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Impact of physiologically relevant viscosity on intrinsic - - PowerPoint PPT Presentation

Jan 30, 2024 287 likes •469 views

Impact of physiologically relevant viscosity on intrinsic dissolution rate of poorly soluble compounds in simulated gastric media. Enhedens navn og Sted og dato: vlg Indst > Sidehoved / Sidefod. Indfj Sted

slide-1
SLIDE 1

”Enhedens navn”

  • g ”Sted og dato”:

vælg ”Indsæt” > ”Sidehoved / Sidefod”. Indføj ”Sted og dato” i feltet for dato og ”Enhedens navn” i Sidefod

Dias 1

Impact of physiologically relevant viscosity on intrinsic dissolution rate of poorly soluble compounds in simulated gastric media.

slide-2
SLIDE 2

en ”Enhedens navn”

  • g ”Sted og dato”:

vælg ”Indsæt” > ”Sidehoved / Sidefod”. Indføj ”Sted og dato” i feltet for dato og ”Enhedens navn” i Sidefod

Dias 2

Agenda

  • Introduction
  • Aim
  • Viscosity characterization of human gastric aspirates
  • Preparation/viscosity characterization of viscous biorelevant

dissolution media

  • Dissolution study
  • Conclusion
  • Perspectives
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SLIDE 3

en ”Enhedens navn”

  • g ”Sted og dato”:

vælg ”Indsæt” > ”Sidehoved / Sidefod”. Indføj ”Sted og dato” i feltet for dato og ”Enhedens navn” i Sidefod

Dias 3

Introduction

  • Physiologically relevant conditions are important dissolution

testing.

  • The purpose of biorelevant dissolution media (BDM) is to

simulate the conditions in the gastrointestinal tract.

  • Several factors such as pH, osmolality and surface tension

has been taken into account.

  • Viscosity is a factor not considered in currently used BDM.
  • The viscosity of gastrointestinal fluid is expected to be

higher than BDM due to the presence of mucus.

  • An increased viscosity is supposed to decrease the

dissolution rate.

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SLIDE 4

en ”Enhedens navn”

  • g ”Sted og dato”:

vælg ”Indsæt” > ”Sidehoved / Sidefod”. Indføj ”Sted og dato” i feltet for dato og ”Enhedens navn” i Sidefod

Dias 4

Aim

  • Determine the viscosity range of human gastric fluid.
  • Produce biorelevant dissolution media based on commonly used

biorelevant dissolution media with viscosities similar to human gastric fluid.

  • Investigate whether the dissolution rate is altered compared to

traditional biorelevant dissolution media.

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SLIDE 5

en ”Enhedens navn”

  • g ”Sted og dato”:

vælg ”Indsæt” > ”Sidehoved / Sidefod”. Indføj ”Sted og dato” i feltet for dato og ”Enhedens navn” i Sidefod

Dias 5

Experimental approach

  • Viscosity characterization of human gastric aspirates.
  • Preparation/ characterization of viscous biorelevant dissolution

media.

  • Dissolution study
slide-6
SLIDE 6

en ”Enhedens navn”

  • g ”Sted og dato”:

vælg ”Indsæt” > ”Sidehoved / Sidefod”. Indføj ”Sted og dato” i feltet for dato og ”Enhedens navn” i Sidefod

Dias 6

Theory - Characterization of the viscosity of human gastric aspirates

Rheology is the study of flow and deformation of matter.

A F s shearstres  H V shearrate  shearrate s shearstres ity vis  cos A F s shearstres 

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SLIDE 7

en ”Enhedens navn”

  • g ”Sted og dato”:

vælg ”Indsæt” > ”Sidehoved / Sidefod”. Indføj ”Sted og dato” i feltet for dato og ”Enhedens navn” i Sidefod

Dias 7

Experimental - Viscosity characterization of human gastric aspirates

  • Viscosity measurements were performed on human gastric aspirates

from 7 volunteers

  • Viscosity characterization was based on a steady-state flow test
  • The apparant viscosity was measured as a function of shear rate
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SLIDE 8

en ”Enhedens navn”

  • g ”Sted og dato”:

vælg ”Indsæt” > ”Sidehoved / Sidefod”. Indføj ”Sted og dato” i feltet for dato og ”Enhedens navn” i Sidefod

Dias 8

Experimental - Characterization of the viscosity of human gastric aspirates

It was expected to observe following:

  • Shear-thinning behavior as shown below
  • An apparant viscosity above the viscosity of water (<1 mPa∙s)

Steady-state flow profile of a typical shear thinning fluid. Modified from TA Instruments Rheology Symposium.

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SLIDE 9

en ”Enhedens navn”

  • g ”Sted og dato”:

vælg ”Indsæt” > ”Sidehoved / Sidefod”. Indføj ”Sted og dato” i feltet for dato og ”Enhedens navn” i Sidefod

Dias 9

Results - Viscosity characterization of human gastric aspirates

Steady-state flow test:

  • Newtonian behavior at high shear rates
  • Supposed shear-thinning behavior at lower shear rates
  • Measured at a shear rate of 30 to 1000 sec-1
  • Viscosities between 1.7 and 12 mPa∙s at 178 s-1 were found
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SLIDE 10

en ”Enhedens navn”

  • g ”Sted og dato”:

vælg ”Indsæt” > ”Sidehoved / Sidefod”. Indføj ”Sted og dato” i feltet for dato og ”Enhedens navn” i Sidefod

Dias 10

Preparation of viscous biorelevant dissolution media

Viscous biorelevant dissolution media (BDM) were based on fasted-state simulated gastric fluid (FaSSGF). FaSSGF contains physiologically relevant amounts of bile salts and pepsin, and properties such as pH, osmolality and surface tension are close to in vivo data.

Composition of FaSSGF and in vivo data of human gastric fluid1 Composition FaSSGF In vivo data Sodium taurocholate (μM) 80 ~80 Lecithin (μM) 20

  • Pepsin (mg/mL)

0.1 ~0.8, 0.11 – 0.22 Sodium chloride (mM) 34.2 68 ± 29 Hydrochloric acid q.s. pH 1.6

  • Properties

pH pH 1.6 1.4 - 2.1 Osmolality (mOsm/kg) 120.7 ± 2.5 191 ± 36 Surface tension (mN/m) 42.6 ~40

1Vertzoni, M., Dressman, J. B., Butler, J., Hempenstall, J., Reppas, C.: Simulation of fasting gastric conditions and

its importance for the in vivo dissolution of lipophilic compounds. Eur. J. Pharm. Biopharm. 2005; 60:413–417

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SLIDE 11

en ”Enhedens navn”

  • g ”Sted og dato”:

vælg ”Indsæt” > ”Sidehoved / Sidefod”. Indføj ”Sted og dato” i feltet for dato og ”Enhedens navn” i Sidefod

Dias 11

Results – Characterization of the viscosity of human gastric aspirates

HPMC: 0.2 – 0.6 % HPMC represents physiologically relevant viscosities Steady-state flow tests: Samples are proposed to display a shear-thinning behavior

Steady-state flow test conducted on FaSSGF containing different concentrations of HPMC (n=3; mean ± SD). Represents the viscosity range found in human gastric

  • aspirates. FaSSGF

, 0.2 % HPMC, 0.4 % HPMC and 0.6 % HPMC.

0,001 0,01 0,1 10 100 1000 Shear rate (1/s) Viscosity (Pa*s)

Hydroxypropyl methylcellulose (HPMC):

  • Semi-synthetic polymer
  • Non-charged
slide-12
SLIDE 12

en ”Enhedens navn”

  • g ”Sted og dato”:

vælg ”Indsæt” > ”Sidehoved / Sidefod”. Indføj ”Sted og dato” i feltet for dato og ”Enhedens navn” i Sidefod

Dias 12

Theory - Dissolution study

The dissolution of a drug compound is divided into two steps:

  • The liberation of molecules from the tablet surface under the creation of

a saturated boundary layer adjacent to the surface

  • Transport of the solutes from the boundary layer and into the bulk

solution The dissolution process can be described by the Noyes-Whitney equation2: It is expected to observe a decreased intrinsic dissolution rate (IDR) as the viscosity is increased.

h C C A D dt dM

S

) (   

2Noyes, A. S., Whitney, W. R.: The rate of solution of solid substances in their

  • wn solutions. J. Amer. Chem. Soc. 1897; 19:930– 934
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SLIDE 13

en ”Enhedens navn”

  • g ”Sted og dato”:

vælg ”Indsæt” > ”Sidehoved / Sidefod”. Indføj ”Sted og dato” i feltet for dato og ”Enhedens navn” i Sidefod

Dias 13

Dissolution study – Model drugs

Griseofulvin Cinnarizine

logP 2.18 Solubility (water) 10 μg/ml MW 352.766 g/mol BCS II logP 5.8 pKa 1 1.95 pKa 2 7.5 Solubility (1 M HCl) 0.29 mg/ml Solubility (phosphate buffer, pH=7.2) 0.002 mg/ml MW 368.514 g/mol BCS II

slide-14
SLIDE 14

en ”Enhedens navn”

  • g ”Sted og dato”:

vælg ”Indsæt” > ”Sidehoved / Sidefod”. Indføj ”Sted og dato” i feltet for dato og ”Enhedens navn” i Sidefod

Dias 14

Experimental - Dissolution study

Dissolution experiments using HPMC were performed using the μDISS Profiler system at 37 ºC and 100 RPM. Vials were covered with para-film. Intrinsic dissolution rate was calculated by the software as

Parts of the μDISS profiler system. A) Steel dies with compressed powder. B) Dies inserted into teflon rotating disk carriers. C) Rotating disk carriers with dies placed on the bottom of the glass vials. Fibre optic probes are immersed into dissolution medium. D) μDISS Profiler. (Pictures from avdeef and Tsinman 2008)

A DR IDR /

max

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SLIDE 15

en ”Enhedens navn”

  • g ”Sted og dato”:

vælg ”Indsæt” > ”Sidehoved / Sidefod”. Indføj ”Sted og dato” i feltet for dato og ”Enhedens navn” i Sidefod

Dias 15

Results - Dissolution study

IDR obtained from dissolution of Griseofulvin in FaSSGF containing different amounts of HPMC:

IDR’s obtained from dissolution of Griseofulvin in FaSSGF of different viscosities. FaSSGF , 0.2 % HPMC, 0.4 % HPMC and 0.6 % HPMC. The viscosities are measured at 178 s-1.

0,001 0,01 0,1 10 100 1000 log(Shear rate (1/s)) log(Viscosity (Pa*s))

Steady-state flow test conducted on FaSSGF containing different concentrations of HPMC (n=3; mean ± SD). represents the viscosity range found in human gastric aspirates. 0.2 % HPMC, 0.4 % HPMC and 0.6 % HPMC.

IDR was decreased up to 70 % within the viscosity range found for human gastric fluid.

1 2 3 4 5 6 7 8 0,002 0,004 0,006 0,008 0,01 0,012 Viscosity (Pa*s) IDR (ug/cm2*min)

slide-16
SLIDE 16

en ”Enhedens navn”

  • g ”Sted og dato”:

vælg ”Indsæt” > ”Sidehoved / Sidefod”. Indføj ”Sted og dato” i feltet for dato og ”Enhedens navn” i Sidefod

Dias 16

Results - Dissolution study

IDR obtained from dissolution of Cinnarizine in FaSSGF containing different amounts of HPMC:

0,001 0,01 0,1 10 100 1000 log(Shear rate (1/s)) log(Viscosity (Pa*s))

Steady-state flow test conducted on FaSSGF containing different concentrations of HPMC (n=3; mean ± SD). represents the viscosity range found in human gastric aspirates. 0.2 % HPMC, 0.4 % HPMC and 0.6 % HPMC.

IDR was decreased up to 62 % within the viscosity range found for human gastric fluid.

100 200 300 400 500 600 700 0,002 0,004 0,006 0,008 0,01 0,012 Viscosity (Pa*s) IDR (ug/cm2*min)

IDR’s obtained from dissolution of Cinnarizine in FaSSGF of different viscosities. FaSSGF , 0.2 % HPMC, 0.4 % HPMC and 0.6 % HPMC. The viscosities are measured at 178 s-1.

slide-17
SLIDE 17

en ”Enhedens navn”

  • g ”Sted og dato”:

vælg ”Indsæt” > ”Sidehoved / Sidefod”. Indføj ”Sted og dato” i feltet for dato og ”Enhedens navn” i Sidefod

Dias 17

Results - Dissolution study

  • The IDR is decreased in viscous BDM
  • The IDR of Griseofulvin and Cinnarizine could be influenced by:
  • different drug-polymer interactions
  • size of the model drug
  • Differences in IDR is attributed to the significant different solubility
  • f the drugs at pH 1.6
  • Cinnarizine is positively charged and Griseofulvin uncharged at pH

1.6 which can explain some of the solubility differences.

slide-18
SLIDE 18

en ”Enhedens navn”

  • g ”Sted og dato”:

vælg ”Indsæt” > ”Sidehoved / Sidefod”. Indføj ”Sted og dato” i feltet for dato og ”Enhedens navn” i Sidefod

Dias 18

Conclusion

The viscosity of human gastric fluid was investigated.

  • An apparent viscosity of 1.7 - 12 mPa∙s at a shear rate of 178 s-1 was

found for human gastric aspirates. Addition of the viscosity enhancer HPMC was tested.

  • Addition of 0.2 – 0.6 % HPMC to FaSSGF produced media with

viscosities in the range found in human gastric fluid. Dissolution analyses were performed on the physiologically relevant BDM containing HPMC.

  • The IDR of Griseofulvin was lowered up to 70 % in FaSSGF containing

up to 0.6 % HPMC.

  • The IDR of Cinnarizine was lowered up to 62 % in FaSSGF containing up

to 0.6 % HPMC.