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“FORMULATION AND EVALUATION OF IN-SITU OPHTHALMIC GEL OF MOXIFLOXACIN AND KETOROLAC TROMETHAMINE COMBINATION” MASTER OF PHARMACY DISSERTATION PROTOCOL SUBMITTED TO THE RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES, KARNATAKA, BANGALORE BY SOUDHA BEGUM M.PHARM - I Under the Guidance Of DR. HARISH.N.M.M.PHARM ,Ph.D ASSOCIATE PROFESSOR DEPARTMENT OF INDUSTRIAL PHARMACY SRINIVAS COLLEGE OF PHARMACY, VALACHIL, MANGALORE-574143. 2013-2014 RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES, BANGALORE,KARNATAKA ANNEXURE - II PROFORMA FOR REGISTRATION OF SUBJECTS FOR DISSERTATION 1. Name of the Candidate and Address: MISS. SOUDHA BEGUM 1st YEAR M.PHARM, DEPARTMENT OF INDUSTRIAL PHARMACY SRINIVAS COLLEGE OF PHARMACY, VALACHIL, MANGALORE-574143. 2. Name of the Institution: SRINIVAS COLLEGE OF PHARMACY, VALACHIL, FARANGIPETE POST, MANGALORE-574143. 3. Course of Study and Subject: MASTER OF PHARMACY (INDUSTRIAL PHARMACY) 4. Date of Admission: 5. Title of the Project: 25/07/2013 “FORMULATION AND EVALUATION OF IN-SITU OPHTHALMIC GEL OF MOXIFLOXACIN AND KETOROLAC TROMETHAMINE COMBINATION” 6.0 Brief resume of the intended work 6.1 Need of the study Eye is the most vital organ of the body. To achieve effective ocular therapy, an adequate amount of active ingredients must be delivered and maintain at the site of action within the eye. The anatomical structure and the protective physiological process of the eye exert a formidable defense against ophthalmic drug delivery, leads to poor precorneal drug loss results in poor ocular bioavailability and ultimately poor ocular therapy. To improve ophthalmic drug bioavailability, there are considerable efforts directed towards newer drug delivery systems for ophthalmic administration. Since Conventional delivery systems often result in poor bioavailability and therapeutic response because of high tear fluids turn over and dynamics cause rapid elimination of the drug from the eyes. Newer research in ophthalmic drug delivery systems is directed towards a amalgamation of several drug delivery technologies, that includes to build up systems which is not only extend the contact time of the vehicle at the ocular surface, but which at the same time slow down the removal of the drug. There are various new dosage forms like in-situ gel, collagen shield, minidisc, ocular film, ocusert, nanosuspension, nanoparticulate system, liposomes, niosomes, dendrimers, ocular iontophoresis etc. So, to overcome bioavailability problems, ophthalmic in-situ gels were developed. This deals with the study of a novel in-situ gel approach as a means to localize and prolong drug activity at its site of action. These are solutions, instilled as drops into the eye and undergo a sol to gel transition in the culde-sac, improved ocular bioavailability by increasing the duration of contact with corneal tissue, thereby reducing the frequency of administration required in case of conventional ophthalmic solutions, thus optimizing ocular therapy.1 Eye-drops are the conventional dosage forms that account for 90% of currently accessible ophthalmic formulations. Despite the excellent acceptance by patients, one of the major problems encountered is rapid precorneal drug loss. To improve ocular drug bioavailability, there is a significant effort directed towards new drug delivery systems for ophthalmic administration. This chapter will focus on three representative areas of ophthalmic drug delivery systems: polymeric gels, colloidal systems, cyclodextrins and collagen shields. Hydrogels generally offer a moderate improvement of ocular drug bioavailability with the disadvantage of blurring of vision. In-situ activated gel-forming systems are preferred as they can be delivered in drop form with sustained release properties. Colloidal systems including liposomes and nanoparticles have the convenience of a drop, which is able to maintain drug activity at its site of action and is suitable for poorly water-soluble drugs. It seems that new tendency of research in ophthalmic drug delivery systems is directed towards a combination of several drug delivery technologies. There is a tendency to develop systems which not only prolong the contact time of the vehicle at the ocular surface, but which at the same time slow down the elimination of the drug. Combination of drug delivery systems could open a new directive for improving results and the therapeutic response of non-efficacious systems. One of the ways to optimize ocular drug delivery is to prolong the precorneal drug residence time. This focus on recent findings on the formulation effects in ocular drug bioavailability, employing polymers for the preparation of hydrogels, bioadhesive dosage forms, in-situ gelling systems and colloidal systems including liposomes and nanoparticles. The results observed suggested that mucoadhesion or bioadhesion played a role in the sustained action of drugs more significantly compared to non-mucoadhesive polymers.2 In-situ hydrogels are instilled as drops into the eye and undergoes a sol to gel transition in the cul-desac, improved ocular bioavailability by increasing the duration of contact with corneal tissue, thereby reducing the frequency of administration. Clinical applications of Moxifloxacin hydrochloride and Ketorolac tromethamine3:Moxifloxacin hydrochloride is long acting fourth generation fluoroquinolones having high activity against gram-positive bacteria including beta lactam/macrolide resistant ones and some anaerobes. It is used against acute bacterial exacerbations of chronic bronchitis, Community acquired pneumonia, sinusitis, otitis media. It shows the bactericidal effect by specifically inhibiting the DNA gyrase (topoisomerase II) and topoisomerase IV, which is required by bacteria for DNA replication, transcription repair and recombination. Ketorolac tromethamine is an novel NSAID with potent analgesic and modest antiinflammatory activity. In post-operative pain it has similar efficacy as opioids and is free of opioid side effects. Like other NSAIDs, it inhibits prostaglandin synthesis and relives the pain by peripheral mechanism. In short-lasting pain, it has compared favourably with aspirin. The purpose of the present work is to develop an in-situ ophthalmic gel of Moxifloxacin hydrochloride, a fluoroquinolone antibiotic and Ketorolac tromethamine combination for the treatment of bacterial infection and reduction of ocular pain. 6.2 Review of Literature 1) Hareesh B, Mohammed G, Narayana R4 have developed and evaluate in-situ gels of moxifloxacin for the treatment of periodontitis using gellan gum and sodium alginate based on the concept of ion activated systems. The system utilizes polymers that exhibit sol-to-gel phase transition due to change in specific physico-chemical parameters. Sol-to-gel transformation occurred in the presence of monovalent /divalent cations. It was found that increase in the concentration of calcium ions produced stronger gels. Formulations were evaluated for gelling capacity, drug content, clarity, viscosity, gel strength, spread ability, microbiological studies and in vitro release. The results shown by the above characterization studies were found to be satisfactory. Experimental part showed that viscosity of sols and gel strength was increased with increase in the concentration of polymers and the sustained release of drug was observed. 2) Sirish V, Sadhna K, Nalini S, Sadanandam M5 have formulated and evaluated ion activated ocular gels of ketorolac tromethamine by using ion activated gelling systems of Ketorolac tromethamine. These gelling systems involve the use of Gelrite as polymer. The formulations were evaluated for clarity, pH measurement, gelling capacity, drug content estimation, rheological study, in vitro drug release, ocular irritancy studies (as per draize test) and ex-vivo corneal permeation studies using isolated goats cornea. The developed formulations showed sustained release of drug for upto 6 hrs. The formulations were found to be non‐irritating with no ocular damage. 3) Shashank N, Bharani S, Thakur R6 had designed and characterized pH triggered in-situ ophthalmic gel forming solution using a fourth generation fluoroquinolone antibiotic, Moxifloxacin hydrochloride. Polyacrylic acid (Carbopol 934) was used as gelling agent in combination with hydroxyl propyl methyl cellulose(k15M) as viscosifying agent. Benzalkonium chloride in suitable concentration was used as preservative. The formulations were sterilized by autoclaving at 1210 C for 15 min at 21 psi. The prepared formulation were evaluated for visual appearance, clarity, pH measurement, gelling capacity, drug content and in-vitro diffusion studies, sterility test, microbiological studies and stability studies. Under rheological condition both solution and gel have shown pseudo plastic behaviour. 4) Hanan L, Demiana N, Shoukry M7 had developed and evaluate temperature triggered in-situ gelation using pluronic, and pH triggered in-situ gelation using carbopol 934 The developed formulae were evaluated regarding their gelation temperature (for PL systems), gelling capacity, rheological measurements. characteristics, in-vitro release behavior and mucoadhesion 5) Kavitha K, Rajas N8had prepared sustained release in-situ ocular gels of levofloxacin hemihydrates using gelrite as gel forming polymer, which is used in treatment of various bacterial infections. Formulations were evaluated for physical parameters like Clarity, pH, drug content, gelation, rheological studies, sterility test, in-vitro drug release study and ocular irritancy studies. The formulated gels were transparent, uniform in consistency and had spreadability with a pH range of 7.1 to 7.4. Six different formulations with increasing polymer concentrations were prepared which was found to have drug content of 72-86%. From the preliminary studies it was observed that as the concentration of polymer was increased, the rate of drug release decreased to produce sustained drug delivery for prolonged period of more than 8 hours. A maximum of90.2% drug release was observed in in-vitro studies. Further in-vivo results conclude that it is be possible to formulate in-situ ocular gel containing Levofloxacin Hemihydrate. 6) Saritha M, Amulya CH9 had developed ophthalmic drug delivery system using two different gelling agents with different mechanisms for gelation of Moxifloxacin hydrochloride, a fluoroquinolone antibiotic. Sodium alginate – an ion sensitive gelling agent and Poloxamer – a temperature sensitive gelling agent were employed in the formation of in-situ hydrogel along with HPMC K4M as viscosifying agent. The developed formulations were therapeutically efficacious, stable, non-irritant and provided sustained release of the drug over an 8 hour. 7) Sumegha M, Surendrakumar J, Nishiprakash J10 had formulate and evaluate in-situ gelling system of ketorolac tromethamine using Carbopol 940 as the gelling agent in combination with HPMC K4M which acted as a viscosity enhancing agent. The prepared formulations were evaluated for pH, clarity, gelling capacity, in-vitro drug release, drug-excipient interactions (FTIR), and Short-term stability studies (40±2° C/75±5% RH for 3 months). IR spectroscopic studies indicated that there are no drug-excipient interactions. drug release data of optimized formulation was treated according to Zero, First, Korsmeyer Peppas and Higuchi kinetics to access the mechanism of drug release. Eye irritation test using the HET-CAM test data of optimized formulation and calculated S value. The gel provided sustained drug release over an 9 hour period and the reduced frequency of instillation resulting in better patient acceptance. 8) Basavaraj N, Manjappa S, Murthy R., Yuvaraj P11had formulate and evaluate an ophthalmic delivery system for a nonsteroidal anti-inflammatory drug, ketorolac tromethamine, based on the concept of pH-triggered in-situ gelation using Polyacrylic acid (Carbopol® 934) was used as the gelling agent in combination with hydroxypropylmethylcellulose (Methocel K4M) which acted as a viscosity enhancing agent. Compatibility studies of the drug excipients were carried out using differential scanning calorimetry (DSC). The prepared formulations were characterized for clarity, pH, drug content, sol-to-gel transition by scanning electron microscopy (SEM), in-vitro and in-vivo drug release, ocular irritation and stability. The clarity, pH and drug content of the developed formulation were found to be satisfactory. The developed formulation was therapeutically efficacious, stable, non-irritant, and provided sustained drug release over an 8-h period. 9) Hiremath et al12 had prepared and evaluated novel in-situ gum based ophthalmic drug delivery system of linezolid. Hydroxypropyl guar (HPG) and xanthum (XG) were used as gum with the combination of hydroxyethyl cellulose (HEC), carbopol (CP), and sodium alginate as viscosity enhancing agents. Suitable concentrations of buffering agents were used to adjust the pH to 7.4. All the formulations were sterilized in an autoclave at 121°C for 15mins. The formulations were evaluated for clarity, pH measurement, gelling capacity, drug content estimation, rheological study, in-vitro diffusion study, antibacterial activity, isotonicity testing, eye irritation testing. The developed formulations exhibited sustained release of drug from formulation over a period of 6 hours thus increasing residence time of the drug. 6.3 Objectives of the study:The present research study is planed with the following objectives. 1) To formulate the in-situ ophthalmic gel of moxifloxacin hydrochloride and ketorolac tromethamine combination. 2) To check the compatibility of moxifloxacin hydrochloride and ketorolac tromethamine with all the polymers by using FTIR. 3) To evaluate the prepared formulation for12 a) Visual appearance b) Clarity c) pH measurement d) Gelling capacity e) Drug content f) In-vitro diffusion studies g) Sterility test h) Microbiological studies 4) To carry out rheological studies. 5) To carry out stability studies as per ICH guidelines. 7 Material and Method Materials: Drug: Moxifloxacin hydrochloride and Ketorolac tromethamine. Polymers: Gellan gum, sodium alginate,Gelrite, Carbomer, Cellulose acetate phthalate, Poloxamers (Pluronic,Tetronics), cellulose derivatives (MC, HPMC), Xyloglucan etc. Excipients: Calcium chloride, Sodium citrate, Benzalkonium chloride etc. Method13: The ophthalmic gel of moxifloxacin hydrochloride and ketorolac tromethamine will be formulated by using any one of the following method: pH trigged method Ion activated method Temperature activated method 7.1 Source of Data: Review of literature from Journals such as, o European Journal of Pharmaceutical Sciences. o Journal of Drug Delivery and Therapeutics o Indian Journal of Pharmaceutical sciences o Asian Journal of Pharmaceutical Sciences o World Journal of Pharmaceutical Sciences o International Journal Pharmatech Research o International Journal Of Pharmacy And Pharmaceutical Sciences o International Journal Of Pharmaceutical Science Research And Review 7.2 – Method of Collection of Data: 1. An Overview of ophthalmic gel for sustained drug delivery. 2. Different approaches for achieving sustained drug delivery by using gel systems. 3. Different methods of preparing ophthalmic gel 4. Evaluation of various parameters of prepared gel formulations as follows: pH Drug Content In-vitro Drug Release Rheological Studies Stability Studies Microbiological studies Gelling capacity Ocular irritation studies 7.3-Does the study require any investigation to be conducted on patients or other humans Or animals? If so, please describe briefly. NOT APPLICABLE 7.4 Has ethical clearance been obtained from your institution in case of 7.3 NOT APPLICABLE List of References:1. Lalit K, Ravindra S, Stuti G, Dhiraj K. In-situ Gel: A Novel System For Ocular Drug Delivery. Int J Pharm Sci Rev Res 2011; 9(2): 83-91. 2. Sampath K, Debjit B, Shravan P, Shweta S. Recent Challenges and Advances in Ophthalmic Drug Delivery System. The Pharm Inno 2012; 1(4): 19-31. 3. Tripathi KD, Quinolones, General consideration, Essential of Medical Pharmacology, 6th edn, New Delhi:Jaypee Brothers Medical Publishers(P) Ltd; 2008: 687-693. 4. Hareesh B, Mohammed G, Narayana R. Development And Evaluation Of In- Situ Gels Of Moxifloxacin For The Treatment Of Periodontitis. Indonesian J Pharm 2012; 23(3): 141 – 146. 5. Sirish V, Sadhna K, Nalini S, Sadanandam M. Formulation And Evaluation Of Ion Activated Ocular Gels Of Ketorolac Tromethamine. Int J Curr Pharm Res 2010; 2(3): 33-38. 6. Shashank N, Bharani S, Thakur R. Formulation And Evaluation Of pH Triggered Ophthalmic Gel Of Moxifloxacin Hydrochloride. Int J Pharmacy Pharm Sci 2012; 4(2): 452-459. 7. Hanan L, Demiana N, Shoukry M. Evaluation of two in-situ gelling systems for ocular delivery of Moxifloxacin: In-vitro and in-vivo studies. J Chem Pharm Res 2011; 3(2): 66-79. 8. Kavitha K, Rajas N. Sustained Ophthalmic Delivery of Levofloxacin Hemihydrate from An Ion Activated In-Situ Gelling System. Int J PharmTech Res 2011; 3(2): 702-706. 9. Saritha M, Amulya CH. Opthalmic Drug Delivery By Controlled Release In-Situ Forming Moxifloxacin Hydrogel. Int J Adv Pharm Sci 2012; 3(5): 375-379. 10. Sumegha M, Surendrakumar J, Nishiprakash J. Formulation And Evaluation Of In-Situ Opthalmic Gel Of Ketorolac Tromethamine. World J Pharmacy Pharm Sci 2013; 2(3): 13701384. 11. Basavaraj N, Manjappa S, Murthy R., Yuvaraj P. A novel pH-triggered in-situ gel for sustained ophthalmic delivery of ketorolac tromethamine. Asian J Pharm Sci 2009; 4(3): 189-199. 12. Hiremath SP, Dasankoppa F, Nadaf A, Jamakandi VG, Jameel M, Sreenivas A, Hasanpasha S, Aezazahmed, Nanjundaswamy G. Formulation and Evaluation of a Novel In-Situ Gum Based Ophthalmic Drug Delivery System of Linezolid. Sci Pharm 2008; 76: 515–532. 13. Pandya T, Modasiya M, Patel V. Opthalmic in-situ gel sytems. IntJ Pharm Life Sci 2011; 2(5): 730-738. 9. Signature of candidate (SOUDHA BEGUM) 10. Remark of the guide The work, which is assigned to SOUDHA BEGUM is under my guidance. 11 Name & Designation of Dr. HARISH.N.M. M.PHARM, Ph.D 11.1 Guide Associate Professor, Department of Industrial Pharmacy Srinivas College Of Pharmacy, Valachil, Mangalore-574143. 11.2 Signature 11.3 Co-Guide (if any) 11.4 Signature 11.5 Head of the Department Dr. HARISH.N.M. M.PHARM, Ph.D Associate Professor Department of Industrial Pharmacy Srinivas College of Pharmacy, Valachil, Mangalore-574143. 11.6 Signature 12 12.1 Remark of the Director principal Recommended and forwarded for favourable consideration 12.2 Signature Dr. A. R. SHABARAYA M.PHARM, Ph.D Principal and Director, Srinivas College Of Pharmacy,Mangalore-574143.