Formulation Effects on Drug Absorption

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					Formulation Effects on Drug
                  Sigrid Stokbroekx
  Bioavailability and Bioequivalence: Focus on Physiological
      Factors and Variability - EUFEPS and COST B25
                     October 1-2, 2007
                       Athens, Greece

 • Introduction
 • Basic Factors affecting Absorption
 • Evolution of Drug Candidates Properties
 • Formulation Approaches for improving Drug
 • Conclusions
Biopharmaceutical Fitness

 For an oral drug candidate (that is for 80% of all
 drugs in development) to be developed, the
 compound must dissolve, be absorbed through
 the gut and possess sufficient metabolic
 stability to generate adequate drug
 concentrations at the pharmacologically
 relevant site so that the desired action is
 obtained in a reproducible manner
Nature Drug Disc., March 2003, Vol 2, pp 192
For the delivery of a drug in a solid
dosage form…
The Effects of Molecular Properties on
Solubility and Permeability

     Physical Form                   Melting Point

     Charge                               Solubility

   Ionization             H-bonding                       Size                 Shape

                                         Permeability                        Charge

   Modified after Han van de Waterbeemd, Eur. J. Pharm. Sci., 1998, 7, 1-3
BCS Classification

                        Type III                     Type I

               ↑Solubility, ↓Permeability   ↑Solubility, ↑Permeability

                        Type IV                       Type II
               ↓Solubility, ↓Permeability   ↓Solubility, ↑Permeability

BCS Classification
BCS Classification
                       I             II              III            IV
                   High Sol.     Poor Sol.       High Sol.      Poor Sol.
                  High Perm.    High Perm.      Poor Perm.      Poor Perm.

 Rate Control       Gastric      Dissolution    Permeability        ?

 In Vitro –
 In Vivo          Can be good      Good           Not good          ?

 Effect of Food
 on Absorption     Can delay    Can enhance    Can decrease F       ?
                                 F and/or ka
Pipelines are becoming more complex

 • Lead identification in Discovery has
   fundamentally changed in the last 20 years
 • High throughput screening has placed a
   number of pressures on drug candidates:
   –   compounds are becoming less water soluble
   –   more lipophilic
   –   of higher molecular weight
   –   of higher molecular complexity
Industry Wide the Average Solubility for a
Drug Candidate is Falling

   Curr. Drug. Disc. 1:17 (2001)
Industry Wide the Average Solubility for a
Drug Candidate is Falling
         2.000                                       MLogP

         1.000                                       SLogP
         0.000                                       LogS Sw mg/ml
         -1.000   2001   2002   2003   2004   2005

Physical Form Issues are Increasing

 •   Early compound isolation approaches (precipitation versus
      – Effect on crystallinity and purity
 •   Increased molecular weight and entropic flexibility of leads
 •   Increased scrutiny and improved analytical methodology
 •   Based on DS limitations (I.e., low solubility) and the early use of
     solid formulations, physical form optimization is applied more
     and more to generate bioavailable dosage forms
Physical Form Issues are more and more

 • A pharmaceutically stable from is needed to avoid
   downstream issues (polymorphic conversions -
   Ritonovir, Imazalil)
 • Solid state forms are important for line extensions
 • Generic incroachment and other legal issues have
   focussed on solid state form (Ranitidine, Paroxetine)
 • The use of co-crystals in pharmaceutics is a hot topic
Pipelines are becoming more complex

 • Poor solubility can be related to
   ligand for a specific target or class
   of targets
 • Potency is more or less constant (1
   mg/kg) but bioavailabilities are
   decreasing (higher doses have to
   be dealt with)
Drugability Space
0         1                         Log P                                5           6

2         4                         pKa                                  9           12

50        100                       MP oC                            275           325

1 μg/mL   50 μg/mL                   Sw                         50 mg/ml     100 mg/mL

                           Brickdust - Greasball

                Dissolution Rate-limited - Solubility-limited

          0.5x10-6                PAMPA                         1.0x10-6

          0.5x10-6                CACO-2                        1x10-6

          3x10-5                  IN SITU                       6x10-5

                       Biopharmaceutical Properties
                     Suspension/Solution in Rats/Dogs
Development Pressure
  Phase           MW          Log P   HBD   HBA   RB

     PI            423         2.6    2.5   6.4   7.8

     DI            397         3.5    1.8   5.5   7.1

    PII            388         3.1    2.2   5.5   6.8

    DII            396         3.5    2.0   5.4   7.9

    PIII           374         2.5    2.3   5.5   7.3

    DIII           378         3.3    1.8   4.9   7.8

  Prereg           355         2.5    1.8   5.0   5.8

  Market           337         2.5    2.1   4.9   5.9

J. Med. Chem 46:1250 (2003)
BCS Classification
Marketed Drugs

               Type III                  Type I

               ~25%                      ~35%

               Type IV                   Type II

               ~10%                      ~30%

BCS Classification

                          Type III                     Type I

                            5%                         5%

                         Type IV                       Type II

                          20%                          70%

       L. Benet, EDAN, Leuven, BE, March 18-20, 2007
Formulation Approaches for improving
          Drug Absorption
Expanding Formulate-ability Space
   Poor Drugability     Traditional      Solid Dispersions
                                         Complexing Agent
                        Formulation      Stealth Liposomes
   Good Drugability                      Iontophoresis
                          Space          Etc…

                      Innovation Space

                      Terra Incognito
Complex Class II compounds requires various
technologies for Solid Formulations
              Increasing Formulation Difficulty

    Class I             Class II (simple)                     Class II (complex)

                    Wetting Agents, Surfactants




                                          Solid Dispersions


                                       Amorphous Dispersions/Supersaturated systems

          1 mg/mL                                 10 μg/mL             1-10 ng/mL

                           Solubility (at neutral pH)
Noyes-Whitney-based Strategies
 •   Classical
     – Affect the unstirred water layer at the drug interface (by
       altering wettability, disperse-ability) via use of surfactants
     – Increase the surface area of the drug by reducing particle size
       (by micronizing)
     – Increase the saturation solubility of the drug (by changing its
       salt form)
 •   Innovative
     – Nanosizing (Particle size affects)
     – Preparation of Solid Dispersion/Solutions (Particle size,
       wettability and saturation solubility)
     – Complexation, amorphous form, co-crystals (saturation
       solubility and supersaturation)
Particle Size Reduction

 • Micronization and nanonization can increase the
   DS/DP surface area and therefore rate of dissolution
 • Micronization can be completed using traditional
   milling techniques (dry, wet and air milling) as well as
   with other particle sizing approaches such as
   supercritical fluid processing
 • Nanosizing usually requires special techniques to
   reduce aggregation (use of surfactants) and include
   wet milling and high pressure homogenization
Methods for Reducing Particle/Crystal Size
(Wet Milling and Homogenization with Stabilizers)
  •   Ball Mill
  •   High Energy Dispersion
  •   Netzsch Mill
       – nanocrystal
      Particles are ground by shearing and impacting forces
  •   High Pressure Homogenization
       – nanocrystals
       – amorphous nanoparticles
      Cavitation is believed to be the main cause of size reduction. In
      addition to cavitation, turbulence, collision and shear also leads to
      particle reduction
Methods for Reducing Particle/Crystal Size

  • SCF-based Particle Reduction (GASS,
    RESS, PGSS and SEDS)
    Particle size reduction is based on controlled
  • Stabilized nanoglass
     – Nanomorph
    Crystalline drug is converted to a nanodispersed
    amorphous state via precipitation in the presence of
    a stabilizer (gelatin/casein)
Nanocrystal Applications

 • Oral
   – Rapamune® (sirolimus, Wyeth, Aug 2000)
   – Emend® (aprepitant, Merck, Mar 2003)
   – TriCor® (fenofibrate, Abbott, Dec 2004)
   – Megace® ES (megestrol acetate, Par, July
Marketed NanoCrystal-Based Formulations
Nanocrystal Applications

 • Parenteral
   – Itraconazole
   – Paliperidone Palmitate
Itraconazole (R51211, IV)

           N        N
                                   N         N
               O                                 N
                        O    N
               O                             O



      Log P: >5
      pKa = 4
      Aqueous Solubility (pH 7) ~1 ng/mL
      Solubility in 0.1N HCl ~4 μg/mL
      Solubility in 20% w/v HPβCD (pH 7) ~ 0.5 mg/mL
      MP = 167 oC
Potential Advantages

 • Rapid dissolution for IV applications
 • High drug loading, low excipient burden
 • Very simple formulation (drug, water and
   stabilizer (Pluronic 338))
 • Extended indications for some patients not
   able to take current formulation (creatinine
   clearance < 30 min-1)
Wet Milling Apparatus

      Ball Mill         Netzsch Mill
Nanomilled Itraconazole
Paliperidone palmitate (IM)
               O             N   O

               N                      F



      Log P: >5
      pKa = 8.3
      Aqueous Solubility (pH 7) <<10 μg/mL
      Solubility in 0.1N HCl <<10 μg/mL
      MP = 118 oC (waxy)
  Particle Morphology

RM                      NM

HPH                     SCF
Altering Apparent Solubility:
Cyclodextrin Structure and
Beneficial Pharmaceutical Properties
 •   Enhanced Solubility
 •   Enhanced Bioavailability
 •   Enhanced Stability
 •   Modification of liquids to powders
 •   Reduce evaporation/stabilize flavors
 •   Reduce odors or tastes
 •   Reduce stomach injury
 •   Inhibit hemolysis
 •   Prevent admixture incompatibilities
     Selected Approved Products
Hydrocortisone      HPβCD    Dexacort    mouth wash            Actavis                Europe
Mitomycin           HPβCD    MitoExtra   I.v. Infusion         Novartis               Europe
Itraconazole        HPβCD    Sporanox    oral solution         Janssen                Europe/USA
Itraconazole        HPβCD    Sporanox    I.V. solution         Janssen                Europe/USA
Indomethacin        HPβCD    Indocid     eye drop              Chauvin                France
Cisapride           HPβCD    Prepulsid   suppository           Janssen                Belgium/Holland
Ziprazidone         SBEβCD   Zeldox      I.M. Solution         Pfizer                 USA/Europe
Voraconazole        SBEβCD   Vfend       I.V. solution         Pfizer                 USA/Europe
Aripiprazole        SBEβCD   Abilify     I.M. Solution         BMS/Otuska             USA/Europe
Maropitant          SBEβCD   Cerenia     Parenteral Solution   Pfizer Animal Health   USA
Diclofenac          HPγ CD   Voltaren    Eye Drop              Novartis               France
Tc-99 Teoboroxime   HPγ CD   CardioTec   I.V. Solution         Bracco                 USA
Methods for Forming Solid
Solutions/Amorphous Dispersions
 • Melt Processing
   –   Melt Compounding
   –   Melt Compression
   –   Melt Extrusion
   –   Spin Melting
 • Solvent Methods
   – Solvent Casting
   – Spraying, Bead coating
   – Spray drying
Marketed Products using Solid
Solution/Dispersion Technology

  • Gris-PEG (Griseofulvin) Novartis
  • Nimotop (Nimodipine) Bayer
  • Ibuprofen Abbott
  • Isoptin SR-E 240 (Verapamil) Abbott
  • Sporanox (Itraconazole) Janssen/J&J
  • Kaletra (Lopinavir/Ritonovir) Abbott
Sporanox Oral Capsule
 •   A solid dispersion of itraconazole (40%) and HPMC (60%) is
     prepared by spraying an organic solution onto inert sugar
 •   As the carrier dissolves, itraconazole is released at
     supersaturated concentrations
 •   The co-dissolving HPMC acts to inhibit crystallization and
     physically stabilize the formed systems
 •   The solutions are sufficiently long-lived to ensure good oral
 •   Thus for a drug with a solubility at neutral pH of ~1 ng/mL, a Fab
     of greater than 85% is obtained and a BA of >50%
Sporanox Bead
Itraconazole Melt Extruded Tablet
 • A solid solution of itraconazole (40%) and HPMC
   (60%) is prepared by melt extrusion
 • The collected extrudate is milled and pressed into
   tablets with other ingredients including an exploding
 • Dissolution of the tablet is useful
 • Human oral bioavailability is high
 • 100 mg tablet was marketed in the Far East
Kaletra Melt Extruded Tablet
October 2005

 • Original formulation was in soft gelatin
   capsules (133 mg lopinavir and 33 mg
   ritonavir) required refrigeration, was dosed at
   6 capsules/d and had to be taken with food
 • Melt extruded tablet has a higher drug
   loading (200 mg/50 mg per unit) reducing the
   pill burden from 6 to 4 units/d, can be stored
   at room temperature and can be taken with or
   without food
Lipid-Based Systems
 •   Oil-soluble drugs can be formulated in gelatin capsule with a
     number of pharmaceutically acceptable lipids. Examples
      – Accutane (Isotreinoin) Roche
      – Marinol (Dronabinol) Unimed
      – Vesanoid (Tretinoin) Roche
 •   Drug release via lipase, solubilization
     by bile salts, emulsification
Lipid Assemblies
               Micelle   Liposome   Emulsion   μ-Emulsion

 Thermodyn.    Yes       No         No         Yes

 Turbid        No        Yes        Yes        No

 Size (μm)     <0.01     0.25-10    0.5-5      <0.15

 Surfactant    5%        0.2-20%    1-20%      5-10%

 Dispersed     1%        1-10%      1-30%      1-20%
 Phase Conc.
 •   Cyclosporin A (Neorale) Novartis
 •   Norvir (Ritnavir) Abbott
 •   Fortovase (Saqunovir) Roche
 •   Gengraf (Cyclosproin) Abbott

 • Drug candidate evolution and
   development pressures are often
 • Both upstream (Med Chem) and
   downstream (Pharmaceutics)
   optimization is needed
 • The impact of personalized medicine
   will likely also call for a paradigm shift

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