final dissertation 2010

Formulation and evaluation of in-situ ophthalmic gel of Norfloxacin : 

Formulation and evaluation of in-situ ophthalmic gel of Norfloxacin DEPARTMENT OF PHARMACEUTICS AND PHARMACEUTICAL TECHNOLOGY S.K. PATEL COLLEGE OF PHARMACEUTICAL EDUCATION AND RESEARCH. GANPAT UNIVERSITY- 382711 DIST: MAHESANA (GUJARAT), INDIA. Guided by: Dr. Girish N. Patel M.Pharm, Ph.D. Presented by: Mr. Amit M. Patel B.Pharm

Outline : 

Outline Aim of present work Rationale of drug and drug delivery system Experimental work Conclusion References

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AIM OF PRESENT WORK To preparation and evaluation of insitu ophthalmic gel of norfloxacin. To provide an increase residence time resulting in prolonged drug delivery in Ocular site. To provide drug release in sustained manner thereby decrease in dosage frequency and thus Improve bioavailability of drug by preventing precorneal loss of drug.

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Conventional ocular dosage forms Eye drops(95% +$8-12 billion mkt.) Eye ointments Eye lotion

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Limitations of conventional dosage form

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In-situ system: In-situ : at place Improved local bioavailability Reduced dose concentration Less total drug Improved patient acceptability ( patient complience) Reduced dosing frequency Homogeneity of drug distribution Simplest to formulate and inexpensive

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Advantages of in-situ forming gel : Generally more comfortable than soluble or insoluble insertion. Less blurred vision than ointment. Increased bioavailability due to: Increased precorneal residence time decreased nasolacrimal drainage of the drug Chances of undesirable side effects arising due to systemic absorption of the drug through nasolacrimal duct is reduced. Drug effect is prolonged hence frequent instillation of drug is not required.

In situ gelling system : 

In situ gelling system In-situ forming hydrogels are liquid upon instillation and undergo phase transition in ocular cul-de-sac to form viscoelastic gel and this provide a response to environmental changes. ISGS three method: Change in pH (carbopol) Change in temperature (pluronic F127) Ion activation (sodium alginate)

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Rationale of drug

MATERIALS USED FOR OF RESEARCH WORK: : 

MATERIALS USED FOR OF RESEARCH WORK:

Experimental Work : 

Experimental Work Calibration curve in 1% v/v acetic acid: (for drug content ) Calibration curve in artificial tear solution: (for in-vitro release) Y = 0.1314x – 0.0202 R2 = 0.9923 Y = 0.114x + 0.0306 R2 = 0.9903

Selection of polymers in the formulation of in-situ ophthalmic gel : 

Selection of polymers in the formulation of in-situ ophthalmic gel Generally viscosity values in the range of 15-50 cps significantly improve the contact time in the eye. Different placebo formulations were developed and evaluated for rheological properties (viscosity), gel strength and gelling capacity to identify whether it is suitable for use as in situ gelling system.

Drug-excipient compatibility study : 

Drug-excipient compatibility study DSC spectra of pure drug Norfloxacin DSC Spectra of mixture of norfloxacin and Excipients IR spectrum of mixture of norfloxacin and Excipients IR spectrum of Norfloxacin

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Formulation of preliminary trial of Norfloxacin in-situ ophthalmic gel All formulations contains norfloxacin (0.3%w/v), Methyl Paraben (0.1% w/v), Citric acid (0.2% w/v), Boric acid (0.3% w/v), Sodium chloride (0.9 % w/v), Disodium EDTA (0.0625% w/v), Sodium metabisulfite (0.02% w/v).

Evaluation Parameters : 

Evaluation Parameters Physical appearance (clarity and colour) and pH In vitro gelling capacity Gel strength Drug content

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Viscosity Profile

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In-vitro drug release profile of prepared in situ ophthalmic gel of norfloxacin

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Optimization of in situ ophthalmic gel of norfloxacin using 2 3 full factorial designs

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Evaluation ( 23 full factorial) In vitro gelling capacity Drug content pH measurement Gel strength

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Viscosity Profile

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In-vitro drug release profile of prepared in situ ophthalmic gel of norfloxacin

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Kinetic modeling and mechanism of drug release study From the results, the in vitro drug release of batch N1 to N8 were best explain by Korsmeyer–Peppas model as a plot showed highest linearity (R2) but in case of N1 to N5, drug was released by Fickian diffusion (because n < 0.5) while in case of N6 to N8, drug release was follow non-Fickian model (because n > 0.5). Among all batches from N1 to N8, N5 showed highest linearity (R2 = 0.9985).

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Effect of Independent Variable on Dependent Variable by 23 Full Factorial Design

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Effect of formulation variable on CPR at 1 hr (Q1)

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Effect of formulation variable on CPR at 8 hr (Q8)

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Effect of formulation variable on gel strength(Y3)

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Selection of the best batch: Isotonicity testing Blood cells with norfloxacin as standard Blood cells with norfloxacin formulation The selection of the best batch depends on viscosity, drug content, Q1, Q8, release kinetics as well as gelling properties like gelation capacity and gel strength. Formulation N5 was found to be best among all formulation from N1 to N8 as per earlier discussion. So, the batch N5 was selected for further study.

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Ocular irritancy test: (In vitro human hemoglobin denaturation test)

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Based on the above data it is concluded that there was no any types of irritation shown in hemoglobin because the blank absorbance of hemoglobin & with the formulation absorbance of Hb was nearly same. Formulation N5 caused no hemolysis on contact with human blood which reveals the non-irritating nature of the formulation.

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Sterility test (Sterilization by autoclave) Image of FTM & SCDM culture media of formulation N5 and N6 at first day Image of FTM culture media of formulation N5 and N6 after 14 days Image of SCDM culture media of formulation N5 and N6 after 14 days

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Accelerated Stability study Stability study revealed that no any major changes taken place throughout the stability study for 3 months so we can say that formulation N5 has good stability.

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The comparative in vitro drug release profile between the marketed conventional ophthalmic drops and the formulation N5 showed 83.90 % and 39.7 % after initial 60min. At the and of 120 min. the drug release found to be 97.65 % and 56.2 % from the marketed product and N5 formulation, respectively, indicating that the drug release was significantly prolong by using the in situ gelling system. In-vitro Drug Release Profile of Marketed Norfloxacin Eye Drops

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Conclusion The present investigation deals with the formulation, optimization and evaluation of sodium alginate based insitu ophthalmic gel of norfloxacin. Sodium alginate, xanthan gum and HPMC K15 were used as polymer. The in situ formulation exhibited well viscosity, drug content, gelling properties (gelling capacity and gel strength) and sustained drug release; this study reports that ocular administration of aqueous solutions containing sodium alginate results in formation of in situ gel, such formations are homogeneous liquid when instilled in eye and become gel at the contact site. The results of a 23 full factorial design revealed that the concentration of sodium alginate (X1) and concentration of HPMC K15 (X3) significantly affected the dependent variables Q1 and Q8 while the concentration of xanthan gum (X2) and concentration of HPMC K15 (X3) significantly affected the dependent variable Y3 (gel strength). These insitu ophthalmic gel are, are thus, suitable for ocular sustained release of norfloxacin.

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Claude Mazuel. Norfloxacin. In Klaus florey-Analytical profiles of drugsubstances. Published by Elsevier. 2005;20:572;584. A Sindhu, f Sharon, S Bharath, B. V. Basavaraj, R Deveswaran and V. Madhavan. Sustained ophthalmic delivery of ofloxacin from an ion-activated in situ gelling system. Pak. J. Pharm. Sci. 2009;22:178. A. R. Shaikh, Rajani Giridhar. Bismuth-norfloxacin complex: Synthesis, physicochemical and antimicrobial evaluation. International Journal of Pharmaceutics. 2007;332:27. B. Sustar, N. Bukovec, P. Bukovec. Journal of Thermal Analysis. 1993;40: 475-481. Claude Mazuel. Norfloxacin. In Klaus florey-Analytical profiles of drug substances. Published by Elsevier. 2005;20:561-564. J. C. Roberson, C. M. Christian. Instrumental data for drug analysis. 3rd edition. Published by Taylor and Francis, New York. 2006;3:2265. R. V. Keny and C. F. Lourenco. formulation and evaluation of thermoreversible in situ gelling and mucoadhesive diltiazem hydrochloride liquid suppository. International journal of pharma and bio sciences. 2010;1(1). Paulo Costa, Jose Manuel Sousa Lobo. Modeling and comparison of dissolution profiles. European Journal of Pharmaceutical Sciences. 2001;13:123–133. References

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