristics.

Advantages of In-situ nasal gel^[21]

§ Prolong drug release

§ Reduced systemic side effect

§ Reduced number of application

§ Ease of administration

§ Reduced frequency of administration

§ Better patient compliance

Properties of Nasal In-situ Gel^[22]

a) It should be low viscous.

b) It should be free flowing to allow for reproducible administration to the nasal cavity, as droplet mist or as spray.

c) Nasal in-situ gel should have long residence time.

d) The nasal in-situ gel follows phase transition mechanism and to stand with shear forces in the nasal cavity wall .

Approaches of an In-situ Gelling system:

The various approaches for in situ gelling system

1)Stimuli response in situ gel system

a)Temperature induced in situ gel system

b)pH induced in sit gel systems

2)Osmotic ally induced in situ gelling system

3) Chemically induced in situ gelling system

a)Ionic cross liking

b)Enzymatic cross linking

c)Photo-polymerization

1) Stimuli responsive in situ gelling system:

Physical or chemical changes in response to small external changes in the environmental condition

a) Temperature induced in situ gel system:

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 vitro and in vivo. In this system, gelling of the solution is triggered bychange 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 The polymers which show temperature induced gelation arepoloxamers or pluronics, cellulose derivatives (methyl cellulose, HPMC, ethyl (hydroxyl- ethyl) cellulose (EHEC) and xylogluca etc. ^[23,24]

b) pH induced in situ gel system:

Polymers containing acidic or alkaline functional groups that respond to changes in pH are called pH sensitive polymers. Gelling of the solution is triggered by a change in pH. At pH 4.4 the formulation 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 acetate phthalate(CAP)Latex, Carbomer and its derivatives polyvinylacetyldiethyl amino acetate (AEA), Polymeth- acrilic acid (PMMA), polyethylene glycol (PEG).

2) Osmotic ally induced in –situ gelling system:

In this method, gelling of the solution instilled is triggered by change in the ionic strength. It is assumed that the rate of gelation depend on the osmotic gradient across the surface of the gel.

3 ) Chemically induced in situ gelling system:

The chemical reaction which forms in situ gel system are cross linking, enzymatic cross linking , and photo-polymerization .

a) Ionic cross linking

Certain ion sensitive polysaccharides such as carragenan, 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. For example, Alginic acid undergoes gelation in presence of divalent/polyvalent cations e. g. Ca2+ due to the interaction.^[26]

b) Enzymatic cross linking:

In situ formation catalyzed 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 .^[27]

c) Photo- polymerization:

In sit photo-polymerization has been used in biomedical applications for over more than decade. A solution of monomers or reactive macromere and initiator can be injected into a tissues site and the application of electromagnetic radiation used to form gel. Acryl ate or similar polymerizable functional groups are typically used as the polymerizable groups on the individual monomers and macromere because they rapidly undergo photo-polymerization in the presence of suitable photo initiator .^[28]

Ideal Characteristics of Polymer used on Nasal In-situ gel:^[2,29]

· It should be non -toxic

· It should be biodegradable and biocompatible.

· It should have Mucoadhesive properties .

· It should have good tolerance.

Polymer used for the preparation of in situ gelling system:^[2]

Polymers

1 pH Sensitive Polymers-

§ Carbomer

§ Polyacrylic acid

§ Cellulose acetate phthalate

2) Temperature sensitive polymer

§ Poloxomer

§ Methyl cellulose

§ Chitosan

§ Hydroxylpropyl methyl cellulose

3) Ion sensitive polymer

§ Xanthum gum

§ Gellan gum

§ Sodium alginate

1) Polymers used in pH sensitive In-Situ gelling system:^[2]

Carbomer:

It is high molecular weight, cross linked polyacrylic acid derivative and has a strong Mucoadhesive property. Carbopol polymers are having very good water sorption property. Carbopol 934 and Carbopol 981 are mostly used as gelling agent. They swell in water upto 1000 times their original volume and 10 times their original diameter to form a gel when exposed to a pH environment above 4.0-6.0 because the pKa of these polymers is 6.0 ± 0.5. If there is an addition of cellulose then it will reduce polymer concentration and improve gelling property.

2) Temperature sensitive polymers:^[2,4]

Poloxamer:

Poloxamer are water soluble tri-block copolymer consisting of two polyethylene oxide and polypropylene oxide core in an ABA configuration. Poloxamer commercially also known as pluronic and has good thermal setting property and increased drug residence time. It is used as gelling agent, and solubilizing agent. Poloxamer gives colorless, transparent gel. Depending upon the ratio and distribution of hydrophilic and hydrophobic chain several molecular weights available, having different gelling property. ^{[ 5 , 31]}

3) Polymers used of ion sensitive in-situ gelling system:

a) Sodium alginate:^[2]

Sodium alginate is a salt of alginic acid extracted from brown algae. It is a linear block polysaccharide consisting of two type monomers β-D-Mannuronic acid and α-L glucuronic acid residues joined by 1,4 glycosidic linkages. It is biodegradable and non-toxic and exhibit good Mucoadhesive property due to its carboxylic group.

b) Gellan Gum:

Gellan gum (commercially available as Gelrite TM or Kelcogel TM ) is an anionicdeacetylatedexocellular polysaccharide secreted by Pseudomonas elodea with atetrasaccharide repeating unit of one α-L-rhamnose, one β-D-glucuronic acid and two β-Dglucuronic acid residues It has the tendency of gelation which is temperature dependent or cations induced . This gelation involves the formation of double helical junction zones followed by aggregation of the double helical segments to form a three-dimensional network by complication with cations and hydrogen bonding with water.35The sol-gel transition process is induced by the presence of monovalent or divalent ions such as Na+ and Ca2+.such as temperature and pH responsive gels, have, on the other hand, appeared more frequently in nasal drug delivery studies and have been shown to increase the residence time and improve drug absorption.^[31]

Cellulose Derivative:

There are many pharmaceutical grade derivatives of cellulose widely used in different Administration routes. Several cellulose derivatives have proved to be effective on enhancing. The intranasal absorption of drugs, including soluble cellulose derivatives such as Hydroxypropyl methylcellulose, hydroxypropyl cellulose [HPC], methylcellulose [MC], and insoluble cellulose derivatives such as ethyl cellulose and microcrystalline cellulose [MCC]. Using celluloses as absorption enhancer can lead to improved intranasal absorption and increased bioavailability.^[32]

Evaluation of in-situ gel:

1)Clarity:

The clarity of formulated solution can be determined by visual inspection under and white background.^[33]

2)Viscosity:

The viscosity and rheological properties of the polymeric formulation, either in solution or in gel made with artificial tissue fluid were determined with different viscometer like Brookfield viscometer. ^[34]

3)Texture analysis:

The firmness, consistency and cohesiveness of formulation are assessed using texture analyzer which mainly indicates the syringability of sol so the formulation can be easily administered in vivo. ^{[33, 34]}

4) Gel Strength:

This parameter can be evaluated using a rheometer. Depending on the mechanism of the 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 can be measured as a function of depth of immersion of the probe below the gel surface. ^[35]

5 ) In vitro drug release studies:

For the in situgel formulations to be administered by oral, ocular or rectal routes, 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. For inject able in sit gels, the formulation is placed into vials containing receptor media and placed on a shaker water bath at required temperature and oscillations rate. Samples are withdrawn periodically and analyzed. ^{[36, 37]}

6) Sol-Gel transition temperature and gelling time:

For in situgel forming systems, the sol-gel transition temperature and pH should be determined. Gelling time is the time required for first detection of gelation of in situgellingsystem. Thermo sensitive in –situgel should be checked for in situgelling at body temperature.^{[38, 39]}

7) pH of the gel:

For determining the pH of the formulation of nasal in situ gel, taken 1 ml quantity of each formulation transferred into a different beaker and diluted it with distilled water up to 25 ml and then pH of each formulation was determined by using pH meter.^[40]

Advancement in the nasal dosage forms:

Nasal Drops:

Nasal drops are one of the most simple and convenient system developed for nasal delivery. Due to ease of self- administration it is becoming more popular.

Nasal Sprays:

Suspension formulations can be formulated into nasal sprays. Due to the availability of metered dose pumps and actuators, a nasal both solution and spray can deliver an exact dose.

Nasal Powders:

These formulations are developed when there is problem with stability.

Nasal Gel:

The nasal gel showed growing interest due to reduction of post-nasal drip, high viscosity, and reduction of taste impact due to reduced swallowing ,target delivery to mucosa for better absorption.

Nasal Inserts:

Nasal inserts are novel , bioadhesive, solid dosage forms for prolonged systemic drug delivery via the nasal route.

CONCLUSION:

Nasal drug delivery is a novel platform and it is a promising alternative route of administration. This route provides future potential for several drugs through the development of safe and efficacious formulation for simple, painless and long –term therapy. Sustained and prolonged release of the drug, stability and biocompatibility makes the in situ system very reliable. In the in situ gelling nasal formulation, there is no need to remove the dosage form from the nasal cavity; therefore this formulation will become the efficient way of the drug delivery. In the future, the in situ gelling nasal drug delivery will continue to advance and will represent a viable alternative to the oral and inject able routes of administrations. Bioavailability of nasal drug products is one of the major challenges in the nasal product development.

REFERENCES:

1 Ram Chan Dhakar, Sheo Datta Maurya, Vijay K Tilak, Anish K Gupta, A Review on Factor Affecting The Design Of Nasal Drug Delivery System, Int. J. Drug Delivery,2011;Vol-3:194-208.

2 Aishwarya J Jadhav, Sheetal B Gondkar, Ravindra B Saudagar. A Review on nasal drug delivery system. World Journal of Pharmacy and Pharmaceutical Sciences, (WJPPS), 2014; 3(8): 231-254.

3 Hicke A.J., Pharmaceutical Inhalation Aerosol Technology, 2nd Ed Marcel Dekker, Inc: New York, 2004.

4 Ugwoke M.I. ,Verbek N., and Kinget R. The biopharmaceutical aspects of nasal mucoadhesion drug delivery. J Pharm Pharmacol. 2001; 59:3-22.

5 Nisha Prajapati, Anju Goyal. A Review: Thermoreversible Mucoadhesive In- Situ Gel. International Journal of Innovative Drug Discovery, 2013; 3(2): 67-84.

6 Michael J, Rathbone Jonathan Hadgraft, Michaels. Roberts, Majella E. Lane Modified Release Drug Delivery Tech, 2^ndEdition, 427-450.

7 Robert O. Williams, David. R. Taft, Jason, T, Mcconville, Advanced Drug Formulation Design To Optimize Therapeutic Outcomes, Vol-172:281-301.

8 Yiew Chein, Informa Healthcare, Novel Drug Delivery System, 2^nd Edition, Volume-50:229-268.

9 Vasant V. Rande, Manfred A. Hollinger, Drug Delivery System, Special Indian Edition, 249-267.

10 J.S. Pasun, A.A. Bagada, M.K, Raval, Nasal Drug Delivery-As An Effective Tool For Brain Targeting: A Review, I.J.P.S.A, 2010; 1(2): 43-55.

11 Anaisa Pire’s, Ana Fortuna, Gilberto Alves, Amilcar Falcao, Intranasal Drug Delivery: How, Why and What For. J. Pharmacy. Pharm. Sci, 2009; 12(3): 288-311.

12 Pratik Kumar A. Mistri, Dimendra J. Patel, Jatin J. Prajapati, Intranasal Drug Delivery System- A Review, I.J.P.I, 2012;2(2):43-55.

13 Jignesh Patel, Girish Jani, Intranasal Delivery to Brain: Pathway and Formulation Approaches , Inventi Impact NDDS, 2013;1:17-25.

14 Senthil Kumar K, Manoj Varma G, Vuday Kiran A, R Arun Kumar, B Sudhakar, Nasal Drug Delivery System-An Overview, I.J.P.C.S, 2012; 1(3):1009-1019.

15 M. Alagysundaram, B. Chengaiah, K. Ganaprakash, S. Ramkanth, C. Madhusudhanahetty, D. Dhachinamoorti, Nasal Delivery System-An Overview, I .J. Res. Pharma. Sci, 2010; 1(4):454-465.

16 Patel Chirag, Dhruv Mangukia, SojtraIshita, Umesh Kumar. Recent Review On Alternative System of Parenteral Delivery: Nasal Drug Delivery System. Journal of Drug Discovery and Therapeutics, 2013; 1(1);12-18.

17 Choudhary Rakhi, Goswami Lakshmi, Nasal Route Novelistic Approach for Targeted Drug Delivery to CNS, I .R. J. Pharmacy, 2013; 4(3): 59-62.

18 Mable sheeba john, Sreeja C Nair, Anoop KR. Research article- Thermoreversible Mucoadhesive Gel for Nasal Delivery of Anti-Hypertensive drugs. International Journal of Pharmaceutical Sciences Review and Research. Jul-Aug 2013; 21(1): 57-63.

19 Pagar S. A., Shinkar D.M., Saudagar R.B., “A Review on Intranasal Drug Delivery System”, Journal of Advanced Pharmacy Education & Research, 3(4), 2013, 333-346.

20 Swamy N G N, Zaheer A, “Mucoadhesive In situ Gels as Nasal Drug Delivery Systems: An Overview”, Asian Journal of Pharmaceutical Sciences, 7(3), 2012, 168-180.

21 Harnish Patel, Priyanka Patel, Tushar Brahmbhatt, Mayur Suthar, In Situ Gelling System- A Review, J. Chem. Pharm. Res, 2011; 3(6):217-221.

22 Bajpai Vibha. In-Situ Gel Nasal Drug Delivery System- A Review. International Journal of Pharma Sciences, 2014; 4(3): 577-580.

23 Gonjari J.D, Solid In Situ Gelling Nasal Formulation: A Tool for Systemic Drug Delivery, Pharmainfo.Net, 2007; 5(2).

24 A.P. Patil, A.A. Tagalpallawar, G.M. Rasve, A.V. Bendre, P.G. Khapekar, A Novel Ophthalmic Drug Delivery System-In Situ Gel, I.J.P.S.R, 2012; 3(9):2938-2946.

25 Kanhaiya. L. Agraval, Naveen Mehta, Ashish Namdev, Anil Gupta, In Situ Gel Formulation For Ocular Drug Delivery System-An Overview, A.J. Biomedical And Pharma. Sci, 2011; 1(4):17.

26 Arohi Gupta, Nimita Manocha, Formulation and Evaluation Of In Situ Ophthalmic Drug Delivery System, I.J.P.B.A, 2012; 3(4):715-718.

27 Ramya Devi. D, Abhirami M, Brindha .R, Gomathi .S,VedheHari B.N, In Situ Gelling System-Potential Tool for Improving Therapeutic Effect of Drug, I.J.P. Pharma.Sci, 2013; 5(3):27-30.

28 Kishor K. Bhalerao, Meghna S. Kamble, Pravin P. Aute, Sandeep M. Dange, Rohini P. Chavan, Krunal K. Vadiya, Sanket B. Munot, Pravin D. Chaudhari, A Short Review On Stomach Specific Floating In Situ Gel, J. Biomed. And Pharm Res2012; 1(3):1-4.

29 Parekh Hejal, Rishad Jivani. Review: Noval In-Situ Polymeric drug delivery system. Journal of Drug Delivery and Therapeutics, 2012; 2(5): 136-145.

30 J.U Kute, A.B Darekar, R.B Saudagar. A Review: In-Situ Gel-Novel approach for nasal delivery. World Journal of Pharmacy and Pharmaceutical Sciences, 2014; 3(1): 187-203.

31 Shaikh RG, Shah SV, Patel KN, Patel BA, Patel PA, A Review on Polymers Used in In- Situ Gel Drug Delivery Systems, 2012; 2(1):17-34.

32 Saraswat R., Bhan C. S., Gaur A, A Review on Polymers Used In In-Situ Gel Drug Delivery Systems, I. J. P. Inov, 2012; 1(2): 110-118.

33 P. B. Patel, D. H. Shastri, P. K. Shelat, K. Shukla, Development And Evaluation Of ph Trigerred In Situ Opthalmic In Situ Gel Formulation Of Ofloxacin, Am. J. Pharmatech. R, 2011; 2(4):431-445.

34 Hanan M. El-Laithya, Demiana I. Nesseemb, M. Shoukry, Evaluation of two in situ gelling Systems for ocular delivery of Moxifloxacin:In vitro and in vivostudies J. Chem. Pharm. Res., 2011; 3(2):66-79.

35 Sumegha Meshram, Surendra Kumar Jain, Nishiprakash Jain, Formulation and Evaluation of Formulation and Evaluation Of In Situ Ophthalmic Gel of Ketorolac Tromethamine, W.J.P.P.S, 2013; 2(3):1370-1384.

36 Hetangi Rathod, Vishnu Patel, Moin Modasiya, In Situgel: Development, Evaluation and Optimization Using 32 Factorial Design , J. Pharm. Sci. Res.2011; Vol.3 (4):1156-1162.

37 J. Padma Preetha, K. Karthika, Rekha. NR and Khalid Elshafie, Formulation and evaluation of in situ ophthalmic gels of Diclofenac sodium. Chem. Pharm. Res., 2010, 2(3):528-535.

38 Aparna V. Bhalerao, Sitanshu S. Singh, In Situ Gelling Ophthalmic Drug Delivery System For Glaucoma, I.J.P.B.S, 2011;2(2):7-14.

39 Chandra Mohan Eaga, Jagan Mohan Kandukuri1, Venkatesham Allenki1 And Madhusudan Rao Yamsani, In-situgels -a novel approach for ocular drug delivery, Der Pharmacia Letter; 2009; 1 (1): 21-33.

40 Chavan P. Dhole S., Yadav M., “Nasal drug delivery system: a review” World Journal of Pharmacy and Pharma. Sciences, 3(12), 2014, 598-617.

Received on 29.10.2015 Modified on 24.12.2015

Res. J. Pharm. Dosage Form. & Tech. 8(1): Jan.-Mar. 2016; Page 09-14

DOI: 10.5958/0975-4377.2016.00001.X