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3. Product Development Design Case Study

3. Product Development Design Case Study . Case Study Product Line extension. Your company markets an oral product for migraine – you are the PLE department and the commercial team have asked you to design a faster acting product.

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3. Product Development Design Case Study

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  1. 3. Product Development Design Case Study

  2. Case StudyProduct Line extension • Your company markets an oral product for migraine – you are the PLE department and the commercial team have asked you to design a faster acting product. • The product development team is asked to ‘brainstorm’ options for this development • You have 20 minutes to discuss before feeding back your best concept to the Product Development Board What do you need to know about the patient population? What do you need to know about the disease? What do you need to know about the drug?

  3. Terminologies NB: Ph. Eur. uses extended release as denominator rather than modified release

  4. How does MR drug delivery modulation add value? Reduced dosing frequency, thus promote patient compliance Reduced potential for side-effects (lessen peak/trough ratio) Customised profile, link drug level to efficacy performance Targeted delivery to specific GI regions for improved “delivery” opportunities Technical argument

  5. Rates of Non-Compliance All compounds should be once a day

  6. Drug properties * Dose/solubility ratio calculated using the highest dose and lowest solubility in the pH range of 1 to 7.5.

  7. Other considerations

  8. Modes of Oral Modified Drug Delivery • Most popular systems classified as follows: • Osmotic pumps: Oros • Swellable systems: HPMC matrix, Geomatrix etc • Erosion controlled systems: Egalet • Major issues still revolve around • Choice of a suitable animal model • Poor understanding of PK/PD relationships • Chronotherapeutics • Polypharmacy What is the ideal in vivo release profile?

  9. Cross-section of typical oral therapeutic system (OROS) Delivery orifice Drug solution Delivery orifice Semipermeable membrane Drug compartment Osmotic core containing active substance Water Osmotic propellant Flexible partition Osmotic pump systems

  10. Osmotic Pump Systems • Advantages • "Zero order release" • Good in vitro/in vivo correlation is expected(may decrease iterations in formulation development) • pH-independent • No food effects expected • ALZA and their partners have proven the technology (Procardia XL, Glucotrol XL, Covera HS, Efidac 24, several others) • Limitations • Higher development costs • Longer development times (?) • Most companies don’t have internal capability • Royalties leads to higher marketing costs • Some constraints on shape, size, identifiers, etc.

  11. Mechanism of Delivery water water Initial After Delivery During Delivery • Solvation of osmogens creates a constant osmotic pressure difference, Dp • Hydration causes a decrease in viscosity • Drug is extruded or “pushed” via a hydrostatic pressure • Initially water diffuses through film- coating • Hydrates bilayer core • Sweller layer expands, filling void as drug layer extrudes • Intact tablet shell is excreted

  12. Modes of Failure Leading to Incomplete Delivery correct "push around" "break-through"

  13. DRUG LAYER Granulation Mill Blend and lubricate Bi-layer tabletting Coating Drilling SWELLER LAYER Granulation Mill Blend and lubricate Process complexity • Process complex involving multiple steps • Bi-layer compression requires good control • Coating critical to meet dissolution target

  14. PK/PD relationships • Relating drug plasma levelsto pharmacological performance • Usually slow rate of drug release is more beneficial c.f. to bolus dosing • Prolonged exposure may cause issues such as: • sensitization (up-regulation) • desensitization (tolerance or down regulation) • ultimately affects concentration-effect relationship • Need to elucidate the ‘right in vivo release rate profile’

  15. Amoxicillin Beta Lactams require > 1 hr to kill bacteria Require Beta Lactams to be present at infection site for prolonged periods Hence Time above MIC becomes more important even if AUC is lower Candidate for MR formulation Gentamycin Aminoglycosides efficiency is concn dependent Bacteria need to be exposed to bacteriocidal levels Gentamycin for a short time Preferred mode is once a day bolus dosing reduced nephrotoxicity reduced auto-toxicity PK/PD Example Similar relationship for Cytotoxic Drugs, Type I related to AUC & Type II related exposure above minimal cytotoxic level

  16. Chronotherapy • Nightime Risk • Asthma (known since 1698) • Prinzmetal’s Angina • Peptic ulcer disease (more severe) • Early morning Risk • Hypertension • Myocardial infarction (& common Angina) • Stroke • Arthritis

  17. Chronotherapy • Covera-24 was the first oral MR product approved for chronotherapeutic treatment for angina & hypertension • Dose at night & release starts between 0200 - 0300 & counters the surge in blood pressure between 0400 - 0500 • Constant release continues to cover events during the day

  18. Polypharmacy & Prototyping Systems • MR systems which allow actives to be released at different sites within GIT • utilise small amounts of actives • combination products (>2 actives) • rapid to assemble • multi-active release possible (at different rates) • pulsatile delivery possible • solids and/or liquids

  19. Prototyping Systems • PORT system capable of sequentially delivering combinations of drugs with differing pharmacokinetic

  20. Prototyping Systems • Flexible delivery system in that a number of release options are available • can deliver solids or liquids

  21. AccuDep from Delsys • Laminate could be a tablet surface hence a substrate • Potential Polypharmacy dosing vehicle • Pulsatile delivery system: combining IR with SR doses

  22. Conclusion • Industry faces many challenges in adopting new technology & delivery systems • Cost of development • Regulatory approval • more focus on discovery • less time for development • All about timing i.e. having the right delivery system at the right time for the right compound • We deliver drugs but we administer formulations!!

  23. Case StudyProduct Line extension • Your company markets an oral product for migraine – you are the PLE department and the commercial team have asked you to design a faster acting product. • The product development team is asked to ‘brainstorm’ options for this development • You have 20 minutes to discuss before feeding back your best concept to the Product Development Board What do you need to know about the patient population? What do you need to know about the disease? What do you need to know about the properties of the drug?

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