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Improved Bioavailability of a Water-Insoluble Drug by Inhalation of Drug-Containing Maltosyl-β-Cyclodextrin Microspheres Using a Four-Fluid Nozzle Spray Drier

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Abstract

We previously developed a unique four-fluid nozzle spray drier that can produce water-soluble microspheres containing water-insoluble drug nanoparticles in one step without any common solvent between the water-insoluble drug and water-soluble carrier. In the present study, we focused on maltosyl-β-cyclodextrin (malt-β-CD) as a new water-soluble carrier and it was investigated whether drug/malt-β-CD microspheres could improve the bioavailability compared with our previously reported drug/mannitol (MAN) microspheres. The physicochemical properties of bare drug microparticles (ONO-2921, a model water-insoluble drug), drug/MAN microspheres, and drug/malt-β-CD microspheres were evaluated. In vitro aerosol performance, in vitro dissolution rate, and the blood concentration profiles after intratracheal administration were compared between these formulations. The mean diameter of both drug/MAN and drug/malt-β-CD microspheres was approximately 3–5 μm and both exhibited high aerosol performance (>20% in stages 2–7), but drug/malt-β-CD microspheres had superior release properties. Drug/malt-β-CD microspheres dissolved in an aqueous phase within 2 min, while drug/MAN microspheres failed to dissolve in 30 min. Inhalation of drug/malt-β-CD microspheres enhanced the area under the curve of the blood concentration curve by 15.9-fold than that of bare drug microparticles and by 6.1-fold than that of drug/MAN microspheres. Absolute bioavailability (pulmonary/intravenous route) of drug/malt-β-CD microspheres was also much higher (42%) than that of drug/MAN microspheres (6.9%). These results indicate that drug/malt-β-CD microspheres prepared by our four-fluid nozzle spray drier can improve drug solubility and pulmonary delivery.

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REFERENCES

  1. Merisko-Liversidge E, Liversidge GG, Cooper ER. Nanosizing: a formulation approach for poorly-water-soluble compounds. Eur J Pharm Sci. 2003;18(2):113–20.

    Article  CAS  PubMed  Google Scholar 

  2. Rasenack N, Hartenhauer H, Muller BW. Microcrystals for dissolution rate enhancement of poorly water-soluble drugs. Int J Pharm. 2003;254(2):137–45.

    Article  CAS  PubMed  Google Scholar 

  3. Rasenack N, Muller BW. Dissolution rate enhancement by in situ micronization of poorly water-soluble drugs. Pharm Res. 2002;19(12):1894–900.

    Article  CAS  PubMed  Google Scholar 

  4. Merisko-Liversidge E, Liversidge GG. Nanosizing for oral and parenteral drug delivery: a perspective on formulating poorly-water soluble compounds using wet media milling technology. Adv Drug Deliv Rev. 2011;63(6):427–40.

    Article  CAS  PubMed  Google Scholar 

  5. Nagarwal RC, Kumar R, Dhanawat M, Das N, Pandit JK. Nanocrystal technology in the delivery of poorly soluble drugs: an overview. Curr Drug Deliv. 2011;8(4):398–406.

    Article  CAS  PubMed  Google Scholar 

  6. Shegokar R, Muller RH. Nanocrystals: industrially feasible multifunctional formulation technology for poorly soluble actives. Int J Pharm. 2010;399(1–2):129–39.

    Article  CAS  PubMed  Google Scholar 

  7. Keck CM, Muller RH. Drug nanocrystals of poorly soluble drugs produced by high pressure homogenisation. Eur J Pharm Biopharm. 2006;62(1):3–16.

    Article  CAS  PubMed  Google Scholar 

  8. Kenth S, Sylvestre JP, Fuhrmann K, Meunier M, Leroux JC. Fabrication of paclitaxel nanocrystals by femtosecond laser ablation and fragmentation. J Pharm Sci. 2011;100(3):1022–30.

    Article  CAS  PubMed  Google Scholar 

  9. Dong Y, Ng WK, Hu J, Shen S, Tan RB. A continuous and highly effective static mixing process for antisolvent precipitation of nanoparticles of poorly water-soluble drugs. Int J Pharm. 2010;386(1–2):256–61.

    Article  CAS  PubMed  Google Scholar 

  10. Yamamoto H, Hoshina W, Kurashima H, Takeuchi H, Kawashima Y, Yokoyama T, Tsujimoto H. Engineering of poly(DL-lactic-co-glycolic acid) nanocomposite particles for dry powder inhalation dosage forms of insulin with the spray-fluidised bed granulating system. Adv Powder Tech. 2007;18:2125–228.

    Google Scholar 

  11. Grenha A, Seijo B, Remunan-Lopez C. Microencapsulated chitosan nanoparticles for lung protein delivery. Eur J Pharm Sci. 2005;25(4–5):427–37.

    Article  CAS  PubMed  Google Scholar 

  12. Patomchaiviwat V, Paeratakul O, Kulvanich P. Formation of inhalable rifampicin-poly(L-lactide) microparticles by supercritical anti-solvent process. AAPS PharmSciTech. 2008;9(4):1119–29.

    Article  CAS  PubMed  Google Scholar 

  13. Rodrigues M, Li J, Padrela L, Almeida A, Matos H, Azevedo E. Anti-solvent effect in the production of lysozyme nanoparticles by supercritical fluid-assisted atomization processes. J Supercrit Flu. 2009;48(3):253–60.

    Article  CAS  Google Scholar 

  14. Mizoe T, Beppu S, Ozeki T, Okada H. One-step preparation of drug-containing microparticles to enhance the dissolution and absorption of poorly water-soluble drugs using a 4-fluid nozzle spray drier. J Contr Release. 2007;120(3):205–10.

    Article  CAS  Google Scholar 

  15. Mizoe T, Ozeki T, Okada H. Preparation of drug nanoparticle-containing microparticles using a 4-fluid nozzle spray drier for oral, pulmonary, and injection dosage forms. J Contr Release. 2007;122(1):10–5.

    Article  CAS  Google Scholar 

  16. Mizoe T, Ozeki T, Okada H. Application of a four-fluid nozzle spray drier to prepare inhalable rifampicin-containing mannitol microparticles. AAPS PharmSciTech. 2008;9(3):755–61.

    Article  CAS  PubMed  Google Scholar 

  17. Ohashi K, Kabasawa T, Ozeki T, Okada H. One-step preparation of rifampicin/poly(lactic-co-glycolic acid) nanoparticle-containing mannitol microspheres using a four-fluid nozzle spray drier for inhalation therapy of tuberculosis. J Contr Release. 2009;135(1):19–24.

    Article  CAS  Google Scholar 

  18. Ozeki T, Beppu S, Mizoe T, Takashima Y, Yuasa H, Okada H. Preparation of polymeric submicron particle-containing microparticles using a 4-fluid nozzle spray drier. Pharm Res. 2006;23(1):177–83.

    Article  CAS  PubMed  Google Scholar 

  19. Szejtli J, Szente L. Interaction between indometacin and beta-cyclodextrin. Pharmazie. 1981;36(10):694–8.

    CAS  PubMed  Google Scholar 

  20. Frank DW, Gray JE, Weaver RN. Cyclodextrin nephrosis in the rat. Am J Pathol. 1976;83(2):367–82.

    CAS  PubMed  Google Scholar 

  21. Irie T, Otagiri M, Sunada M, Uekama K, Ohtani Y, Yamada Y, Sugiyama Y. Cyclodextrin-induced hemolysis and shape changes of human erythrocytes in vitro. J Pharmacobiodyn. 1982;5(9):741–4.

    Article  CAS  PubMed  Google Scholar 

  22. Holvoet C, Vander Heyden Y, Plaizier-Vercammen J. Inclusion complexation of lorazepam with different cyclodextrins suitable for parenteral use. Drug Dev Ind Pharm. 2005;31(6):567–75.

    Article  CAS  PubMed  Google Scholar 

  23. Rajewski RA, Traiger G, Bresnahan J, Jaberaboansari P, Stella VJ, Thompson DO. Preliminary safety evaluation of parenterally administered sulfoalkyl ether beta-cyclodextrin derivatives. J Pharm Sci. 1995;84(8):927–32.

    Article  CAS  PubMed  Google Scholar 

  24. Tokihiro K, Arima H, Tajiri S, Irie T, Hirayama F, Uekama K. Improvement of subcutaneous bioavailability of insulin by sulphobutyl ether beta-cyclodextrin in rats. J Pharm Pharmacol. 2000;52(8):911–7.

    Article  CAS  PubMed  Google Scholar 

  25. Nishi M, Ishikawa T, Matsumoto Y, Katsube N, Takeishi N, Yonamine H, Matsui T, Okano K, Nakanishi O. Biochemical and physical treatment in rat neuropathic pain and nerve growth factor. Pain Res. 2004;19(4):141–9.

    Google Scholar 

  26. Suzuki A, Omori H, Kinoshita M, Akaike A, Satoh M, Kaneko S. A novel analgesic, ONO-2921, cause a use-dependent inhibition of human N-type (.Alpha.1B) Ca2+ channels and increases inactivated state. Jpn J Pharmacol. 2002;88(1):162.

    Google Scholar 

  27. Komada F, Iwakawa S, Yamamoto N, Sakakibara H, Okumura K. Intratracheal delivery of peptide and protein agents: absorption from solution and dry powder by rat lung. J Pharm Sci. 1994;83(6):863–7.

    Article  CAS  PubMed  Google Scholar 

  28. Weibel ER, Gil J. Structure-function relationship at the alveolar level. In: West JB, editor. Bioengineering Aspects of the Lung. New York: Marcel Dekker; 1977. p. 1–81.

    Google Scholar 

  29. Watanabe M, Ozeki T, Shibata T, Murakoshi H, Takashima Y, Yuasa H, Okada H. Effect of shape of sodium salicylate particles on physical property and in vitro aerosol performance of granules prepared by pressure swing granulation method. AAPS PharmSciTech. 2003;4(4):E64.

    Article  PubMed  Google Scholar 

  30. European Pharmacopoeia. Section 2.9.18 preparations for inhalation: aerodynamic assessment of fine particles. In EP. 3rd ed. Strasbourg: Council of Europe; 2001.

    Google Scholar 

  31. United States Pharmacopoeia. Chapter 601. Physical tests and determinations: aerosols. 2003. p. 2105–23.

    Google Scholar 

  32. Podczrck P. Optimization of the operation conditions of an Andersen-Cascade impactor and the relationship to centrifugal adhension measurements to aid the development of dry powder inhalations. Int J Pharm. 1997;149:51–61.

    Article  Google Scholar 

  33. Higuchi T, Conners K. Advance in analytical chemistry and instrumentation. New York: CN Reilly Interscience; 1965.

    Google Scholar 

  34. Newman SP, Hollingsworth A, Clark AR. Effect of different modes of inhalation on drug delivery from a dry powder inhaler. Int J Pharm. 1994;102:127–32.

    Article  CAS  Google Scholar 

  35. Vidgren M, Karkkainen A, Karjalainen P, Paronen P, Nuutinen J. Effect of powder inhaler design on drug deposition in the respiratory tract. Int J Pharm. 1988;42:211–6.

    Article  CAS  Google Scholar 

  36. Okimoto K, Miyake M, Ohnishi N, Rajewski RA, Stella VJ, Irie T, Uekama K. Design and evaluation of an osmotic pump tablet (OPT) for prednisolone, a poorly water soluble drug, using (SBE)7 m-beta-CD. Pharm Res. 1998;15(10):1562–8.

    Article  CAS  PubMed  Google Scholar 

  37. Okimoto K, Rajewski RA, Stella VJ. Release of testosterone from an osmotic pump tablet utilizing (SBE)7 m-beta-cyclodextrin as both a solubilizing and an osmotic pump agent. J Contr Release. 1999;58(1):29–38.

    Article  CAS  Google Scholar 

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Authors and Affiliations

  1. Drug Delivery and Nano Pharmaceutics, Graduate School of Pharmaceutical Sciences, Nagoya City University, 3-1 Tanabe-dori, Mizuho-ku, Nagoya, Aichi, 467-8603, Japan

    Tetsuya Ozeki & Tatsuaki Tagami

  2. Department of Pharmaceutics and Drug Delivery, School of Pharmacy, Tokyo University of Pharmacy and Life Science, 1432-1, Horinouchi, Hachioji, Tokyo, 192-0392, Japan

    Yoshihito Kano, Norimitsu Takahashi & Hiroaki Okada

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  1. Tetsuya Ozeki
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  2. Yoshihito Kano
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  3. Norimitsu Takahashi
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  4. Tatsuaki Tagami
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  5. Hiroaki Okada
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Correspondence to Tetsuya Ozeki.

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Ozeki, T., Kano, Y., Takahashi, N. et al. Improved Bioavailability of a Water-Insoluble Drug by Inhalation of Drug-Containing Maltosyl-β-Cyclodextrin Microspheres Using a Four-Fluid Nozzle Spray Drier. AAPS PharmSciTech 13, 1130–1137 (2012). https://doi.org/10.1208/s12249-012-9826-z

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