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AAPS PharmSciTech. 2006 March; 7(1): E125–E130.
Published online 2006 February 24. doi:  10.1208/pt070118
PMCID: PMC2750725

Improving cyclodextrin complexation of a new antihepatitis drug with glacial acetic acid

Abstract

The purpose of this study was to develop and evaluate a solid nonaqueous oral dosage form for a new hepatitis C drug, PG301029, which is insoluble and unstable in water. Hydroxypropyl-β-cyclodextrin (HPβCD) and PG301029 were dissolved in glacial acetic acid. The acetic acid was removed by rotoevaporation such that the drug exists primarily in the complexed form. The stability of formulated PG301029 was determined upon dry storage and after reconstitution in simulated intestinal fluid (SIF), simulated gastric fluid (SGF), and water. Formulated PG301029 was found to be stable upon storage and can be reconstituted with water to a concentration 200 times that of the intrinsic solubility. Once reconstituted, the powder dissolves rapidly and PG301029 remains stable for 21 hours in SGF, SIF, and water. The unique use of acetic acid and HPβCD results in a solid dosage form of PG301029 that is both soluble and stable in water.

KeyWords: Hydroxypropyl-β-cyclodextrin, acetic acid, solid dose, oral formulation, complexation, solubility, stability, PG301029

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.
1. He Y, Johnson JLH, Yalkowsky SH. Oral formulation of a novel antiviral agent, PG301029, in a mixture of Gelucire 44/14 and DMA (2:1, wt/wt) AAPS Pharm Sci. Tech. 2005;6:E1–E1. doi: 10.1208/pt060101. [PMC free article] [PubMed] [Cross Ref]
2. Rossi SJ, Wright TL. New developments in the treatment of hepatitis C. Gut. 2003;52:756–757. doi: 10.1136/gut.52.5.756. [PMC free article] [PubMed] [Cross Ref]
3. Thuluvath PJ, Maheshwari A, Mehdi J, et al. Randomised, double blind, placebo controlled trial of interferon, ribavirin, and amantadine versus interferon, ribavirin, and placebo in treatment naïve patients with chronic hepatitis C. Gut. 2004;53:130–135. doi: 10.1136/gut.53.1.130. [PMC free article] [PubMed] [Cross Ref]
4. Centers for Disease Control web site. Available at: http://www.cdc. gov/ncidod/diseases/hepatitis. Accessed: October 28, 2004.
5. Physicians’ Desk Reference. 56th ed. Florence, KY: Thomson Healthcare; 2002.
6. Proctor and Gamble Co. PG301029: A potential agent for treatment of hepatitis C infection. Unpublished company report; 1999.
7. Jia L, Wong H, Cerna C, Weitman SD. Effect of nanonization on absorption of 301029: ex vivo and in vivo pharmacokientic correlations determined by liquid chromatography/mass spectrometry. Pharm Res. 2002;19:1091–1096. doi: 10.1023/A:1019829622088. [PubMed] [Cross Ref]
8. ClogP©for Windows, Version 4 Software. Claremont, CA: BioByte Corporation; 1999.
9. Scifinder Scholar for Windows. 2004. Available at: www.cas.org/SCIFINDER/SCHOLAR2004. Accessed: March 12, 2004.
10. ACD©/Pka Software. Version 7 for Microsoft Windows. Toronto, Ontario: Advanced Chemistry Development; 2004
11. Pop E, Loftsson T, Bodor N. Solubilization and stabilization of a benzylpenicillin chemical delivery system by 2-hydroxypropyl-B-cyclodextrin. Pharm Res. 1991;8:1044–1049. doi: 10.1023/A:1015865209874. [PubMed] [Cross Ref]
12. Connors KA. The stability of cyclodextrin complexes in solution. Chem Rev. 1997;97:1325–1357. doi: 10.1021/cr960371r. [PubMed] [Cross Ref]
13. Tommasini S, Raneri D, Ficarra R, Calabrò ML, Stancanelli R, Ficarra P. Improvement in solubility and dissolution rate of flavonoids by complexation with β-cyclodextrin. J Pharm Biomed Anal. 2004;35:379–387. doi: 10.1016/S0731-7085(03)00647-2. [PubMed] [Cross Ref]
14. Ran Y, Zhao L, Xu Q, Yalkowsky SH. Solubilization of cyclosporin A. AAPS Pharm Sci Tech. 2001;2:E2–E2. doi: 10.1208/pt020102. [PubMed] [Cross Ref]
15. Nalluri BN, Chowdary KPR, Murthy KVR, Hayman AR, Becket G. Physicochemical characterization and dissolution properties of nimesulide-cyclodextrin binary systems. AAPS Pharm Sci Tech. 2003;4:E2–E2. doi: 10.1208/pt040102. [PMC free article] [PubMed] [Cross Ref]
16. Loftsson T, Sigurdsson HH, Masson M, Schipper N. Preparation of solid drug/cyclodextrin complexes of acidic and basic drugs. Pharmazie. 2004;59:25–29. [PubMed]
17. Kruss B, Mauz A, Ruehr K, Stassen J-M, Veit C, Wagner K, inventors. Formulation for the parenteral application of a sodium channel blocker. US patent application 20040019013. January 29, 2004.
18. Loftsson T, inventor. Non-inclusion cyclodextrin complexes. US patent application 20030109492. June 12, 2003.
19. Loftsson T, Masson M, inventors. Method to improve complexation efficacy and produce high-energy cyclodextrin complexes. US patent application 20040242538. December 2, 2004.
20. Wong H, Jia L, Camden JB, Weitman SD. Liquid chromatography-mass spectrometry assay of a thiadiazole derivative in mice: application to pharmacokientic studies. J Chromatogr B Biomed Sci Appl. 2001;765:55–62. doi: 10.1016/S0378-4347(01)00403-0. [PubMed] [Cross Ref]
21. Aree T, Schulz B, Reck G. Crystal structures of β-cyclodextrin complexes with formic acid and acetic acid. J Inclus Phenom Macrocycl Chem. 2003;47:39–45. doi: 10.1023/B:JIPH.0000003923.92981.0f. [Cross Ref]

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