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K S Tan , K H Leong, L Y Chung, M I Noordin

K S Tan , K H Leong, L Y Chung, M I Noordin. Department of Pharmacy Faculty of Medicine University of Malaya Kuala Lumpur. Introduction. Optimization of pharmaceutical formulation Conventional trial-and-error approach Mathematical Modeling Method. Introduction.

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K S Tan , K H Leong, L Y Chung, M I Noordin

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  1. K S Tan, K H Leong, L Y Chung, M I Noordin Department of Pharmacy Faculty of Medicine University of Malaya Kuala Lumpur

  2. Introduction Optimization of pharmaceutical formulation • Conventional trial-and-error approach • Mathematical Modeling Method.

  3. Introduction • Furosemidehas a narrow absorption window (located at upper GI tract)1, 2 & 3. • Conventional oral formulation exhibits erratic bioavailability & unpredictable response4. Furosemide

  4. Introduction Absorption window

  5. Introduction Absorption window o [Concept adapted from Reference 1]

  6. Introduction Gastroretentive dosage form prolongs retention time in stomach & permits continuous drug release to optimal absorption site1, 2 & 5.

  7. Objectives • To optimize a formulation for furosemide characterized by a 12-hour gastroretentive and sustained release profile. • To demonstrate the usefulness of mathematical modeling method in optimization of formulation.

  8. Methods: Overview Determination of 13 model formulations (Formulae A - M) via simplex lattice design. Preparation of tablets (Formulae A – M) Tablet QC tests (Uniformity of weight, friability, tablet size, hardness) • In vitro dissolution tests (8 hours) • Enzyme-free simulated gastric fluid (SGF) pH 1.2 • USP paddle method (100 rpm) • Temperature 37±0.5˚C • Sample buffered to pH 5.8 & Assayed with UV spectrophotometry at 278 nm • In vitro tablet swelling tests • Enzyme-free simulated gastric fluid (SGF) pH 1.2 • USP paddle method (100 rpm) • Temperature 37±0.5˚C • Measurement of swelling tablet diameter (To be continued in next slide)

  9. Methods: Overview (Continued from previous slide) Data of in vitro tablet dissolution tests Data of in vitro tablet swelling tests • Multiple Linear Regression Analysis • Model-fitting • Determination of best-fit models for individual response • Multiple Linear Regression Analysis • Model-fitting • Determination of best-fit models for individual response Optimization of formulation Design-Expert® integrate all models built and solve simultaneously to search for optimal formulation based on the constraints imposed. Verification of optimal formulation (In vitro dissolution tests & tablet swelling test)

  10. Methods Mixture experimental design • Tablet excipients: • Iota-carrageenan, • Lambda-carrageenan • Acacia gum. • Simplex lattice design was employed to determine excipient composition of 13 model formulations. • Each 400 mg tablet contains 60 mg furosemide.

  11. Methods • Composition of tablet excipients for 13 model formulations.

  12. Results & Discussions In Vitro Tablet Dissolution Profiles of 13 model formulations (n = 6)

  13. Results & Discussions In Vitro Tablet Swelling Profiles of 13 model formulations (n = 6)

  14. Results & Discussions Formula D: Dissolution Profile Formula B: Dissolution Profile Formula D: Tablet Swelling Profile Formula B: Tablet Swelling Profile

  15. Results & Discussions Model-Fitting • The data of all response variables (tablet dissolution and swelling tests) for 13 formulations were fitted into various equations:

  16. Results & Discussions Models for Drug Release & Tablet Swelling Profiles

  17. Contour plots of individual response variable for in vitro tablet dissolution studies Y1.5h:% Drug released in 2 hour Y1.5h:% Drug released in 1.5 hour Y1h:% Drug released in 1 hour Y30 min:% Drug released in 30 minutes Y2h:% Drug released in 2 hours Y3h:% Drug released in 3 hours Y4h:% Drug released in 4 hours Y5h:% Drug released in 5 hours Y6h:% Drug released in 6 hours Y7h:% Drug released in 7 hours Y8h:% Drug released in 8 hours

  18. Contour plots of individual response variable for in vitro tablet swelling studies Z15min: Tablet diameter at 15th min Z30min: Tablet diameter at 30th min Z45min: Tablet diameter at 45th min Zih: Tablet diameter at 1st hour Zi.5h: Tablet diameter at 1.5th hour Z2h: Tablet diameter at 2nd hour Z3h: Tablet diameter at 3rd hour Z4h: Tablet diameter at 4th hour Z6h: Tablet diameter at 6th hour Z5h: Tablet diameter at 5th hour Z7h: Tablet diameter at 7th hour Z8h: Tablet diameter at 8th hour

  19. Results & Discussions Optimization of Formulation • Constraints imposed on: • Drug release at 2hr (12-16%), 4hr (24-32%), 6hr (42-52%) & 8 hr (70-100%). • Tablet swelling: 13-19 mm (maximizing). • Optimized formula:

  20. Results & Discussions Optimized formulation Tablet dissolution profile (A) and swelling profile (B) of optimal formulation predicted by the model. B A

  21. Results & Discussions Verification of Optimal Formulation Tablet dissolution profile (A) and swelling profile (B) of optimal formulation (Comparing observed vs. predicted data) B A (Paired-samples T-test, p > 0.05) (Paired-samples T-test, p > 0.05)

  22. Results & Discussions In Vitro Tablet Dissolution Profiles The optimal formulation exhibits a zero-order release kinetic. (Fitted into Korsmeyer-Peppas model, n = 0.94)

  23. Results & Discussions In Vitro Tablet Dissolution Profiles Commercial Product: furosemide 60 mg (Wakelkamp et al 1999) GRDF: A gastroretentive dosage form, furosemide 60 mg developed by Klausner et al (2003)5 OF: The optimal formulation obtained in this study.

  24. Conclusions • Optimal formulation with desirable release profile & tablet swelling characteristics was obtained. • An efficient optimization process: omitting the cost- and time-consuming procedures as in the conventional trial-and-error approach. • Mathematical modeling permits the characterization of drug release kinetics during the optimization process. • Graphical optimization allows evaluation of excipient’s functionality in the dosage form.

  25. References • Chawla, G, Gupta, P, Koradia, V & Bansal, AK 2003, ‘Gastroretention a means to address regional variability in intestinal drug absorption’, Pharmaceutical Technology, vol. 27, no. 7, pp. 50-68. • Davis, SS 2006, ‘Formulation strategies for absorption windows’, Drug Discovery Today, vol. 10, no. 4, pp. 249-257. • Rouge, N, Buri, P & Doelker, E 1996, ‘Drug absorption sites in the gastrointestinal tract and dosage forms for site-specific delivery’, International Journal of Pharmaceutics, vol. 136, pp. 117-139. • Ponto, LLB & Schoenwald, RD 1990, ‘Furosemide (frusemide): a pharmacokinetic/pharmacodynamic review (part I)’, Clinical Pharmacokinetics, vol. 18, no. 5, pp. 381-408. • Klausner, EA, Lavy, E, Stepensky, D, Cserepes, E, Barta, M, Friedmann, M & Hoffman, A 2003b, ‘Furosemide pharmacokinetics and pharmacodynamics following gastroretentive dosage form administration to healthy volunteers’, Journal of Clinical Pharmacology, vol. 43, pp. 711-720. • Wakelkamp, M, Blechert, Å, Eriksson, M, Gjellan, K & Graffner, C 1999, ‘The influence of frusemide formulation on diuretic effect and efficiency’, British Journal of Clinical Pharmacology, vol. 48, pp. 361-366.

  26. Results & Discussions Model-fitting Summary for Tablet Dissolution Profiles

  27. Results & Discussions Model-fitting Summary for Tablet Swelling Profiles

  28. Results & Discussions • Experimental dissolution data of optimal formula fitted into Korsmeyer-Peppas model. Korsmeyer-Peppas model:

  29. Tan K S - Aug 2007

  30. Tan K S - Aug 2007

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