RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES,



RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES

KARNATAKA, BANGALORE

[pic]

M. PHARM SYNOPSIS

YEAR OF ADMISSION - 07/09/2012

TITLE OF THE SYNOPSIS

“FORMULATION AND EVALUATION OF

IN SITU OCULAR GEL OF LEVOFLOXACIN”

BY

Mr. SHASHI RANJAN

M. PHARM, PART- I

DEPARTMENT OF PHARMACEUTICS

UNDER THE GUIDANCE OF

Professor and Head

DEPARTMENT OF PHARMACEUTICS

INSTITUTION

GAUTHAM COLLEGE OF PHARMACY

R. T. NAGAR, BANGALORE-32,

RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES,

BANGALORE, KARNATAKA

ANNEXURE – II

PROFORMA FOR REGISTRATION OF SUBJECT FOR DISSERTATION

| | | |

|1. |NAME OF THE CANDIDATE AND ADDRESS |SHASHI RANJAN |

| | |DEPARTMENT OF PHARMACEUTICS |

| | |GAUTHAM COLLEGE OF PHARMACY |

| | |SULTHAN PALAYA, R.T NAGAR (PO) |

| | |BENGALURU – 32, KARNATAKA. |

| | | |

|2. |NAME OF THE INSTITUTION |GAUTHAM COLLEGE OF PHARMACY, |

| | |SULTHAN PALAYA, R.T NAGAR (PO) |

| | |BENGALURU – 32, KARNATAKA. |

| | | |

|3. |COURSE OF STUDY AND SUBJECT |MASTER OF PHARMACY IN |

| | |PHARMACEUTICS |

| | | |

|4. |DATE OF ADMISSION TO COURSE |07/09/2012 |

| | | |

|5. |TITLE OF THE TOPIC |FORMULATION AND EVALUATION OF |

| | |IN SITU OCULAR GEL OF LEVOFLOXACIN |

|6. |BRIEF RESUME OF THE INTENDED WORK |

| |6.1 NEED FOR THE STUDY |

| | |

| |Eye is the unique and vital organ of body. It is considered as window of the soul. There are many eye ailments which can affect this |

| |organ and one can even loss the eye sight. Therefore many ophthalmic drug delivery systems are available which are classified as |

| |conventional and novel drug delivery systems1. An ideal ophthalmic formulation should be administrated in eye drop form, without causing|

| |blurred vision or irritation2. |

| |Although various formulation exists in market for ocular drug delivery but are not able to provide highest bioavailability related to |

| |administered dose. Whenever an ophthalmic drug is applied through a conventional dosage form to the anterior segment of the eye, only |

| |small amount (5%) actually penetrates the cornea and reaches the interior tissue of the eyes. Factors that affects drug bioavailability |

| |includes rapid solution drainage by gravity, induced lachrymation, blinking reflex, normal tear turnover, superficial absorption of drug|

| |into the conjunctiva and sclera, rapid removal by the peripheral blood flow and low corneal permeability (act as lipid barrier). The |

| |progress has been made in gel technology for the development of droppable gel. They are liquid upon instillation and undergo phase |

| |transition in the ocular cul-de-sac to form visco-elastic gel and this provides a response to environmental changes3. |

| |In situ gel-forming drug delivery systems prepared from polymers that exhibit sol-to-gel phase transitions due to a change in a specific|

| |physicochemical parameter in the cul-de-sac. Deacetylated gellan gum (an exocellular polysaccharide of microbial origin, commercially |

| |available as Gelrite®) is an interesting in situ gelling polymer that has been tested since it seems to perform very well in humans. |

| |Preparations of Gelrite are dropped into eyes; gel formation takes place, induced by the electrolytes of the tear fluid. The other in |

| |situ gelling compound examined, sodium alginate, is widely used in pharmaceutical preparation. Similarly, aqueous solutions of alginate |

| |(a natural polysaccharide extracted from brown sea algae) also form gels when instilled into the eye4. |

| | |

| |Ideally,  an  in situ  gelling  system  should  be  a  low  viscous,  free flowing liquid to allow for reproducible administration to |

| |the eye as drops, and the gel formed following phase transition should be strong enough to withstand the shear forces in the cul-de-sac |

| |and demonstrated long residence times in the eye. In order to increase the effectiveness of the drug, a dosage form should be chosen |

| |which increases the contact time of the drug in the eye. This may then prolong the residence time of the gel formed in situ along with |

| |its ability to release drugs in sustained manner will assist in enhancing the bioavailability, reduce systemic absorption and reduce the|

| |need of frequent administration leading to improved patient compliance5. |

| |Levofloxacin is a broad spectrum antibiotic of the Fluoroquinolone drug class. Its spectrum of activity includes most strains of |

| |bacterial pathogens responsible for respiratory, urinary tract, gastrointestinal, and abdominal infections, including Gram negative |

| |bacteria, Gram positive bacteria and atypical bacterial pathogens. It is used for the treatment of bacterial conjunctivitis caused by |

| |organisms like Corynebacterium species, Staphylococus aureus, Staphylococcus epidermidis, Streptococcus pneumoniae, Streptococcus and |

| |Serratia marcescens. Levofloxacin inhibits bacterial type II topoisomerases, topoisomerase IV and DNA gyrase. Levofloxacin, like other |

| |fluoroquinolones, inhibits the subunits of DNA gyrase, two subunits encoded by the gyrA gene. This results in strand breakage on a |

| |bacterial chromosome, supercoiling, and resealing; DNA replication and transcription are inhibited. Levofloxacin and other |

| |fluoroquinolones are valued for this broad spectrum of activity, excellent tissue penetration, and for their availability in both oral |

| |and intravenous formulations. The plasma half-life of the drug has been estimated to range from 6 to 8 hours. It is subjected to renal |

| |metabolism6. Levofloxacin is a zwitterion at physiological pH, possessing a carboxylic group with pKa = 5.5, a piperazinyl group with pKa|

| |= 8.0 and another proton accepting function with pKa = 6.8 ± 0.37. |

| |Levofloxacin is available in tablet form, injection, oral solution, as well as used in prescription eye and ear drops. The aim of the |

| |present study is to prepare in situ ophthalmic gel of Levofloxacin to enhance ocular bioavailability and reduce dose frequency and |

| |thereby increasing patient compliance. |

| |6.2 REVIEW OF LITERATURE |

| |Srividya et al (2001)., describes the formulation and evaluation of an ophthalmic delivery system of an antibacterial agent, ofloxacin, |

| |based on the concept of pH triggered in situ gelation. Polyacrylic acid (Carbopol 940) was used as the gelling agent in combination with|

| |hydroxypropylmethyl cellulose (Methocel E50LV) which acted as a viscosity enhancing agent. The developed formulation was therapeutically|

| |efficacious, stable, non-irritant and provided sustained release of the drug over an 8 h period. The developed system is thus a viable |

| |alternative to conventional eye drops8. |

| |Harish et al (2009)., developed in situ oral topical gels of clotrimazole based on the concept of pH triggered and ion activated |

| |systems. The system utilizes polymers that exhibit sol-to-gel phase transition due to change in specific physico-chemical parameters. A |

| |pH triggered system consisting of carbopol 934P (0.2-1.4% w/v) and ion triggered system using gellan gum (0.1-0.75% w/v) along with |

| |hydroxyl propyl methyl cellulose E50LV was used to prolong the release of clotrimazole (0.1% w/v). Formulations were evaluated for |

| |gelling capacity, viscosity, gel strength, bioadhesive force, spreadability, microbiological studies and in vitro release. The use of |

| |carbopol as in situ gel forming system was substantiated by the property to transform into stiff gels when the pH was raised, whereas in|

| |gellan gum this transformation occurred in the presence of monovalent/divalent cations. Effect of calcium carbonate and other process |

| |parameters optimized and found that increase in calcium ions produced stronger gels. The drug content, clarity and pH of the formulation|

| |were found to be satisfactory. The viscosity was found to be in the range 5 to 85 centipoise for the sol, whereas for the gels it was up|

| |to 16000 centipoise. The formulation showed pseudoplastic flow with thixotrophy. The maximum gel strength (using texture analyzer) and |

| |bioadhesion was found to be up to 6.5 g and 4 g respectively. The optimized formulations were able to release the drug up to 6 h. The |

| |formulation containing gellan gum showed better sustained release compared to carbopol based gels9. |

| |Kamel et al (2002)., developed Pluronic F-127 based formulations of timolol maleate to enhance its ocular bioavailability. The effect of|

| |isotonic agents and PF-127 on concentrations on the rheological properties of the prepared formulations was examined. Different |

| |formulations containing combinations of PF -127 with HPMC/CMC/MC in various concentrations were also prepared and the effects of these |

| |agents on the viscosity and drug release characteristics of PF-127gels were studied. In vivo studies on albino rats showed highest % |

| |(15%) with PF-127 in combination with 3% MC when compared with 0.5% timolol maleate aqueous solution10. |

| |Yadav et al (2008)., evaluated and compared the efficacies of eye drops and in situ forming gel of pefloxacin mesylate in pseudomonas |

| |induced conjunctivitis in 40 rabbits. The in situ forming gel of pefloxacin mesylate was formulated as a liquid and when administered in|

| |the cul-de-sac, it gets converted to gel. The objective of the present research work was to demonstrate the in vivo activity of in situ |

| |gelling formulation and compared with marketed eye drops. No difference was obtained in all parameters of conjunctivitis on day 0, |

| |between in situ gelling formulation and marketed eye drops, indicating that severity of conjunctivitis was similar initially between the|

| |two groups. Comparison of scores obtained with marketed eye drops and in situ gel formulation indicated that In situ gelling formulation|

| |was faster in relieving symptoms of conjunctivitis. The findings of the present study indicate that in situ forming gel of pefloxacin |

| |mesylate is a potential delivery system for the treatment of pseudomonas induced conjunctivitis11. |

| |Shivsharan et al (2011)., developed three simple, precise and economical UV methods for the estimation of norfloxacin in pharmaceutical |

| |dosage form. Method A is absorbance maxima method, norfloxacin has the absorbance maxima at 277 nm. Method B is the first order |

| |derivative spectra, the absorbance was measured at λmax =287 nm and λmin =264 nm and the difference was measured for the respective |

| |concentration of standard and was plotted against concentration and regression equation was calculated. Method C applied was area under |

| |curve (AUC), in the wavelength range of 262-289 nm. Linearity for detector response was observed in the concentration range of 1-6μg/mL |

| |for all three methods. The proposed methods were successfully applied for the determination of norfloxacin in commercial pharmaceutical |

| |preparation12. |

| |Hongyi et al (2007)., developed a thermo-sensitive in situ gelling and mucoadhesive ophthalmic drug delivery containing puerarin based |

| |on poloxamer analogs (21% (w/v), poloxamer407/5% (w/v), poloxamer188 and carbopol (0.1% (w/v) or 0.2% (w/v), carbopol 1342P NF). The|

| |combined solutions would convert to firm gels under physiological condition and attach to the ocular mucosal surface for a |

| |relative long time. The incorporation of carbopol 1342P NF not only affected the pseudoplastic behavior with hysteresis of the|

| |poloxamer analogs solution and lead to higher shear stress at each shear rate, but also enhanced the muco-adhesive |

| |force significantly. In vitro release studies demonstrated diffusion-controlled release of puerarin from the combined |

| |solutions over a period of 8 hour. In vivo evaluation indicated the combined solutions had better ability to |

| |retain drug than poloxamer analogs or carbopol alone. It appeared that ocular bioavailability can be increased more |

| |readily by using in situ gelling and mucoadhesive vehicle13. |

| |J. Varshosaz et al (2008)., formulated thermosensitive chitosan/poloxamer in situ gel for ocular delivery of ciprofloxacin. Aqueous |

| |solutions of drug in chitosan/ Pluronic (poloxamer) were prepared to identify suitable compositions with regard to gel forming |

| |properties and drug release behavior. Mixtures of solutions of Pluronic (10-25% w/w) with chitosan (0.1-0.3% w/w) of different molecular|

| |weights (Mw) were prepared. The formulation consisted of 15% Pluronic and 0.1% low Mw chitosan, with the highest release efficiency |

| |(46.61 ± 0.41%) and an acceptable mean release time (1.94 ±0.27hr), is suggested as asuitable ophthalmic preparation for sustained |

| |release of ciprofloxacin14. |

| |Basavaraj K Nanjwade et al (2009)., formulated and evaluated an opthalmic delivery system for non steroidal anti-inflammatory drug, |

| |ketorolac tromethamine, based on the pH triggered in situ gelation. Polyacrylic acid was used as a gelling agent along with |

| |hydroxypropylmethylcellulose (Methocel K4M) which acted as a viscosity enhancing agent. Compatibility studies of the drug and excipients|

| |were carried out using differential scanning calorimetry (DSC). The developed formulation was therapeutically efficacious, stable, |

| |non-irritant, and provided sustained drug release over an 8h. The developed formulation is a viable alternative to conventional eye |

| |drops by virtue of its ability to enhance bioavailability through its longer precorneal residence time and ability to produce sustained |

| |drug release15. |

| | |

| |6.3 OBJECTIVES OF THE STUDY |

| |The main objective of the present study is to formulate and evaluate Levofloxacin in situ ocular gel to |

| |Improve the local bioavailability |

| |Reduce dose concentration |

| |Improve patient acceptability |

| |Increase contact time |

| |Increase precorneal residence time |

| |Decrease nasolacrimal drainage of the drug |

| |Prolong the effect of the drug hence frequent instillation of the drug is not required. |

|7. |MATERIALS AND METHODS |

| | Drug : Levofloxacin |

| |Polymer : HPMC, HEC, HPC, Carbomer, Carbopol-934P, Chitosan, Methylcellulose, Tween 90, EDTA, PVA or any other |

| |suitable polymers. |

| |Excipients : HPMC, HEC, HPC, Carbomer, Carbopol-934P, Chitosan, Methylcellulose, Tween 90, EDTA, PVA or any other |

| |suitable polymers. |

| |Method : Ocular in situ gelling system of Levofloxacin drug can be prepared by any one of the method |

| |pH induced in situ gelation |

| |Ion activated in situ gelation |

| |Thermo- sensitive in situ gelation |

| | |

| |7.1 EVALUATIONS |

| |Pre formulation studies includes |

| |Complete characterization of drug and polymers and its analytical method development |

| |Drug excipient compatibility studies can be confirmed by carrying out FTIR spectral studies16 |

| |Melting point |

| |Formulation studies includes |

| |Determination of pH17 |

| |Clarity 17 |

| |Gelation studies18 |

| |Rheology19 |

| |a. Viscosity |

| |b. Spreadability |

| |Phase transition temperature20 |

| |Isotonicity studies19 |

| |Sterility studies19 |

| |Drug content uniformity17 |

| |In vitro drug release study in simulated tear fluid18 |

| |Ocular irritancy test19 |

| |Accelerated stability studies21 |

| | 7.2 METHOD OF COLLECTION OF DATA |

| | |

| |Literature review including pub med/med line and internet search |

| |Lab experiment |

| |Does the study require any investigations or invention to be conducted on patients or other human or animals? If so, please mention |

| |briefly. |

| |Yes |

| |7.4 Has ethical clearance been obtained from your institution in case of |

| |7.3? |

| |Yes |

|8. |REFERENCES |

| |Mohan EC, Jagan MK, Venkatesham A. Preparation and evaluation of in situ gels for ocular drug delivery, J. Pharm. Res, 2009, |

| |2(6),1089-1094. |

| |Ganguly S, Dash AK. A novel in situ gel for sustained drug delivery and targeting. Int. J. Pharm, 2004, 276, pp. 83–92. |

| |Swati G, Suresh PV. Carbopol/chitosan based pH triggered in situ gelling system for ocular delivery of Timolol Maleate, Pharm. Sci. |

| |2010, 78, pp. 959-976. |

| |Balasubramaniam J, Kant S, Pandit JK. In vitro and in vivo evaluation of the Gelrite gellan gum-based ocular delivery system for |

| |indomethacin, Acta Pharm, 2003, 53(4), pp. 251-61. |

| |Indu PK, Manjit S, Meenakshi K. Formulation and evaluation of ophthalmic preparations of Acetazolamide,  Int. J.  Pharm, 2000, 199, pp. |

| |119–127. |

| | Laurence B, John L, Keith P. Goodman & Gilman's The Pharmacological Basis of Therapeutics. McGraw-Hill Prof |

| |Med/Tech. ISBN 978-0-07-142280-2. Retrieved 30 October 2012. |

| |Michot JM, Seral C, Van Bambeke F, Mingeot-Leclercq MP, Tulkens PM. Influence of efflux transporters on the accumulation and efflux of four|

| |quinolones (ciprofloxacin, levofloxacin, garenoxacin, and moxifloxacin) in J774 macrophages. Antimicrob. Agents Chemother, 2005, 49(6), pp.|

| |2429-2437. |

| |Srividya B, Cardoza RM, Amin PD. Sustained ophthalmic delivery of ofloxacin from a pH triggered in situ gelling system, J. Control. Rel,|

| |2001, 73(2‐3), pp. 205‐211. |

| |Harish NM, Prabhu P, Charayu RN, Subrahmanyam. Formulation and evaluation of in situ gel containing clotrimazole for oral candidiasis, |

| |Indian J. Pharm. Sci, 2009, 71(4), pp. 421‐427. |

| |Kamel LAH. In vitro and in vivo evaluation of pluronic F 127-based ocular delivery system for timolol maleate, Int. J. Pharm, 2002, 241,|

| |pp. 47-56. |

| |Yadav S, Parvez N. A comparative evaluation of 0.3% eye drops and in situ forming gel of pefloxacin mesylate in experimentally induced |

| |Pseudomonas conjunctivitis. Continental J. Pharmacol. Toxicol. Res, 2008, pp. 1-579. |

| |Shivsharan T, Ghante MR, Sawant SD. Three simple spectrometric methods for norfloxacin in bulk and tablet dosage form, Int. J. Pharm. |

| |Tech, 2011, 3(2), 2757-2764. |

| |Hongyi Q, Wenwen C, Chunyan H, Chuming C, Wenmin L, Chunjie W. Development of a poloxomer analogs /carbopol in situ Gelling and |

| |mucoadhesive ophthalmic delivery system for puerarin, Int.J.Pharm, 2007,337, pp. 178-187. |

| |Varshosaz J, Tabbakhian M, Salmani Z. Designing of a thermoreversible chitosan/poloxamer in situ gel for ocular delivery of |

| |ciprofloxacin, The open drug delivery, 2008, 2, pp. 61-70. |

| |Basavaraj K, Nanjwade, MAS, Murthy RSR, Yuvaraj P D. A novel pH-triggered in situ gel for sustained ophthalmic delivery of Ketorolac |

| |tromethamine. Asian J pharm sci, 2009, 4(3), pp. 189-99. |

| |Rahul N, Venkatakrishnakiran P, Dhanalakshmi P, Prasannaraju Y: Formulation and evaluation of in situ gelling systems for ocular |

| |delivery of Doxycycline hyclate. Journal of Innovative Trends in Pharmaceutical Sciences, 2012, 3(1), pp. 1-7. |

| |Shashank N, Bharani S, Thakur RS. Formulation and evaluation of pH triggered in situ ophthalmic gel of moxifloxacin hydrochloride, Int. |

| |J. Pharm. Sci, 2012, 4(2), pp. 452-459. |

| |Jagdish B, Shri k, Jayanta KP. In vitro and in vivo evaluation of the gelrite gellan gum-based ocular delivery system for indomethacin, |

| |Acta Pharm, 2003, 53, pp. 251-261. |

| |Lekhraj V, Mohammad S, Navdeep S, Ritu M, Gilhotra, Siddharth M. Development of phase change solutions for ophthalmic drug delivery |

| |based on ion activated and pH induced polymers, Int. J. Pharm, Professional’s Res, 2010, 1(2), pp. 137-144. |

| |Mansour M, Mansour S, Mortada N. In situ Forming Gels Ocular Poloxamer-based ciprofloxacin hydrochloride in situ forming gels, Ind. |

| |Pharm, 2008, 34, pp. 744-752. |

| |Bhoyar BS, Agnihotri VV, Bodhankar MM. Design of polyethylene polyoxypropylene block Co-Polymer based in situ gelling system for |

| |localized ocular drug delivery, Int. J. Res. Pharm and Chem, 2011, 1(3). |

|9. |Signature of Candidate | |

|10. |Remarks of the guide |

| |The above information is true to the best of my knowledge and the work will be done under my guidance. |

|11. |11.1 Name and Designation of Guide |Dr. PRASANTH V.V, M. Pharm., PhD |

| | |Department of Pharmaceutics |

| | |Gautham College of Pharmacy |

| | |Sulthan palaya, R.T Nagar (P.O) |

| | |Bangalore – 560 032, Karnataka. |

| |11.2 Signature | |

| |11.3 Co-Guide (IF ANY) | |

| |11.4 Signature | |

| |11.5 Head of the Department |Dr. PRASANTH V.V ,M. Pharm., PhD |

| | |Professor & Head |

| | |Department of Pharmaceutics |

| | |Gautham college of Pharmacy |

| | |Sulthan palaya, R.T Nagar (P.O) |

| | |Bangalore – 560 032, Karnataka. |

| |11.6 Signature | |

|12. |12.1 Remarks of the Chairman and Principal |

| |The above mentioned information is correct and I recommend the same for approval. |

| |12.2 Signature |Mrs. ARCHANA SAMY,M. Pharm, (PhD) |

| | |Principal |

| | |Gautham college of pharmacy |

| | |Sulthan playa, R.T Nagar (P.O) |

| | |Bangalore-32, Karnataka. |

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