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Solid dispersion formulations of megestrol acetate with copovidone for enhanced dissolution and oral bioavailability

  • Soon Wook Hong
  • Bong Sang Lee
  • Su Jun Park
  • Hong Ryeol Jeon
  • Ki Young Moon
  • Mean Hyung Kang
  • Sang Han Park
  • Sung-Up Choi
  • Woo Heon Song
  • Jaehwi Lee
  • Young Wook ChoiEmail author
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Abstract

In order to enhance the dissolution profile and oral bioavailability of megestrol acetate (MA), solid dispersions of MA (MASDs) were formulated with copovidone and crystal sugar as a hydrophilic polymeric carrier and an inert core bead, respectively. Solvent evaporation method and fluidized bed coating technique were employed. MASDs were categorized as crystalline solid dispersion by the characterization of differential scanning calorimetry and X-ray diffraction. The mass-median diameters of MASDs were in a range of 1.4 to 2.6 μm. Based on drug to polymer ratio, MASD (1:1) and (1:2) were considered as optimized formulations, resulting in a smooth-surfaced homogeneously coated layer with enhanced dissolution rate. Dissolution of MASD was gradually increased up to 15 min, after which it reached a plateau. For the initial period, dissolution rates were in the decreasing order of MASD (1:2) ≥ MASD (1:1) > MASD (1:3) > MASD (1:5) > MASD (1:0.5) > MA powder. In the comparative pharmacokinetic study with Megace OS, a reference drug product, MASD (1:1) showed improved bioavailability of over 220% with 2-fold higher Cmax and 30% faster Tmax. We conclude that MASD (1:1) is a good candidate for the development of oral solid dosage forms.

Key words

Megestrol acetate Solid dispersion Copovidone Fluidized bed coating Dissolution Bioavailability 

References

  1. Alakhov, V., Pietrzynski, G., Patel, K., Kabanov, A., Bromberg, L., and Hatton, T. A., Pluronic block copolymers and Pluronic poly(acrylic acid) microgels in oral delivery of megestrol acetate. J. Pharm. Pharmacol., 56, 1233–1241 (2004).PubMedCrossRefGoogle Scholar
  2. Al-Hamidi, H., Edwards, A. A., Mohammad, M. A., and Nokhodchi, A., To enhance dissolution rate of poorly watersoluble drugs: Glucosamine hydrochloride as a potential carrier in solid dispersion formulations. Colloids Surf. B Biointerfaces, 76, 170–178 (2010).PubMedCrossRefGoogle Scholar
  3. Arida, A, I., Al-Tabakha, M. M., and Hamoury, H. A., Improving the high variable bioavailability of griseofulvin by SEDDS. Chem. Pharm. Bull., 55, 1713–1719 (2007).PubMedCrossRefGoogle Scholar
  4. Barreiro-Iglesias, R., Bromberg, L., Temchenko, M., Hatton, T. A., Alvarez-Lorenzo, C., and Concheiro, A., Pluronic-gpoly( acrylic acid) copolymers as novel excipients for site specific, sustained release tablets. Eur. J. Pharm. Sci., 26, 374–385 (2005).PubMedCrossRefGoogle Scholar
  5. Blagden, N., de Matas, M., Gavan, P. T., and York, P., Crystal engineering of active pharmaceutical ingredients to improve solubility and dissolution rates. Adv. Drug Deliv. Rev., 59, 617–630 (2007).PubMedCrossRefGoogle Scholar
  6. Bloch, D. W. and Speiser, P. P., Solid dispersions — fundamentals and examples. Pharm. Acta Helv., 62, 23–27 (1987).Google Scholar
  7. Brewster, M. E. and Loftsson, T., Cyclodextrins as pharmaceutical solubilizers. Adv. Drug Deliv. Rev., 59, 645–666 (2007).PubMedCrossRefGoogle Scholar
  8. Bromberg, L., Polymeric micelles in oral chemotherapy. J. Control. Release, 128, 99–112 (2008).PubMedCrossRefGoogle Scholar
  9. Bruera, E., Ernst, S., Hagen, N., Spachynski, K., Belzile, M., and Hanson, J., Symptomatic effects of megestrole acetate (MA): a double blind cross-over study (abstract).Proc. Am. Soc. Clin. Oncol., 1716, 531 (1996).Google Scholar
  10. Bühler, V., Polyvinylpyrrolidone excipients for pharmaceuticals; Povidone, crospovidone and copovidone. Springer, Germany (2005).Google Scholar
  11. Carrier, R. L., Miller, L. A., and Ahmed, I., The utility of cyclodextrins for enhancing oral bioavailability. J. Control. Release, 123, 78–99 (2007).PubMedCrossRefGoogle Scholar
  12. Chen, Y., Zhang, G. G. Z., Neilly, J., Marsh, K., Mawhinney, D., and Sanzgiri, Y. D., Enhancing the bioavailability of ABT-963 using solid dispersion containing Pluronic F-68. Int. J. Pharm., 286, 69–80 (2004).PubMedCrossRefGoogle Scholar
  13. Chiou, W. L. and Riegelman, S., Pharmaceutical applications of solid dispersion systems. J. Pharm. Sci., 60, 1281–1302 (1971).PubMedCrossRefGoogle Scholar
  14. Cho, E., Cho, W., Cha, K. H., Park, J., Kim, M. S., Kim, J. S., Park, H. J., and Hwang, S. J., Enhanced dissolution of megestrol acetate microcrystals prepared by antisolvent precipitation process using hydrophilic additives. Int. J. Pharm., 396, 91–98 (2010).PubMedCrossRefGoogle Scholar
  15. Duchëne, D., Ponchel, G., and Wouessidjewe, D., Cyclodextrins in targeting application to nanoparticles. Adv. Drug Deliv. Rev., 36, 29–40 (1999).PubMedCrossRefGoogle Scholar
  16. Feliu, J., Gonzàlez-Barón, M., Berrocal, A., Artal, A., Ordóñez, A., Garrido, P., Zamora, P., Garcia de Paredes, M. L., and Montero, J. M., Usefulness of megestrol acetate in cancer cachexia and anorexia. A placebo-controlled study. Am. J. Clin. Oncol., 15, 436–440 (1992).PubMedCrossRefGoogle Scholar
  17. Hasegawa, S., Hamaura, T., Furuyama, N., Kusai, A., Yonemochi, E., and Terada, K., Effects of water content in physical mixture and heating temperature on crystallinity of troglitazone-PVP K30 solid dispersions prepared by closed melting method. Int. J. Pharm., 302, 103–112 (2005).PubMedCrossRefGoogle Scholar
  18. Ho, H.-O., Su, H.-L., Tsai, T., and Sheu, M.-T., The preparation and characterization of solid dispersions on pellets using a fluidized-bed system. Int. J. Pharm., 139, 223–229 (1996).CrossRefGoogle Scholar
  19. Karatas, A., Yüksel, N., and Baykara, T., Improved solubility and dissolution rate of piroxicam using gelucire 44/14 and labrasol. Farmaco, 60, 777–782 (2005).PubMedCrossRefGoogle Scholar
  20. Karavas, E., Georgarakis, E., Sigalas, M. P., Avgoustakis, K., and Bikiaris, D., Investigation of the release mechanism of a sparingly water-soluble drug from solid dispersions in hydrophilic carriers based on physical state of drug, particle size distribution and drug-polymer interactions. Eur. J. Pharm. Biopharm., 66, 334–347 (2007).PubMedCrossRefGoogle Scholar
  21. Kawabata, Y., Yamamoto, K., Debari, K., Onoue, S., and Yamada, S., Novel crystalline solid dispersion of tranilast with high photostability and improved oral bioavailability. Eur. J. Pharm. Sci., 39, 256–262 (2010).PubMedCrossRefGoogle Scholar
  22. Kawakami, K., Oda, N., Miyoshi, K., Funaki, T., and Ida, Y., Solubilization behavior of a poorly soluble drug under combined use of surfactants and cosolvents. Eur. J. Pharm. Sci., 28, 7–14 (2006).PubMedCrossRefGoogle Scholar
  23. Keck, C. M. and Müller, R. H., Drug nanocrystals of poorly soluble drugs produced by high pressure homogenisation. Eur. J. Pharm. Biopharm., 62, 3–16 (2006).PubMedCrossRefGoogle Scholar
  24. Kesisoglou, F., Panmai, S., and Wu, Y., Nanosizing—oral formulation development and biopharmaceutical evaluation. Adv. Drug Deliv. Rev., 59, 631–644 (2007).PubMedCrossRefGoogle Scholar
  25. Li, F. -Q., Hu, J. H., Deng, J. X., Su, H., Xu, S., and Liu, J. Y., In vitro controlled release of sodium ferulate from Compritol 888 ATO-based matrix tablets. Int. J. Pharm., 324, 152–157 (2006).PubMedCrossRefGoogle Scholar
  26. Loprinzi, C. L., Michalak, J. C., Schaid, D. J., Mailliard, J. A., Athmann, L. M., Goldberg, R. M., Tschetter, L. K., Hatfield, A. K., and Morton, R. F., Phase III evaluation of four doses of megestrol acetate as therapy for patients with cancer anorexia and/or cachexia. J. Clin. Oncol., 11, 762–767 (1993).PubMedGoogle Scholar
  27. Merisko-Liversidge, E., Liversidge, G. G., and Cooper, E. R., Nanosizing: a formulation approach for poorly-water-soluble compounds. Eur. J. Pharm. Sci., 18, 113–120 (2003).PubMedCrossRefGoogle Scholar
  28. Monnoyer, S., Capancioni, S., Richard, M., Pacaud, M., and Guyonnet, J., Development of a high-performance liquid chromatography-tandem mass spectrometry method for the determination of flurogestone acetate in ovine plasma. J. Chromatogr. B Analyt. Technol. Biomed. Life Sci., 819, 245–251 (2005).PubMedCrossRefGoogle Scholar
  29. Newa, M., Bhandari, K. H., Li, D. X., Kwon, T., Kim, J. A., Yoo, B. K., Woo, J. S., Lyoo, W. S., Yong, C. S., and Choi, H. G., Preparation, characterization and in vivo evaluation of ibuprofen binarysolid dispersions with poloxamer 188. Int. J. Pharm., 343, 228–237 (2007)PubMedCrossRefGoogle Scholar
  30. Patel, D. and Sawant, K. K., Oral bioavailability enhancement of acyclovir by self-microemulsifying drug delivery systems (SMEDDS).Drug Dev. Ind. Pharm., 33, 1318–1326 (2007).PubMedCrossRefGoogle Scholar
  31. Pouton, C. W., Formulation of poorly water-soluble drugs for oral administration: Physicochemical and physiological issues and the lipid formulation classification system. Eur. J. Pharm. Sci., 29, 278–287 (2006).PubMedCrossRefGoogle Scholar
  32. Rasenack, N., Hartenhauer, H., and Müller B. W., Microcrystals for dissolution rate enhancement of poorly watersoluble drugs. Int. J. Pharm., 254, 137–145 (2003).PubMedCrossRefGoogle Scholar
  33. Sant, V. P., Smith, D., and Leroux, J. C., Enhancement of oral bioavailability of poorly water-soluble drugs by poly(ethylene glycol)-block-poly(alkyl acrylate-co-methacrylic acid) self-assemblies. J. Control. Release, 104, 289–300 (2005).PubMedCrossRefGoogle Scholar
  34. Serajuddin, A. T., Solid dispersion of poorly water-soluble drug: early promises, subsequent problems, and recent breakthroughs. J. Pharm. Sci., 88, 1058–1066 (1999).PubMedCrossRefGoogle Scholar
  35. Shah, N. H., Carvajal, M. T., Patel, C. I., Infeld, M. H., and Malick, A. W., Self-emulsifying drug-delivery systems (SEDDS) with polyglycolyzed glycerides for improving invitro dissolution and oral absorption of lipophilic drugs. Int. J. Pharm., 106, 15–23 (1994).CrossRefGoogle Scholar
  36. Simamora, P., Alvarez, J. M., and Yalkowsky, S. H., Solubilization of rapamycin. Int. J. Pharm., 213, 25–29 (2001).PubMedCrossRefGoogle Scholar
  37. Singh, A. K., Chaurasiya, A., Awasthi, A., Mishra, G., Asati, D., Khar, R. K., and Mukherjee, R., Oral bioavailability enhancement of exemestane from self-microemulsifying drug delivery system (SMEDDS).AAPS PharmSciTech, 10, 906–916 (2009).PubMedCrossRefGoogle Scholar
  38. Sun, N., Wei, X., Wu, B., Chen, J., Lu, Y., and Wu, W., Enhanced dissolution of silymarin/polyvinylpyrrolidone solid dispersion pellets prepared by a one-step fluid-bed coating technique. Powder Technology, 182, 72–80 (2008).CrossRefGoogle Scholar
  39. Taylor, L. S. and Zografi, G., Spectroscopic characterization of interactions between PVP and indomethacin in amorphous molecular dispersions. Pharm. Res., 14, 1691–1698 (1997).PubMedCrossRefGoogle Scholar
  40. Tchekmedyian, N. S., Hickman, M., Siau, J., Greco, F. A., Keller, J., Browder, H., and Aisner, J., Megestrol acetate in cancer anorexia and weight loss. Cancer, 69, 1268–1274 (1992).PubMedCrossRefGoogle Scholar
  41. Vasconcelos, T., Sarmento, B., and Costa, P., Solid dispersions as strategy to improve oral bioavailability of poor water soluble drugs. Drug Discov. Today, 12, 1068–1075 (2007).PubMedCrossRefGoogle Scholar
  42. Vippagunta, S. R., Wang, Z., Hornung, S., and Krill, S. L., Factors affecting the formation of eutectic solid dispersions and their dissolution behavior. J. Pharm. Sci., 96, 294–304 (2007).PubMedCrossRefGoogle Scholar
  43. Walsh, P., Physicians’ desk reference, 56th Ed., Medical Economics Co., USA (2002).Google Scholar
  44. Wang, L., Cui, F. D., and Sunada, H., Preparation and evaluation of solid dispersions of nitrendipine prepared with fine silica particles using the melt-mixing method. Chem. Pharm. Bull., 54, 37–43 (2006).PubMedCrossRefGoogle Scholar
  45. Wang, X., de Armas, H. N., Blaton, N., Michoel, A., and Van den Mooter, G., Phase characterization of indomethacin in binary solid dispersion with PVP VA64 or Myrj 52. Int. J. Pharm., 345, 95–100 (2007).PubMedCrossRefGoogle Scholar
  46. Won, D. H., Kim, M. S., Lee, S., Park, J. S., and Hwang, S. -J., Improved physicochemical characteristics of felodipine solid dispersion particle by supercritical anti-solvent precipitation process. Int. J. Pharm., 301, 199–208 (2005).PubMedCrossRefGoogle Scholar
  47. Yeh, S. S., Wu, S. Y., Lee, T. P., Olson, J. S., Stevens, M. R., Dixon, T., Porcelli, R. J., and Schuster, M. W., Improvement in quality of life measures and stimulation of weight gain after treatment with megestrol acetate oral suspension in geriatric cachexia: results of a double blind, placebocontrolled study. J. Am. Geriatr. Soc., 48, 485–492 (2000).PubMedGoogle Scholar
  48. Yi, Y., Yoon, H. J., Kim, B. O., Shim, M., Kim, S. -O., Hwang, S. -J., and Seo, M. H., A mixed polymeric micelles formulation of itraconazole: Characteristics, toxicity and pharmacokinetics. J. Control. Release, 117, 59–67 (2007).PubMedCrossRefGoogle Scholar
  49. Zhang, X., Sun, N., Wu, B., Lu, Y., Guan, T., and Wu, W., Physical characterization of lansoprazole/PVP solid dispersion prepared by fluid-bed coating technique. Powder Technology, 182, 480–485 (2008).CrossRefGoogle Scholar

Copyright information

© The Pharmaceutical Society of Korea and Springer Netherlands 2011

Authors and Affiliations

  • Soon Wook Hong
    • 1
  • Bong Sang Lee
    • 1
  • Su Jun Park
    • 2
  • Hong Ryeol Jeon
    • 2
  • Ki Young Moon
    • 1
  • Mean Hyung Kang
    • 1
  • Sang Han Park
    • 1
  • Sung-Up Choi
    • 1
  • Woo Heon Song
    • 1
  • Jaehwi Lee
    • 1
  • Young Wook Choi
    • 1
    Email author
  1. 1.Division of Pharmaceutical Sciences, College of PharmacyChung-Ang UniversitySeoulKorea
  2. 2.CTCBIO Inc.HwaseongKorea

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