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  • Oral Formulations for Poorly Water Soluble Compounds

    SAQ - Fachgruppe Pharma & ChemieOskar Kalb, Novartis Pharma AG BaselOlten, 23. June 2009

  • 2 | Drug Delivery Systems for PWSD | Oskar Kalb | SAQ Conference, Olten, 23. June 2009

    Oral Delivery of Poorly Water Soluble Compounds

    For systemic activity of an API molecule after oral administration it must be absorbed from the intestine and reach the bloodstream / the site of action

    from. P. D. Ward et.al. Pharmaceutical Sciences and Technology Today Vol. 3, No.10 Oct. 2000

    Passive diffusion is the most dominant mechanism of drug absorption from the intestinal lumen (GIT)

  • 3 | Drug Delivery Systems for PWSD | Oskar Kalb | SAQ Conference, Olten, 23. June 2009

    Oral Delivery of Poorly Water Soluble Compounds

    With a few exceptions, molecular dispersion of a drug is a prerequisite for its absorption across biological membrans

    Tablet Powder Solution

    Systemic circulation

    Disintegration Dissolution Absorption

    This implies that the dissolution of a poorly water soluble drug can become the rate limiting step for the onset of drug levels in the blood (if absorption is reasonable fast) Negative impact on Oral Bioavailability

    This dictates that after oral administration the drug has to dissolve in the gastrointestinal fluid before partitioning into and across the enterocyte

  • 4 | Drug Delivery Systems for PWSD | Oskar Kalb | SAQ Conference, Olten, 23. June 2009

    Drug Dissolution Noyes Whitney

    dx/dt Dissolution rateA Interfacial surface areaD Diffusion coefficienth Thickness of diffusion layerXd Amount of drug dissolvedCs Saturation solubilityV Volume of dissolution medium

    Key parameter that influence dissolution rate Solubility of the API

    - Polymorph, pKa, Gastro-intestinal pH, Buffer Capacity of the GIT

    Surface area (A)- Particle size, wetting properties

    Physico-chemical properties of the API AND the physiological state of the GIT can have a significant impact on the in-vivo dissolution of the drug

  • 5 | Drug Delivery Systems for PWSD | Oskar Kalb | SAQ Conference, Olten, 23. June 2009

    Dose and Dose number (D0)

    Solubility and Dose always have to be considered together

    Do = Mo/VoCs

    Mo = dose administered (mg)Vo = 250 ml (reference volume of human stomach, FDA-approach)Cs = solubility (mg/ml)

    Remarks: Do = > 20 at pharmacological doses -> already critical In practice, Do values often between 20 and 100 for pharmacological and human doses.

    For TOX doses, Do up to 1000 and more are frequent !

  • 6 | Drug Delivery Systems for PWSD | Oskar Kalb | SAQ Conference, Olten, 23. June 2009

    Absolute bioavailability vs. variability

    From Hellriegel E.T et al. Clin. Phamacol. Ther. 1996; 60: 601-607.

    Inverse relationship between the absolute bioavailability (F) of an oral dosage form and its total intersubject variability (CV).

    To lower the variability means for a formulation scientist in To lower the variability means for a formulation scientist in most cases to improve the bioavailability in the fasted statemost cases to improve the bioavailability in the fasted state

  • 7 | Drug Delivery Systems for PWSD | Oskar Kalb | SAQ Conference, Olten, 23. June 2009

    Biopharmaceutical Classification Scheme

    Class IILow solubHigh perm

    Class IHigh solubHigh perm

    Class IIIHigh solubLow perm

    Class IVLow solubLow perm

    Class II Class I

    Class IIIClass IV

    Formulation

    Limited formulation influence

    Solubility and Permeability are key determinant of oral bioavailability Biopharmaceutical Classification System

  • 8 | Drug Delivery Systems for PWSD | Oskar Kalb | SAQ Conference, Olten, 23. June 2009

    Use of Drug Delivery Systems in Major Pharmaceutical Companies

    47%

    18% 16%11%

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    Source: Kermani, F., et.al., Drug Delivery Technology, Oct. 2001

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  • 9 | Drug Delivery Systems for PWSD | Oskar Kalb | SAQ Conference, Olten, 23. June 2009

    Approaches to improve Solubility, Dissolution of poorly water soluble APIs and decrease Variability

    1. Physical modifications Particle size reduction

    (Nanosuspensions, micronization) Dispersion of drug in a polymer matrix

    (Solid Dispersions, solid solutions) Polymorphs / Pseudopolymorphs Complexation / Solubilization

    2. Lipid-based systems e.g. Microemulsions (SMEDDS)

  • 10 | Drug Delivery Systems for PWSD | Oskar Kalb | SAQ Conference, Olten, 23. June 2009

    Examples

    Impact of a particle size reduction on dissolution and oral bioavailability of a poorly water soluble drug

    Nanosuspenions

  • 11 | Drug Delivery Systems for PWSD | Oskar Kalb | SAQ Conference, Olten, 23. June 2009

    I. Nanosuspensions

    Technology Downstream Process (e.g. Milling) Up-stream Process (e.g. Precipitation) Drying of nanosuspension Solid Dosage Form

    Working principleIncreased dissolution rate by reducing particle size to the nanometer range (and thereby increasing the surface area)

    Noyes Whitney (modified)

  • 12 | Drug Delivery Systems for PWSD | Oskar Kalb | SAQ Conference, Olten, 23. June 2009

    I. Nanosuspensions

    Nanosizing Most prominent manufacturing technology

    (e.g. NanoCrystal wet milling technology by Elan)

    Ref. E. Merisko-Liversidge et.al. Eur. J. Pharm.Sci. 18 (2003), 113-120

    Particle size distribution of Naproxen crystals before milling (triangle, mean 24.2 um) and after milling (circle 0.147 um)

    Addition of stabilizers (polymers, surfactants) to prevent agglomeration of nanosized particles

  • 13 | Drug Delivery Systems for PWSD | Oskar Kalb | SAQ Conference, Olten, 23. June 2009

    I. NanosuspensionsImpact of particle size reduction on dissolution rate

    Example: Cilostazol (BCS II)

    Particle size (median)- Hammer-milled () 13 m- Jet-milled () 2.4 m- NanoCrystal () 0.2 m

    Dissolution rate testing- water 37C, 900ml- 50rpm, USP apparatus 2- 5 mg cilostazol

    Ref. Jinno J. J. Contr. Rel. 2006; 111:56-64

    Dissolution rate of Cilostazol from a suspension is clearly increased by a reduction of the drug substance particle size

  • 14 | Drug Delivery Systems for PWSD | Oskar Kalb | SAQ Conference, Olten, 23. June 2009

    I. NanosuspensionsPharmacokinetic of Cilostazol suspensions in fasted and fed beagle dogs

    Major increase in bioavailability with minimal food effect observed for the Cilostazol nanosuspension (NanoCrystal)

    D

    Ref. Jinno J. J. Contr. Rel. 2006; 111:56-64

    Serum concentration vs. time after oral administration of cilostazol suspensions (100mg/body) in fasted (open) and fed (closed) beagle dogs (n=4) (mean; SD)

    (C) Hammer-milled ()

    (B) Jet-milled ()

    (A) NanoCrystal ()

  • 15 | Drug Delivery Systems for PWSD | Oskar Kalb | SAQ Conference, Olten, 23. June 2009

    Examples

    Impact of a formulation parameter on oral bioavailability of a poorly soluble compound

    Solid dispersion

  • 16 | Drug Delivery Systems for PWSD | Oskar Kalb | SAQ Conference, Olten, 23. June 2009

    II. Solid Dispersions

    DefinitionA poorly water soluble drug that is highly dispersed and stabilized in a hydrophilic carrier

    Working principle Ultimate particle size reduction No crystal structure Hydrophilic carrier

    improved wetting of the drugimproved wetting of the druginhibits recrystalization/precipitationinhibits recrystalization/precipitation of supersaturated solutionof supersaturated solution

    Surfactant (optional)increase solubilization of the drugincrease solubilization of the drug

  • 17 | Drug Delivery Systems for PWSD | Oskar Kalb | SAQ Conference, Olten, 23. June 2009

    Solvent evaporation

    Melting

    II. Solid DispersionsOral Absorption of Poorly Water Soluble Drugs

    Solid Dispersions

    Melt-extrusion

    NOT bioavailable

    Organic Solution

    Bioavailable

  • 18 | Drug Delivery Systems for PWSD | Oskar Kalb | SAQ Conference, Olten, 23. June 2009

    II. Solid Dispersions In-vitro dissolution rate and in-vivo pharmacokinetic data of NVS02 (BCSII)

    Dissolution rateWater, 0.1% SDS(20mg NVS02)

    - Crystaline drug - Amorphous drug- Solid Dispersion- Solid Dispersion with 10% SDS

    Same rank order of tested formulations in in-vitro dissolution rate and in-vivo plasma level curves

    Fasted dogs, 20mg/animal (n=8)

  • 19 | Drug Delivery Systems for PWSD | Oskar Kalb | SAQ Conference, Olten, 23. June 2009

    II. Solid Dispersions Impact of surfactant on pharmacokinetic of NVS02 (BCSII)

    30 mg ASM981 (MF, fasted, 2 x 15 mg)30 mg ASM981 (FMI, fasted, 1 x 30 mg)

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    Time post-dose (h)0 12 24 36 48 60 72

    SD with 10% surfactantSD without surfactant

    30 mg ASM981 (MF, fasted, 2 x 15 mg)30 mg ASM981 (FMI, fasted, 1 x 30 mg)

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