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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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case study product line extension
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?

terminologies
Terminologies

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

technical argument
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
rates of non compliance
Rates of Non-Compliance

All compounds should be once a day

drug properties
Drug properties

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

modes of oral modified drug delivery
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?

osmotic pump systems

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
osmotic pump systems1
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.
slide11

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
slide12

Modes of Failure Leading to Incomplete Delivery

correct

"push around"

"break-through"

process complexity

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
pk pd relationships
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’
pk pd example
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

chronotherapy
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
chronotherapy1
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
polypharmacy prototyping systems
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
prototyping systems
Prototyping Systems
  • PORT system capable of sequentially delivering combinations of drugs with differing pharmacokinetic
prototyping systems1
Prototyping Systems
  • Flexible delivery system in that a number of release options are available
    • can deliver solids or liquids
accudep from delsys
AccuDep from Delsys
  • Laminate could be a tablet surface hence a substrate
  • Potential Polypharmacy dosing vehicle
  • Pulsatile delivery system: combining IR with SR doses
conclusion
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!!
case study product line extension1
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?