Optimized formulation of solid self-microemulsifying sirolimus delivery systems

Wonkyung Cho, Min Soo Kim, Jeong Soo Kim, Junsung Park, Hee Jun Park, Kwang Ho Cha, Jeong Sook Park, Sung Joo Hwang

Research output: Contribution to journalArticle

42 Citations (Scopus)

Abstract

Background: The aim of this study was to develop an optimized solid self-microemulsifying drug delivery system (SMEDDS) formulation for sirolimus to enhance its solubility, stability, and bioavailability. Methods: Excipients used for enhancing the solubility and stability of sirolimus were screened. A phase-separation test, visual observation for emulsifying efficiency, and droplet size analysis were performed. Ternary phase diagrams were constructed to optimize the liquid SMEDDS formulation. The selected liquid SMEDDS formulations were prepared into solid form. The dissolution profiles and pharmacokinetic profiles in rats were analyzed. Results: In the results of the oil and cosolvent screening studies, Capryol™ Propylene glycol monocaprylate (PGMC) and glycofurol exhibited the highest solubility of all oils and cosolvents, respectively. In the surfactant screening test, D-α-tocopheryl polyethylene glycol 1000 succinate (vitamin E TPGS) was determined to be the most effective stabilizer of sirolimus in pH 1.2 simulated gastric fluids. The optimal formulation determined by the construction of ternary phase diagrams was the T32 (Capryol™ PGMC:glycofurol:vitamin E TPGS = 30:30:40 weight ratio) formulation with a mean droplet size of 108.2 ± 11.4 nm. The solid SMEDDS formulations were prepared with Sucroester 15 and mannitol. The droplet size of the reconstituted solid SMEDDS showed no significant difference compared with the liquid SMEDDS. In the dissolution study, the release amounts of sirolimus from the SMEDDS formulation were significantly higher than the raw sirolimus powder. In addition, the solid SMEDDS formulation was in a more stable state than liquid SMEDDS in pH 1.2 simulated gastric fluids. The results of the pharmacokinetic study indicate that the SMEDDS formulation shows significantly greater bioavailability than the raw sirolimus powder or commercial product (Rapamune® oral solution). Conclusion: The results of this study suggest the potential use of a solid SMEDDS formulation for the delivery of poorly water-soluble drugs, such as sirolimus, through oral administration.

Original languageEnglish
Pages (from-to)1673-1682
Number of pages10
JournalInternational Journal of Nanomedicine
Volume8
DOIs
Publication statusPublished - 2013 May 3

Fingerprint

Sirolimus
Drug Delivery Systems
Solubility
Pharmacokinetics
Vitamins
Liquids
Glycols
Powders
Biological Availability
Propylene
Phase diagrams
Stomach
Screening
Oils
Dissolution
Fluids
Excipients
Succinic Acid
Mannitol
Surface-Active Agents

All Science Journal Classification (ASJC) codes

  • Biophysics
  • Bioengineering
  • Biomaterials
  • Pharmaceutical Science
  • Drug Discovery
  • Organic Chemistry

Cite this

Cho, Wonkyung ; Kim, Min Soo ; Kim, Jeong Soo ; Park, Junsung ; Park, Hee Jun ; Cha, Kwang Ho ; Park, Jeong Sook ; Hwang, Sung Joo. / Optimized formulation of solid self-microemulsifying sirolimus delivery systems. In: International Journal of Nanomedicine. 2013 ; Vol. 8. pp. 1673-1682.
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abstract = "Background: The aim of this study was to develop an optimized solid self-microemulsifying drug delivery system (SMEDDS) formulation for sirolimus to enhance its solubility, stability, and bioavailability. Methods: Excipients used for enhancing the solubility and stability of sirolimus were screened. A phase-separation test, visual observation for emulsifying efficiency, and droplet size analysis were performed. Ternary phase diagrams were constructed to optimize the liquid SMEDDS formulation. The selected liquid SMEDDS formulations were prepared into solid form. The dissolution profiles and pharmacokinetic profiles in rats were analyzed. Results: In the results of the oil and cosolvent screening studies, Capryol™ Propylene glycol monocaprylate (PGMC) and glycofurol exhibited the highest solubility of all oils and cosolvents, respectively. In the surfactant screening test, D-α-tocopheryl polyethylene glycol 1000 succinate (vitamin E TPGS) was determined to be the most effective stabilizer of sirolimus in pH 1.2 simulated gastric fluids. The optimal formulation determined by the construction of ternary phase diagrams was the T32 (Capryol™ PGMC:glycofurol:vitamin E TPGS = 30:30:40 weight ratio) formulation with a mean droplet size of 108.2 ± 11.4 nm. The solid SMEDDS formulations were prepared with Sucroester 15 and mannitol. The droplet size of the reconstituted solid SMEDDS showed no significant difference compared with the liquid SMEDDS. In the dissolution study, the release amounts of sirolimus from the SMEDDS formulation were significantly higher than the raw sirolimus powder. In addition, the solid SMEDDS formulation was in a more stable state than liquid SMEDDS in pH 1.2 simulated gastric fluids. The results of the pharmacokinetic study indicate that the SMEDDS formulation shows significantly greater bioavailability than the raw sirolimus powder or commercial product (Rapamune{\circledR} oral solution). Conclusion: The results of this study suggest the potential use of a solid SMEDDS formulation for the delivery of poorly water-soluble drugs, such as sirolimus, through oral administration.",
author = "Wonkyung Cho and Kim, {Min Soo} and Kim, {Jeong Soo} and Junsung Park and Park, {Hee Jun} and Cha, {Kwang Ho} and Park, {Jeong Sook} and Hwang, {Sung Joo}",
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Optimized formulation of solid self-microemulsifying sirolimus delivery systems. / Cho, Wonkyung; Kim, Min Soo; Kim, Jeong Soo; Park, Junsung; Park, Hee Jun; Cha, Kwang Ho; Park, Jeong Sook; Hwang, Sung Joo.

In: International Journal of Nanomedicine, Vol. 8, 03.05.2013, p. 1673-1682.

Research output: Contribution to journalArticle

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AU - Kim, Min Soo

AU - Kim, Jeong Soo

AU - Park, Junsung

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AU - Cha, Kwang Ho

AU - Park, Jeong Sook

AU - Hwang, Sung Joo

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