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Oral controlled release formulation design and case study

Oral controlled release formulation design and case study. Enxian (Andy) Lu, Ph.D. Shanghai Aucta Pharmaceuticals Co., Ltd, GM NDDS China, Oct 23, 2012. Outline. Oral controlled release formulation overview Factors for formulation design Formulation and technology selection

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Oral controlled release formulation design and case study

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  1. Oral controlled release formulation design and case study Enxian (Andy) Lu, Ph.D. Shanghai Aucta Pharmaceuticals Co., Ltd, GM NDDS China, Oct 23, 2012

  2. Outline • Oral controlled release formulation overview • Factors for formulation design • Formulation and technology selection • Formulation evaluation • Case study

  3. Overview Type of controlled release formulation Common formulation • Matrix tablet • Multiparticulates • Osmotic tablet Nonconventional formulation • Gastric retention device (GR) • Colonic specific system • Buccal dosage form • Microsphere

  4. OverviewCR Formulation comparison

  5. OverviewBenefit of CR formulation Reduce the dose frequency Mitigate the side effect Site of release modified Improve the efficiency

  6. Formulation design Physicochemical factors • Dose • Dose/solubility ratio • Stability Biopharmaceutical factors • Physiology-gastric emptying, intestinal transit,pH • Absorption mechanism • Regional permeability Pharmacokinetic factors • Plasma half-life • GI and first pass metabolism Pharmacology factors • Efficacy (microsphere)

  7. Formulation designDose Thombre AG, Drug Discov. Today 2005, 17,1159

  8. Formulation designDose/solubility Ratio Thombre AG, Drug Discov. Today 2005, 17,1159

  9. Formulation design Stability • Chemical stability Solid and solution stability Excipient compatibility • Physical stability Phase transition-anhydrous/hydrous, polymorphism • Colonic stability Microorganism –reduction and hydrolysis

  10. Formulation design Physiology Yu LX, Int J Pharm. 1998, 171, 157

  11. Formulation design Absorption mechanism 4 2 3 1 Apical Basolateral

  12. Formulation design Regional permeability (colonic absorption)

  13. Formulation design Half life

  14. Formulation design GI and first pass metabolism

  15. Formulation and technology selection pH–solubility profile pH-stability profile Excipient compatibility Regional absorption Caco-2 permeability Predict or actual human ADME Experiment data Simulation Understand technology attributes Define target dose and release Cost, IP, scale-up etc Select formulation and technology

  16. Formulation evaluation • Dissolution Apparatus, hydrodynamics, media, two or more steps • In vivo study Animal, Human data • pK simulation GastroPlus, Kinetica, Berkeley Madonna, STELLA • IVIVC Level A, B, C • Other tools Capsule camera, Gamma scintigraphy, MRI

  17. Case 1 • Half life (~3 hr) • Dose 800mg BID or 400mg TID • Weak acid pKa 3.9 • Solubility 0.4 mg/ml (pH 1-3) and >100mg/ml (pH7) • Colonic absorption 30% of Oral (poor permeability) Assessment Short half life drug need long duration CR, which means the need of good colonic absorption High dose, > 1.6 g daily Not recommended for CR formulation

  18. Case 2 • Half life ~3h • Dose 3mg and 10mg • Weak base pKa 7.7 • Solubility pH 4 > 100mg/ml, pH 7 ~5mg/ml • Papp, Caco = 5*10-6 cm/sec (moderate absorption) • Excellent solid and solution stability Assessment Good candidate for CR formulation. Matrix tablet and osmotic tablet are feasible, but osmotic tablet is less sensitive to the environment Short half life, need 12 or 24hr release duration

  19. Case 2 Osmotic tablet

  20. Case 2 Oral solution 12hr release 24hr release Thombre AG, Drug Discov. Today 2005, 17,1159

  21. Case 2 Level A point-to-point comparison IVIVC

  22. Case 3 • Half life ~7h • Dose 4, 8, 12mg bid • Solubility pH 1-7 > 30mg/ml • Good absorption(IR > 90% bioavailability) • Need both IR and CR Assessment Low dose. Need both IR and CR Use multiparticulate technology

  23. Primary Coat Drug Coat Sugar Sphere Functional Coat Primary Coat Drug Coat IR Pellet ER Pellet Sugar Sphere Case 3

  24. Case 3 Multipartculates

  25. Case 3 8mg 25% IR + 75% ER 4mg IR

  26. Case 4 • Half life ~8.5hr • Dose 600mg tid • Freely soluble in pH 1-7 media • Absorption need the transporter , narrow absorption window in upper GI Assessment Narrow absorption window in upper GI and high dose (1.8 g), nonconventional CR formulation (GR) was developed

  27. Gastric retention dosage form (GR) • GR can remain in the gastric region for several hours and hence significantly prolong the gastric residence time of drugs, reduces drug waste, and improves solubility for drugs that are less soluble in a high pH environment, then improves bioavailability . • Four types: High density system (sedimentation, pellet) Mucoadhensive system (biohensive polymer ) Floating system (low density, hydrogel, 3-4hr) Expandable system

  28. Physiology of gastrointestinal tract Moses AJ, Crit. Rev. Ther. Drug Carrier Syst.1993, 10, 143

  29. Expandable system Intec Accordion Pill Depomed Acuform Tech Need food to help the gastric retention

  30. Case 4 1800mg GR(pink) vs 3*600mg IR (blue) www. fda.gov

  31. Aucta gastric retention dosage formSimulation result Drug has the narrow absorption window (only at upper GI track)

  32. Food intake vs gastric retention time Kumer et al., Gastroenterology. 91: 926-930

  33. Gastrointestinal chronopharmacologyGI mobility During the night human has a more regular and slower GI motility than during the day. Sander et al., PharmacTher. 1992, 54:1

  34. Gastrointestinal chronopharmacologyGastric emptying rate In the evening gastric emptying half-time for the meal is much longer than in the morning Sander et al., PharmacTher. 1992, 54:1

  35. Gastrointestinal chronopharmacologyGastric acid In the evening gastric acid secretion is much higher than in the morning Sander et al., PharmacTher. 1992, 54:1

  36. 上海奥科达生物医药科技有限公司

  37. Amorphous Capabilities GR, MultiparticulatesCapabilities ODT Capabilities ODT, Microemulsion Nanoparticle, Hydrogel Pediatric - Taste masking Speed of onset Dose reduction Reduce PK variability Improve safety Remove food effect label Aucta Pharmaceuticals:Technology Platform Aucta Drug Delivery Technology Water-Insoluble Drug Platform Alternative Delivery Platform Controlled Release Platform IR Matrix Tablets IR Multiparticulate Matrix Tablets Release OROS OROS Multiparticulate Cp Time Time Amorphous Patent pending GR Patent pending

  38. Aucta Pharmaceuticals: Value Proposition Improve delivery, Better medicine 改良剂型， 更好医药 Delivery better drug product for patients and our partners 为病人及客户提供更优质的产品 网址：http://www.auctapharma.com/

  39. Thank you!

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