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In Vivo Performance of an Oral MR Matrix Tablet Formulation in the Beagle Dog in the Fed and Fasted State: Assessment of Mechanical Weakness

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Abstract

Purpose

To evaluate the behaviour of an oral matrix modified release formulation in the canine gastrointestinal tract, and establish if a mechanical weakness previously observed in clinical studies would have been identified in the dog model.

Materials and Methods

In vitro release profiles were obtained for two modified release matrix tablets containing UK-294,315, designed to release over either 6 (formulation A) or 18 (formulation B) hours. Tablets were labelled with 153samarium and in vivo pharmacoscintigraphy studies were performed in four beagle dogs in the fasted state for both formulations, and following ingestion of an FDA high fat meal for formulation B.

Results

The matrix tablet formulations displayed significantly different in vitro release profiles (F 2 < 50), with time to 80% release for formulation A and B of 406 and 987 min respectively. Complete in vivo disintegration occurred at 339 ± 181 and 229 ± 171 for formulation A and B respectively in the fasted state, and at 207 ± 154 min for formulation B in the fed state, in disagreement with in vitro release.

Conclusion

The fed/fasted dog model would have predicted a lack of physical robustness in the matrix tablet formulation B, however it would not have predicted the clear fed/fasted effects on performance observed previously in man.

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Notes

  1. 4-Amino-5-(4-fluorophenyl)-6,7-dimethoxy-2-[4-(morpholinocarbonyl)-perhydro-1,4-diazepin-1-yl]quinoline

  2. 4-amino-5-(4-chlorophenyl)-6,7-dimethoxy-2-[4-(morpholinocarbonyl)-perhydro-1,4-diazepin-1-yl]quinoline

Abbreviations

ANOVA:

Analysis of variance

AUC:

Area under the curve

AUC(0–8) :

Area under the plasma concentration curve from 0–8 h.

\( {\rm{AUC}}_{{{\left( {0 - \infty } \right)}}} \) :

Area under the plasma concentration curve from 0 h extrapolated to infinity.

CD:

Complete tablet disintegration time

C max :

Maximum plasma concentration

GEC:

Gastric emptying complete

GI:

Gastrointestinal

HPMC:

Hydroxypropylmethylcellulose

ID:

Initial tablet disintegration time

IV:

Intravenous

K el :

Elimination rate constant

MBq:

Megabequerel

MMC:

migrating myoelectric complex

MR:

Modified release

ROI:

Region of interest

SIT:

Small intestinal transit time

Sm:

Samarium

152Sm:

samarium oxide-152

Tc:

Technetium

T max :

Time to reach maximum plasma concentration

T 50% :

Time to 50% of parameter

T 1/2 :

Plasma half life

99mTc-DTPA:

Technetium-99m-diethylenetriaminepentaacetic acid

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Acknowledgments

These studies were funded by Pfizer Global Research and Development, UK.

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Authors and Affiliations

  1. Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, 27 Taylor Street, Glasgow, G4 0NR, UK

    Fiona McInnes & Howard N E Stevens

  2. Pfizer Global Research and Development, Sandwich, UK

    Nicola Clear & Michael Humphrey

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  1. Fiona McInnes
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  2. Nicola Clear
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  3. Michael Humphrey
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  4. Howard N E Stevens
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Correspondence to Fiona McInnes.

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McInnes, F., Clear, N., Humphrey, M. et al. In Vivo Performance of an Oral MR Matrix Tablet Formulation in the Beagle Dog in the Fed and Fasted State: Assessment of Mechanical Weakness. Pharm Res 25, 1075–1084 (2008). https://doi.org/10.1007/s11095-007-9462-6

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