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Utility of Hydroxypropylmethylcellulose Acetate Succinate (HPMCAS) for Initiation and Maintenance of Drug Supersaturation in the GI Milieu

Abstract

Purpose

To identify materials and processes which effect supersaturation of the GI milieu for low solubility drugs in order to increase oral bioavailability.

Methods

A variety of small and polymeric molecules were screened for their ability to inhibit drug precipitation in supersaturated solutions. The best polymeric materials were utilized to create spray-dried dispersions (SDDs) of drug and polymer, and these were tested for drug form and homogeneity. Dispersions were tested in vitro for their ability to achieve and maintain drug supersaturation, for a variety of drug structures.

Results

Of the 41 materials tested, HPMCAS was the most effective at maintaining drug supersaturation. Drug/HPMCAS SDDs were consistently more effective at achieving and maintaining drug supersaturation in vitro than were SDDs prepared with other polymers. Drug/HPMCAS SDDs were effective in vitro for eight low solubility drugs of widely varying structure. Drug/HPMCAS SDDs were more effective at achieving and maintaining supersaturation than were rotoevaporated Drug/HPMCAS dispersions or physical mixtures of Drug and HPMCAS. The degree of achievable drug supersaturation increased with increasing polymer content in the SDD. The drug in Drug /HPMCAS SDDs was amorphous, and the dispersions were demonstrated to have a single glass transition and were thus homogeneous.

Conclusion

HPMCAS has been identified as a uniquely effective polymer for use in SDDs of low solubility drugs, with broad applicability across a variety of drug structures and properties.

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Acknowledgements

The following colleagues did much of the initial work on screening, and on development of HPMCAS SDDs (including many of the formulations included in this paper) at Bend Research: Doug Lorenz, Gina Lorenz, Christi Hostetler, and Kathy Colombo Pugh. Initial spray drying apparatus development was done at Bend Research by Christi Hostetler and Doug Millard. We thank Karen Lillebo, Alison Viles, Ann Patten, and Holly Neighbarger of Bend Research for the dissolution tests. We are indebted to Scott McCray of Bend Research for assembling and organizing much of the data in this paper. We are pleased to acknowledge many helpful discussions with Dwayne Friesen and Chris Babcock of Bend Research, and Ravi Shanker of Pfizer. We gratefully acknowledge the enthusiastic support of David Dresback and Timothy Hagen of Pfizer.

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Correspondence to William Curatolo.

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Curatolo, W., Nightingale, J.A. & Herbig, S.M. Utility of Hydroxypropylmethylcellulose Acetate Succinate (HPMCAS) for Initiation and Maintenance of Drug Supersaturation in the GI Milieu. Pharm Res 26, 1419–1431 (2009). https://doi.org/10.1007/s11095-009-9852-z

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KEY WORDS

  • bioavailability improvement
  • dispersions
  • hydroxypropylmethylcellulose acetate succinate
  • HPMCAS
  • low solubility drugs
  • supersaturation
  • spray-dried dispersions