DEVELOPMENT & EVALUATION OF MUCOADHESIVE MICROSPHERES OF PIOGLITAZONE MALEATE
DEVELOPMENT & EVALUATION OF MUCOADHESIVE MICROSPHERES OF PIOGLITAZONE MALEATE By 2Ram Chand Dhakar, 2Sheo Datta Maurya *1Sanwarmal, 1Manisha Gupta, 1HIMTCollege of Pharmacy, Gr Noida 2 Department of Pharmacy, IEC Group of Institution, Gr NoidaFor CorrespondenceSanwarmalLecturer, HIMT College of Pharmacy, Gr Noida, INDIA-201308E-mail: email@example.com
AIM, SCOPE & OBJECTIVES OF THE STUDYAIM: The present work was aim to formulate & evaluate mucoadhesive microspheres of Pioglitazone maleate. Microspheres were prepared by emulsification solvent evaporation method using SCMC, CP & SA as mucoadhesive polymers.SCOPE: Prepared microspheres are expected to adhere in the gastrointestinal mucosa and can be utilized for controlled release of Pioglitazone maleate for an extended period in the management of Diabetes type-II.Objectives: Reduce the Dosing frequency Fluctuations in therapeutic blood level is avoid Increase patient compliance Decrease in dose-related side effects
INTRODUCTIONWhat is microspheres?Microspheres are solid spherical particlesconsisting of protein or synthetic polymersranging in size from 1-1000μm.A Microsphere has its drug dispersed throughout the particle i.e. the internal structure is a matrix of drug and polymeric excipients.However, the success of these microspheres is limited owing to their short residence time at the site of absorption. This problem can be avoid by coupling mucoadhesion characteristics to the microspheres and developing mucoadhesive microspheres.2-6What is mucoadhesive microspheres?These microspheres are made by polymers that bind or Adhere to the mucosal tissue and offer local as well as systemic controlled release of drug for longer duration.
Selection of drug and Polymers:Pioglitazone maleate is an antidiabetic drug belongs to thiazolidinediones class. It requires control release due to its short t1/2 of 3-4 hours11. To reduce the dosing frequency of drug, it’s necessary to develop a newer formulation which release drug in sustained release manner. Thus mucoadhesive microspheres of pioglitazone would become promising candidate in management of diabetes type-II.Literature survey revealed that SCMC, SA & CP shows good mucoadhesive property & efficiently controlled the drug release. Thus these are the suitable candidate for mucoadhesive microspheres of pioglitazone maleate.
Preparation of microspheres12, 15 W/O Emulsification solvent evaporation method Aq. Sol. of SCMC, SA & CP Drug dissolved in DMSO D-P Solution Syringe containing D-P solutionliquid paraffin containing 0.5 % span 20 D+P droplets Stirring at 500 RPM · · · Microspheres 500 RPM, 800C Evaporation of solvent for 4 Hours Solidification of D-P droplets Drying Washing Filtration
Table-1 Composition of drug loaded microspheres Formulation Drug SCMC CP-934 P Na-alginate code F1 100 mg 900 mg -- -- F2 100 mg -- 900 mg -- F3 100 mg -- -- 900 mg F4 100 mg 450 mg 450 mg -- F5 100 mg 450 mg -- 450 mg F6 100 mg -- 450 mg 450 mgAll formulation were prepared at 2% polymer conc. and 500 rpm stirring speed
Surface morphology:visualize by SEM at BSIP, Lucknow.Drug entrapment efficacy17:50 mg of microsphere were taken and drug was extracted from microspheres by digesting for 24 hours with 10 ml of simulated gastric fluid(pH 1.2). During this period the suspension was agitated. After 24 hours, the solution was filtered & the filtrate was analyzed for the drug content. The drug entrapment efficiency was calculated using the following formula: Entrapment efficiency = (Actual drug content/theoretical drug content) 100
Particle Size17, 18: by optical microscopyA small amount of dry microspheres was suspended in n- hexane (10 mL).A small drop of suspension thus obtained was placed on a clean glass slide. The slide containing microspheres was mounted on the stage of the microscope and particles were measured using a calibrated ocular micrometer. The average particle size was determined by using the Edmondsons equation D mean = ∑nd/∑n,where n= number of microspheresand d= mean size range.
In-vitro mucoadhesivity19:By in-vitro wash-off test.A 1 1 cm piece of rat stomach mucosa was tied onto a glass slide using thread.Microspheres were spread on the wet, rinsed, tissue specimen & prepared slide was hung onto one of the groves of a USP tablet disintegrating test apparatus.The apparatus was operated such that the tissue specimen was given regular up and down movements in a beaker containing the simulated gastric fluid (pH 1.2).At hourly intervals up to 10 hours, the number of microspheres still adhering onto the tissue was counted. % mucoadhesion = (no. of microspheres remains / no. of applied microspheres) 100
In-vitro drug release13 USP XXI paddle type dissolution test apparatus Dissolution medium: simulated gastric fluid (pH 1.2), 900 ml 100 mg Microspheres are spread on wet double layer muslin cloth and hanged with the paddle of disso apparatus.Temperature of bath=37 1 C.Paddle speed = 50 rpm.Sample volume= 10 ml,Sampling interval= 1 hour Sample analyzed for drug content by UV-Visible spectrophotometer at 268.9 nm.
RESULTS AND DISCUSSIONSurface morphology: Examined by SEM.The SEM showed that the mixture of SCMC and CP produced spherical with smooth surface microspheres due to their high solubility in water6.While SA microspheres were of irregular shape with a rough morphology due to less water solubility & non uniform evaporation of water from the surface of microspheres. Figure : SEM of formulation F1 showing population of microspheres
Particle size analysis:Average p. size was found to be in the range of 31.20 to 47.54 μm. Increase in stirring speed Increase in polymer conc produce high energy for breaking high viscosity of polymer sol of droplets Particle size increases Particle size decreasedDrug entrapment efficiency: It was found in the range of 54.00 to 80.00 % . Formulation F2 containing CP showed max drug loading about 80 % Formulation F6 containing CP/SA shows min drug loading about 53% Microspheres of SA are irregular in shape therefore more drug loss from surface during washing leads to less drug entrapment efficiency. Rank order of % drug loading of various formulations: F2 > F4 > F1 > F5 > F3 > F6
Table –2 Comparative % yield, Particle size, % drug entrapment and % mucoadhesion of microspheresFormulation % yield Particle size % Mucoadhesion % Drug code (µm) after 1 hr entrapment F1 73.45 3.20 34.54 2.43 94.33 2.33 69 2.45 F2 71.56 2.80 31.20 1.88 89.22 2.43 80 3.23 F3 79.10 2.95 47.54 3.24 87.23 2.83 57 2.86 F4 75.52 2.84 38.62 2.78 72.20 1.90 78 2.75 F5 72.12 3.10 43.12 2.84 95.33 2.95 63 2.84 F6 74.44 2.60 41.85 3.15 76.44 2.32 54 3.68Values are represented as mean standard deviation (n=3).All formulation were prepared at 2% polymer conc. and 500 rpm stirring speed
In-vitro mucoadhesivity test: Formulation F1 containing SCMC showed the highest mucoadhesivity due to anionic nature of the polymer. Formulation F6 containing SA/CP-934 showed the lowest mucoadhesivity due to the irregular surface of microspheres. Rank order of % mucoadhesivity, after 8 hours was found to be as follows: F1 > F2 > F3 > F5> F4 > F6
DRUG RELEASE STUDY:Dissolution medium: SGF(pH 1.2), Temp: 370C 1. Drug release form these microspheres were found to be slow, extended and dependent on the type and conc. of polymer used. Formulation F1 containing SCMC showed the max. release 91.45 % after 10 hrs, due to rapid swelling property and high dissolution of SCMC in SGF.High swelling of SCMC Faster drug release Dissolution medium permeation is facilitated While SA microspheres showed the slow drug release due to less swelling action as compared to SCMC.
Figure : Comparative % drug release of microspheres formulations
CONCLUSION The SEM reveals smooth surface microspheres. The particle size of microspheres ranged from 31-47 μ. The entrapment efficiency ranged between 54-80%. All the formulation show significant mucoadhesion property and it depends on the type of polymer used. The in-vitro release & the mucoadhesion studies shows SCMC formulation was the best which released 98.60% drug at the end of 12th hour.
ACKNOWLEDGEMENT: Authors is highly thankful to HIMT College of Pharmacy, & Dept of Pharmacy, IEC Group of Institution, Greater Noida for providing us best lab facilities and Indswift Labs Pvt ltd, for providing drug sample.
REFERENCES:1. Rajput G et al. Sys Rev Pharm, vol 1, issue 1, Jan-June 2010. 70-782. Capan Y et al. AAPS PharmSciTech. Vol- 4, 2003. E28.3. Gohel MC et al. J Control Release. Vol-51: 1998. 115-122.4. Nagai T et al. J Control Release. Vol-1: 1984, 15-22.5. Ilium L et al. Int J Pharm. Vol-46: 1988.261-265.6. Wang J et al. J. Control Release. Vol-73, 2001.223-231.7. Lehr CM et al. Int J Pharm. Vol-78: 1992. 43-48.8. Chowdary KPR et al. AAPS PharmSciTech. Vol-4: 2003.E39.9. Chowdary KPR et al. Ind. J. Pharm. Sci.; vol-65(3): 2003. 279-284.10. Goodman and Gilman’s. “The Pharmacological Basis of Therapeutics”, 10 th edition (international edition), McGraw Hill, Medical Publication Division, New York: 1357-1358.11. Complete Pioglitazone maleate information, drug information online, and www.drug_com.mht.12. Semalty A et al. Indian drugs, vol-44(5), 2007.13. Jian-Hwa Guo et al. Drug Delivery Technology. http://www.drugdeliverytech.com/cgi- bin/articles.cpi?idArticle=159.14. Gohel MC et al. Indian J. Pharm Sci. vol-67(8): 2005.575-81.15. Bomati-Miguel O et al. Biomater. 26: 2005.5695–5703.16. Patel JK et al. AAPS PharmSciTech. Vol-6: 2005. 49-55.17. Dashora K et al. Pak J Pharm Sci. vol-19, 2006, 6-10.18. Martin A et al. 4 th ed. New Delhi. BI Waverly Pvt Ltd, 1996.19. Lehr CM et al. J Control Release. Vol-13: 1990.51-62.