Release Forms from Er - PDF - PDF by lel20538

VIEWS: 26 PAGES: 44

Release Forms from Er document sample

More Info
									Biopharmaceutics of modified release
(MR) dosage forms: An overview
                    bertil.abrahamsson@astrazeneca.com




   AAPS Workshop on MR 1-2Oct –09   Biopharmaceutics of MR forms: An overview B Abrahamsson   1/25
                         Background- rationale for MR

Oral Modified Release more than once daily;
 improved efficacy/safety ratio by avoiding ”overshooting” of drug
  exposure
 improved efficacy by matching diurnal variations
 reduce gastric drug degradation
 reduced pharmacokinetic interactions
 targeted delivery in GI tract for local treatment
 reduce undesired high local drug exposure in GI tract

…getting the dose right and getting the delivery rate right are
probably the two major that lead to success om approvals and in
the marketplace...
           Larry Lesko, FDA


     AAPS Workshop on MR 1-2Oct –09   Biopharmaceutics of MR forms: An overview B Abrahamsson   2/25
                                             Background
Clinical performance of a MR product is for systemically
  acting drugs reflected by the drug plasma concentration-time
  profile

This require understanding and biopharm tools to predict
 Regional active drug absorption properties in GI tract
 Delivery rate dependence of first-pass metabolism
 Interactions between gastro-intestinal factors and MR
  product drug release mechanism
   Average/normal situation
   Stress tests

    AAPS Workshop on MR 1-2Oct –09   Biopharmaceutics of MR forms: An overview B Abrahamsson   3/25
                                     Background cont.
Regional intestinal concentration also important if
 Active drug is irritating/damaging for GI mucosa
 Local GI treatment

This require special consideration of
 GI transit and spreading of formulation




    AAPS Workshop on MR 1-2Oct –09   Biopharmaceutics of MR forms: An overview B Abrahamsson   4/25
  Regional active drug absorption in GI tract
  absorption
Permeability
Solubility
Luminal degradation
Gut wall metabolism




   AAPS Workshop on MR 1-2Oct –09   Biopharmaceutics of MR forms: An overview B Abrahamsson   5/25
                                  Regional absorption
                  Human regional absorption data compilation


                             BCS 1 drugs                                                       BCS 3 drugs



                                                                                                                  ?


                   Colonic degradation


                                                Tannergren, A Bergendal, H Lennernäs, B Abrahamsson. Mol Pharm 6 (2009) 60-73



High passive permeability a pre-requisite for good colonic drug
absorption!

 AAPS Workshop on MR 1-2Oct –09   Biopharmaceutics of MR forms: An overview B Abrahamsson   6/25
        Example – plasma profiles of ER formulations


            BCS I drug                                                                           BCS III drug
            Metoprolol                                                                           Amoxicillin




Sandberg, Abrahamsson et al, Int J Pharm 1991                                                     Gottfries, Svenheden et al Scand J Gastroenterol 1996




             AAPS Workshop on MR 1-2Oct –09   Biopharmaceutics of MR forms: An overview B Abrahamsson   7/25
        Colonic drug dissolution/solubility

                                                                   • low water volume
                                                                   • semi-solid slurry
                                                                   • poor agitation
                                                                   • no bile acids
                            Courtesy of Werner Weitsches



....but some low soluble compounds well absorbed
               in the colon! eg felodipine 1 ug/ml
                                nifedipine 10 ug/ml




   AAPS Workshop on MR 1-2Oct –09   Biopharmaceutics of MR forms: An overview B Abrahamsson   8/25
      Characterisation of colonic fluid




Pharm Res 2009 Diakidou[1], M Vertzoni1, K Goumas[2], E Söderlind3, B Abrahamsson[3], J B. Dressman[4], and C Reppas1,[5]

     AAPS Workshop on MR 1-2Oct –09     Biopharmaceutics of MR forms: An overview B Abrahamsson   9/25
                 Intestinal drug degradation


                                                  Acidic degradation
                                                  eg proton pump inhibitors




                                                  Esterase/amidase activity
                                                  eg prodrugs and peptides



                                                  Reductive degradation mediated
                                                  by bacteria
                                                  IBD drugs, many other drugs

AAPS Workshop on MR 1-2Oct –09   Biopharmaceutics of MR forms: An overview B Abrahamsson   10/25
Example colonic drug degradation Ximelagatran ER

    •Ximelagatran regional absorption in colon after admin
    of a solution 56% vs oral reference
    •Colon degradation (t1/2 = 12 min in vitro)/high
    permeability/high solubility

                                          Plasme conc for ER tablets
                                                        Subj ect No. 8
                               0.7        with different duration of drug release         Oral solution
                                                                                          MRI (3 h)
                               0.6                                                        MRII (6 h)
                                                                                          MRIII (12 h)
      Plasma conc. ( µmol/l)




                               0.5                                                        MRIV (30 h)

                               0.4       solution
                               0.3

                               0.2
                                                            4 ER tablets with release over
                               0.1
                                                            3, 12, 20 and 30 h
                                0
                                     0    2   4     6      8      10       12   14   16    18     20
                                                               Ti me (h)
 No increase of duration of plasma drug exposure
 compared to IR formulation!
     AAPS Workshop on MR 1-2Oct –09                         Biopharmaceutics of MR forms: An overview B Abrahamsson   11/25
         Regional variations of intestinal metabolism
     Intestinal metabolism in man shown for CYP3A4, CYP3A5 and
     phase II conjugation!
     No or very low activity metabolic activity in colon!

     Example 1: Human regional absorption study;

nmol/L
                    Jejunum                                               nmol/L
                                                                                                         Colon
 10                                                                        10
                              Budesonide                                                                         Budesonide
                              Budesonide + ketoconazole                                                          Budesonide + ketoconazole
 5                                                                           5



 0                                                                           0
     0    2        4       6     8            10        12                       0        2          4      6     8              10        12
                        Time (hours)                                                                     Time (hours)
                                                                                                  Seidegård, Nyberg et al Eur J Pharm Sci 2008



     Example 2: Oxybutynin ER tablet – 50% increased AUC vs IR
     (reverse effect on main metabolite)
                                                                                     Gupta et al, J Clin Pharmacol 1999

          AAPS Workshop on MR 1-2Oct –09   Biopharmaceutics of MR forms: An overview B Abrahamsson       12/25
      Gastro-intestinal transit of formulations


 GI transit could be affected by design of dosage form
 GI transit/location of importance when;
   • Variations in regional drug absorption
   • Local treatment in GI tract
   • Avoidance of local irritation in GI tract




                                                    Courtesy of Werner Weitsches

  AAPS Workshop on MR 1-2Oct –09   Biopharmaceutics of MR forms: An overview B Abrahamsson   13/25
   GI transit in man – pellets vs single unit tablet
Concommitant adminstration of formulations to healthy volunteers with a light meal




                                                                          Abrahamsson et al., Pharm Res 1993

        AAPS Workshop on MR 1-2Oct –09   Biopharmaceutics of MR forms: An overview B Abrahamsson   14/25
GI transit in man – pellets vs single unit tablet




                                                                                                     Abrahamsson et al., Pharm
                                                                                                     Res 1993




  AAPS Workshop on MR 1-2Oct –09   Biopharmaceutics of MR forms: An overview B Abrahamsson   15/25
   GI transit in man – effect of formulation

• Pellets vs single units main known effect
-------------------------------------------------------
• Other variations no strong effect on GI transit
• Local positioning in stomach could differ
depending on density, stickiness of formulation
• Significant gastric retention in fasting state
only achieved by formulations with size larger
than pylorus (15-20 mm)



  AAPS Workshop on MR 1-2Oct –09   Biopharmaceutics of MR forms: An overview B Abrahamsson   16/25
              Product dissolution testing

In vitro dissolution is the                                               ….but it is a waste of time if
most important test in                                                      not in vivo predictive!
development of ER dosage
forms…...




     AAPS Workshop on MR 1-2Oct –09   Biopharmaceutics of MR forms: An overview B Abrahamsson   17/25
                            Product dissolution testing

How could GI conditions affect drug release from MR dosage forms?

I. Avarage/normal conditions – achieve ”population” IVIVC
II. Stress tests – robustness of product perfomance vs physiological
variations

Key GI factors to consider:
• pH/buffer capacity
    •drug solubility, MR excipient functionality
• osmolarity/ionic strength
    • MR excipient functionality, fluid flow in/out of formulation
• hydrodynamics/pressure forces
    •disintegration/erosion of formulation
• food/etanol
    •all factors above
    AAPS Workshop on MR 1-2Oct –09   Biopharmaceutics of MR forms: An overview B Abrahamsson   18/25
Example – effect of buffer capacity for release of a basic drug
from two different ER matrices
     Medium                                      Buffer capacity                                  Drug dissolution
                                                 (mmol/l/∆pH)                                     rate (%/h)-
                                                                                                  Wax      Gel
     0.1M phosphate 20                                                                            8          7
     buffer pH6.8
     FaSSIF         10                                                                            7         7

     Human intest.                               2.5 – 4.5                                        3*        7*
     fluid
     modified*                                   4                                                2         6
     FaSSIF
    * calculated by deconvolution from in vivo plasma drug conctration time data


       AAPS Workshop on MR 1-2Oct –09   Biopharmaceutics of MR forms: An overview B Abrahamsson   19/25
Tablet erosion rate of HPMC matrix vs ionic strength


                              14
  tablet erosion rate (%/h)



                              12
                              10
                                                                                                     immediate tablet
                              8                                                                      disintegration
                              6
                              4
                              2
                              0
                                   0     0.1                0.2                  0.3                0.4     0.5         0.6
                                       ionic strength of phosphate buffer pH 6.8

      AAPS Workshop on MR 1-2Oct –09      Biopharmaceutics of MR forms: An overview B Abrahamsson   20/25
                    In vivo relevant level of ion/polymer interaction?

                        Cloud point of HPMC 60SH50 as a function of ion
                              Cloud point dependence pH 6.8
                        strength of phosphate buffer on ion strength of phosphate buffer
                   70

                                                                    human intestinal fluid
                   60


                   50
                                                                                                                                       HPMC 60SH50
Cloud Point ( °C




                   40
                                                                                                                                       HPMC 60SH50
                                                                                                                                       in HIF
                   30
                                                                                                                                       Linear (HPMC
                                                                                                                                       60SH50)
                   20


                   10


                   0
                        0              0.1                   0.2                 0.3                  0.4                0.5     0.6
                                                                           Ion Strength



                            AAPS Workshop on MR 1-2Oct –09     Biopharmaceutics of MR forms: An overview B Abrahamsson   21/25
Effect of gastric pressure forces
Critical events: antral contractions in stomach during phase III/IV in fasted
state and fed state, pyloric and ileo-caecal passage

Gastric crushing strength in man determined by pressure sensitive
teflon coated tablets
                 Stomach

                                                                                                           Small intestine



                                                          (○) crushed
                                                          (•) not crushed.



                                                                                    Kamba et al, Int J Pharm 2000 and 2002




   AAPS Workshop on MR 1-2Oct –09   Biopharmaceutics of MR forms: An overview B Abrahamsson     22/25
Potential food interaction mechanisms on MR drug release

 Increase in Cmax often obtained for MR dosage forms!

 Could be explained by;
 gastric pressure and shear forces affecting integrity of formulation
  physico-chemical effects – pH/osmolarity/ionic changes obtained
 by food components affecting release mechanism and drug solubility
  ”physiologic dose dumping effect”
 gastric retention – if regional variations in active drug absorption


 Delayed absorption for enteric-coated formulations, most
 pronounced for single-units!
 gastric retention


      AAPS Workshop on MR 1-2Oct –09   Biopharmaceutics of MR forms: An overview B Abrahamsson   23/25
          Hydrodnamics in the fed stomach


                                                 Gastric flow dynamics computer model
                              Retropulsive Jet                                                      Recirculating Eddies




Pal A., Indireshkumar K., Schwizer W., Abrahamsson B., Fried M., Brasseur J.,
Proc R. Soc (2004) 271; 2587-2594.

             AAPS Workshop on MR 1-2Oct –09   Biopharmaceutics of MR forms: An overview B Abrahamsson   24/25
In vitro method providing well controlled and in vivo relevant
hydrodynamics

                                                 Newtonian viscosity controlled
                                                by addition of polymer to water


                                      700
   average shear stress (dynes/cm2)




                                      600                                                         500 cP

                                      500


                                      400


                                      300
                                                                                         150 cP
                                      200


                                      100

                                                                  25cP
                                       0
                                            0      10        20         30          40          50          60
                                                                        RPM
                                                            beaker rotation-rate
                                                   B. Abrahamsson, A. Pal, M. Sjöberg, M. Carlsson, E. Laurell, J. Brasseur. Pharm Res 2005


                                       AAPS Workshop on MR 1-2Oct –09    Biopharmaceutics of MR forms: An overview B Abrahamsson   25/25
In vivo prediction achieved for new in vitro method!

   In vitro tablet erosion of two different gel matrices at different
   shear forces
                               8


                               7


                               6                                             sensitive tablet (S)
      RElative erostion rate




                                                                                                                                        Erosion rate in man
                               5
                                                                                                                                               fed/fast
                               4
                                                                                                                                        S:     2.50
                               3                                                                                                        R:     1.26
                               2
                                                                                          robust tablet (R)
                               1


                               0
                                   0          100         200          300         400         500         600            700           800

                                                                Average shear stress (dynes/cm^2)
                                       B. Abrahamsson, A. Pal, M. Sjöberg, M. Carlsson, E. Laurell, J. Brasseur. Pharm Res 2005

       AAPS Workshop on MR 1-2Oct –09                           Biopharmaceutics of MR forms: An overview B Abrahamsson         26/25
Food effect through physiologic dose dumping – example felodipine ER



                         Human felodipine plasma concentrations
                14

                              Fasted state
                12            Fed state

                10


                                                                                                                Cmax, fed > Cmax, fasted
  Cp (nmol/l)




                8


                6                                                                                               Lag time in fed state
                4


                2


                0

                     0                 100                 200                   300                   400

                                                      Time (min)
W Weitschies, RSt Wedemeyer, O Kosch, K Fach, S Nagel, E Söderlind, L Trahms, B Abrahamsson and HMönnikes. J Contr Release 2005




                     AAPS Workshop on MR 1-2Oct –09   Biopharmaceutics of MR forms: An overview B Abrahamsson     27/25
           Felodipine ER example -In vivo erosion of gel matrix


                                      10
           released felodipine (mg)




                                       8


                                       6


                                       4

                                                                                                                            fasted
                                       2                                                                                    fed


                                       0
                                           0   60             120               180                240                300            360
                                                                              t (min)
   Tablet erosion did not explain plasma peak obtained by food!
W Weitschies, RSt Wedemeyer, O Kosch, K Fach, S Nagel, E Söderlind, L Trahms, B Abrahamsson and HMönnikes. J Contr Release 2005



           AAPS Workshop on MR 1-2Oct –09           Biopharmaceutics of MR forms: An overview B Abrahamsson   28/25
Localisation in GI tract, matrix erosion and drug plasma conc in one
individual after fed administration of felodipine ER tablet




                                                                                                         Tfundus      67 min
                                                                                                         Gast. Tres   163 min
                                                                                                         Transit, SI 90 min
                                                                                                         Colon        250 min




      AAPS Workshop on MR 1-2Oct –09   Biopharmaceutics of MR forms: An overview B Abrahamsson   29/25
                                                               Individual plasma conc, tablet location and erosion
Consistent delayed, rapidly increasing plasma conc when tablet stays in proximal
stomach!
                                  100                                                                                                  10                                                            100                                                                                               15
                                                                                                                                                                                                                                                                                                                                                                        100                                                                                                                15


                                             80                                                                                                                                                                 80
                                                                                                                                                                                                                                                                                                                                                                                   80
 normalized data (%)




                                                                                                                                                                    normalized data (%)
                                                                                                                                                                                                                                                                                                       10




                                                                                                                                                                                                                                                                                                                                       normalized data (%)
                                             60                                                                                                                                                                 60                                                                                                                                                                                                                                                                         10




                                                                                                                                            cp (nmol/l)




                                                                                                                                                                                                                                                                                                                cp (nmol/l)
                                                                                                                                                                                                                                                                                                                                                                                   60




                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                cp (nmol/l)
                                                                                                                                       5

                                             40                                                                                                                                                                 40
                                                                                                                                                                                                                                                                                                       5                                                                           40
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           5
                                             20                                                                                                                                                                 20
                                                                                                                                                                                                                                                                                                                                                                                   20


                                             0                                                                                         0                                                                        0                                                                                      0




                                                                                                                                                                                                                         prox.
                                                                                                                 stomach (> 6 h)                                                                                                                             small intestine                                                                                                       0                                                                                                       0
                                                                                                                                                                                                                                                                                                                                                                                                                                                       small intestine
                                                               proximal distal                                                                                                                                                           distal             GE                                                                                                                           proximal distal proximal distal
                                                                                                                                                                                                                                                                                                                                                                                                                                                GE
                                                  0        1          2          3                  4        5         6           7                                                                                 0           1          2       3                 4       5           6        7
                                                                                         t (h)                                                                                                                                                              t (h)                                                                                                                       0            1           2                     3                4        5            6        7
                                                                                                                                                                                                                                                                                                                                                                                                                                               t (h)


W Weitschies, RSt Wedemeyer, O Kosch, K Fach, S Nagel, E Söderlind, L Trahms, B Abrahamsson and HMönnikes. J Contr Release 2005
                                                                                                                                                                                                                                                                                                                                                                                    100                                                                                                         20

                                              100                                                                                           90                                                                   100                                                                                        25

                                                                                                                                            80                                                                                                                                                                                                                                          80
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                15
                                                  80                                                                                                                                                                 80                                                                                     20




                                                                                                                                                                                                                                                                                                                                                             normalized data (%)
                                                                                                                                            70
                                                                                                                                                                                                                                                                                                                                                                                        60




                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          cp (nmol/l)
                       normalized data (%)




                                                                                                                                                                                          normalized data (%)




                                                                                                                                            60
                                                  60                                                                                                                                                                 60                                                                                     15                                                                                                                                                                                  10
                                                                                                                                                      cp (nmol/l)




                                                                                                                                                                                                                                                                                                                        cp (nmol/l)
                                                                                                                                            50
                                                                                                                                                                                                                                                                                                                                                                                        40
                                                                                                                                            40
                                                  40                                                                                                                                                                 40                                                                                     10
                                                                                                                                            30                                                                                                                                                                                                                                                                                                                                                  5
                                                                                                                                                                                                                                                                                                                                                                                        20

                                                  20                                                                                        20                                                                       20                                                                                     5
                                                                                                                                            10                                                                                                                                                                                                                                          0                                                                                                       0




                                                                                                                                                                                                                                                                                                                                                                                                                              distal
                                                                                                                                                                                                                                                                                                                                                                                                                      prox.
                                                                                                                                                                                                                                                                                                                                                                                                                                     small intestine                       large intestine
                                                  0                                                                                         0                                                                        0                                                                                      0                                                                                    proximal    distal                GE                                    CA
                                                                                                                                                                                                                                                            prox.
                                                                                           distal




                                                                                                          small intestine                                                                                                                                                             stomach (> 4 h)
                                                               proximal                                 GE                                                                                                                proximal        distal                    distal                                                                                                                   0           1            2                    3                4        5            6        7
                                                                                                                                                                                                                                                                                                                                                                                                                                                 t (h)
                                                       0       1          2          3                  4        5         6           7                                                                                   0         1          2       3                 4       5           6         7
                                                                                            t (h)                                                                                                                                                               t (h)




                                                                              plasma conc                                                                                                                                                 tablet erosion
                                                                   AAPS Workshop on MR 1-2Oct –09                                           Biopharmaceutics of MR forms: An overview B Abrahamsson                                                                                                                                   30/25
Ethanol interactions on drug release from MR dosage forms

                                                                      Example of FDA guidance for product
                                                                      specific ER bioeuivalence testing;




                                                                                                        www.fda.gov

                                                                         ”Based on the literature, a two hour time
                                                                         frame for screening in the vitro dissolution
                                                                         profile of a CR product in ethanol
                                                                         concentrations of up to 40% is strongly
                                                                         supported as physiologically and
                                                                         pharmacologically relevant”
                                                                            Review on ethanol by H Lennernäs in Mol Pharm 2009



     AAPS Workshop on MR 1-2Oct –09   Biopharmaceutics of MR forms: An overview B Abrahamsson   31/25
In vitro artefacts

In vitro dissolution test design factors that affects dissolution results
in a way that is not relevant for in vivo situation!

For example;
• Hydrodynamic effects
    •Coning
    •Sticking
    • Floating
• Interactions between dissolution test media components and drug
release mechanism
    • buffer components or surfactants interacting with polymers
    • drug solubility effects



   AAPS Workshop on MR 1-2Oct –09   Biopharmaceutics of MR forms: An overview B Abrahamsson   32/25
     In vitro artefact for MR - coning



In vitro dissolution of pellets in different apparatus




AAPS Workshop on MR 1-2Oct –09   Biopharmaceutics of MR forms: An overview B Abrahamsson   33/25
In vitro dissolution of enteric coated MR pellets in different at pH 6.8

                                                                       IN VITRO DISSOLUTION
                                         USP II/100rpm                                                         120                   Peak vessel/50 rpm
                 100                 B                                                                                           B
                                                                                                               100
 Dissolved (%)




                                                                                                        Dissolved (%)
                 80
                                                                                                                   80
                 60
                                              A                                                                    60                  A
                 40
                                                                                                                   40
                 20
                                                                                                                   20
                  0
                       0        10       20       30        40         50       60                                      0
                                                                                                                            0   10     20     30   40   50   60
                                          time (min)
                                                                         time (min)
                                     In vivo in man: A and B bioequivalent (Cmax and AUC)

                 Pressure from Regulatory authorities to run testing at mild stirring (eg
                 50 rpm in USP II ) creates unnecessary work through
                 generation of artificial in vitro results!
                           AAPS Workshop on MR 1-2Oct –09        Biopharmaceutics of MR forms: An overview B Abrahamsson              34/25
In vitro artefact polymer/media interaction – example felodipine ER
Felodipine ER tablets with different
gel matrix (HPMC) compostions –
IVIVC
                IVIVC




                                                                                                    Dissolution medium:
                                                                                                    pH 6.8 + 1% SLS




       AAPS Workshop on MR 1-2Oct –09   Biopharmaceutics of MR forms: An overview B Abrahamsson   35/25
In vitro artefact polymer/media interaction – example felodipine ER
    IVIVC used in reformulation of product including change of HPMC grade




  IVIVC established for original formulation not longer valid after change of
  HPMC grade!



     AAPS Workshop on MR 1-2Oct –09   Biopharmaceutics of MR forms: An overview B Abrahamsson   36/25
In vitro artefact polymer/media interaction – example felodipine ER

                        Level B IVIVC for use of different
                        surfactants in dissolution test medium




                                                                                    Abrahamsson. Torstensson, Johansson, Wingstrand, Pharm Res 1994


     The use of SLS provided a poorly discrimnating in vitro test
     compared to non-ionic or cationic surfactants (CTAB, Tween)

      AAPS Workshop on MR 1-2Oct –09   Biopharmaceutics of MR forms: An overview B Abrahamsson    37/25
         Different approaches to obtain IVIVC
• develop in vitro tests that mimics physiological conditions
   – Would allow wide application of in vitro test as a surrogate but this level
     of knowledge not reached yet
• develop in vitro tests that mimics in vivo dissolution results
   – Very limited application of IVIVC within a certain product
• mathematical modelling of relationship between in vitro and in
  vivo
   – Very limited application of IVIVC within a certain product
• develop formulations for which drug dissolution is unaffected by
  physiological conditions
   – Ideal situation by means of product performance but IVIVC product
     specific




     AAPS Workshop on MR 1-2Oct –09   Biopharmaceutics of MR forms: An overview B Abrahamsson   38/25
          Example IVIVC – metoprolol CR
            Metoprolol CR tablets -diffusion
                  controlled pellets

                       Drug

Film controlling
       diffusion




metoprolol characteristics:
weak base pKa 9.5, BCS class I

 AAPS Workshop on MR 1-2Oct –09   Biopharmaceutics of MR forms: An overview B Abrahamsson   39/25
                    Metoprolol CR - in vitro dissolution

                                       Effect of pH                                                                         Effect of agitation


                    100                                                                                      100
                                                                     pH 7.5
                                                                                                             80
  % dissolution




                                                                                           % dissolution
                    80
                                                                     pH 6.8                                                                             50 rpm
                    60                                                                                       60
                                                                     pH 5.0                                                                             100 rpm
                    40                                                                                       40
                                                                     pH 3.0                                                                             150 rpm
                    20                                                                                       20
                                                                     pH 1.2
                     0                                                                                        0
                          0      5       10       15       20                                                      0   5           10    15       20
                                        hours                                                                                  hours



                              Effect of dissolution apparatus                                                          Effect of buffer system

                    100                                                                                      100
    % dissolution




                                                                                             % dissolution
                     80                                                                                       80
                     60                                              paddle                                   60                                       buffer A
                     40                                              basket                                   40                                       buffer B
                     20                                                                                       20
                      0                                                                                        0
                          0       5      10       15       20                                                      0   5           10   15        20

                                        hours                                                                                  hours




AAPS Workshop on MR 1-2Oct –09                  Biopharmaceutics of MR forms: An overview B Abrahamsson                    40/25
                 Metoprolol –regional GI absorption


               120
               100                                                                                                   ileum
Cp (nmol/L)




                80                                                                                                   jejunum
                60                                                                                                   colon
                40
                20
                 0
                            0         1          2           3          4           5           6        7       8
                                                               Time (h)
1) L Nyberg, W Månsson, B Abrahamsson, J Seidegård, O Borgå. Eur J Pharm Sci. 30(2007); 432-440.



              AAPS Workshop on MR 1-2Oct –09   Biopharmaceutics of MR forms: An overview B Abrahamsson   41/25
                  Metoprolol CR IVIVC




                                           Sandberg A. Abrahamsson B. Sjogren J., Int J Pharm, 68 (1991);167-177.


AAPS Workshop on MR 1-2Oct –09   Biopharmaceutics of MR forms: An overview B Abrahamsson   42/25
  Metoprolol CR – use of in vitro dissolution

• Biowaiver granted for change of tablet matrix
  formulation and manufacturing site change
• Risk reduction - No BE failure (10 studies) in
  development of fixed combinations, new strength
  and after change of pellets coating




   AAPS Workshop on MR 1-2Oct –09   Biopharmaceutics of MR forms: An overview B Abrahamsson   43/25
      Conclusions
  • Plasma drug concentration key determinant for clinical safety/efficacy of MR
  product but local intestinal exposure may also be of importance if local effects
  or tolerability issues
  •Plasma drug profiles for MR products may not only be controlled by drug
  release but also regional variations in drug absorption
  •Differences in GI transit between different types of MR dosage forms could
  affect plasma drug conc profiles as well as local intestinal exposure
  • In vivo predictive in vitro dissolution testing without prior IVIVC require either
  products being insenstive to physiological conditions or deep understanding of
  mechanisms for drug release and its interaction with physiological factors
  • IVIVC’s are product specific and if obtained by ”black-box data modelling
  approaches” they should not be applied outside variations included in IVIVC
  study
  • In vitro dissolution testing to show equivalence between formulations not only
  need to cover average performance but robustness towards physiological/food
  variations

Expanded use of dissolution testing as surrogate for BA/BE studies
only reasonable in ”knowledge rich” settings (eg QbD)!
       AAPS Workshop on MR 1-2Oct –09   Biopharmaceutics of MR forms: An overview B Abrahamsson   44/25

								
To top