Evaluation of derivatives of 3-(2-oxo-1-pyrrolidine) hexahydro-1H-azepine-2-one as dermal penetration enhancers: Side chain length variation and molecular modeling

N. Kim, A. F. El-Kattan, C. S. Asbill, R. J. Kennette, J. W. Sowell, R. Latour, B. B. Michniak

Research output: Contribution to journalArticle

21 Citations (Scopus)

Abstract

The present study examined the enhancement effect of two series of compounds derived from 3-(2-oxo-1-pyrrolidine)hexahydro-1H-azepine-2-one. One series possessed alkyl side chains (series I) and the other alkyl ester side chains (series II). An in vitro diffusion study was performed to investigate the effect of variation in alkyl/alkyl ester side chain length of two series of compounds on the permeation of hydrocortisone (HC) across hairless mouse skin. The permeability coefficient (P), 24 h receptor concentration (Q24) and skin content (SC), as well as the enhancement ratios (ER) for each parameter were recorded. A parabolic relationship was observed between the ERP, and the alkyl side chain length of the enhancers. The relationship between the length of ester side chains and ERP appeared to be relatively linear with R2 of 0.9676. The relationship between the calculated lipophilicity (CL) and enhancement activity of the enhancers showed that for CL 5-9, series I showed higher P values compared with Azone®, but this was not observed with series II. For CL values 4.57-7.75, a significant correlation existed between P of HC and CL of series II compounds (R2 = 0.9967). 1-Tetradecyl-3-(2-oxo-1-pyrrolidine)-ε-caprolactam showed the highest P and Q24, with 40.5- and 18.6-fold increases over the control. In conclusion, the alkyl side chain series of compounds showed more enhancing activity than the alkyl ester side chain series.

Original languageEnglish (US)
Pages (from-to)183-196
Number of pages14
JournalJournal of Controlled Release
Volume73
Issue number2-3
DOIs
StatePublished - Jul 12 2001
Externally publishedYes

Fingerprint

Azepines
Esters
Skin
Hydrocortisone
Caprolactam
Hairless Mouse
Permeability
pyrrolidine

All Science Journal Classification (ASJC) codes

  • Pharmaceutical Science

Keywords

  • Enhancer
  • Hydrocortisone
  • Lipophilicity
  • Skin
  • Transdermal

Cite this

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title = "Evaluation of derivatives of 3-(2-oxo-1-pyrrolidine) hexahydro-1H-azepine-2-one as dermal penetration enhancers: Side chain length variation and molecular modeling",
abstract = "The present study examined the enhancement effect of two series of compounds derived from 3-(2-oxo-1-pyrrolidine)hexahydro-1H-azepine-2-one. One series possessed alkyl side chains (series I) and the other alkyl ester side chains (series II). An in vitro diffusion study was performed to investigate the effect of variation in alkyl/alkyl ester side chain length of two series of compounds on the permeation of hydrocortisone (HC) across hairless mouse skin. The permeability coefficient (P), 24 h receptor concentration (Q24) and skin content (SC), as well as the enhancement ratios (ER) for each parameter were recorded. A parabolic relationship was observed between the ERP, and the alkyl side chain length of the enhancers. The relationship between the length of ester side chains and ERP appeared to be relatively linear with R2 of 0.9676. The relationship between the calculated lipophilicity (CL) and enhancement activity of the enhancers showed that for CL 5-9, series I showed higher P values compared with Azone{\circledR}, but this was not observed with series II. For CL values 4.57-7.75, a significant correlation existed between P of HC and CL of series II compounds (R2 = 0.9967). 1-Tetradecyl-3-(2-oxo-1-pyrrolidine)-ε-caprolactam showed the highest P and Q24, with 40.5- and 18.6-fold increases over the control. In conclusion, the alkyl side chain series of compounds showed more enhancing activity than the alkyl ester side chain series.",
keywords = "Enhancer, Hydrocortisone, Lipophilicity, Skin, Transdermal",
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Evaluation of derivatives of 3-(2-oxo-1-pyrrolidine) hexahydro-1H-azepine-2-one as dermal penetration enhancers : Side chain length variation and molecular modeling. / Kim, N.; El-Kattan, A. F.; Asbill, C. S.; Kennette, R. J.; Sowell, J. W.; Latour, R.; Michniak, B. B.

In: Journal of Controlled Release, Vol. 73, No. 2-3, 12.07.2001, p. 183-196.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Evaluation of derivatives of 3-(2-oxo-1-pyrrolidine) hexahydro-1H-azepine-2-one as dermal penetration enhancers

T2 - Side chain length variation and molecular modeling

AU - Kim, N.

AU - El-Kattan, A. F.

AU - Asbill, C. S.

AU - Kennette, R. J.

AU - Sowell, J. W.

AU - Latour, R.

AU - Michniak, B. B.

PY - 2001/7/12

Y1 - 2001/7/12

N2 - The present study examined the enhancement effect of two series of compounds derived from 3-(2-oxo-1-pyrrolidine)hexahydro-1H-azepine-2-one. One series possessed alkyl side chains (series I) and the other alkyl ester side chains (series II). An in vitro diffusion study was performed to investigate the effect of variation in alkyl/alkyl ester side chain length of two series of compounds on the permeation of hydrocortisone (HC) across hairless mouse skin. The permeability coefficient (P), 24 h receptor concentration (Q24) and skin content (SC), as well as the enhancement ratios (ER) for each parameter were recorded. A parabolic relationship was observed between the ERP, and the alkyl side chain length of the enhancers. The relationship between the length of ester side chains and ERP appeared to be relatively linear with R2 of 0.9676. The relationship between the calculated lipophilicity (CL) and enhancement activity of the enhancers showed that for CL 5-9, series I showed higher P values compared with Azone®, but this was not observed with series II. For CL values 4.57-7.75, a significant correlation existed between P of HC and CL of series II compounds (R2 = 0.9967). 1-Tetradecyl-3-(2-oxo-1-pyrrolidine)-ε-caprolactam showed the highest P and Q24, with 40.5- and 18.6-fold increases over the control. In conclusion, the alkyl side chain series of compounds showed more enhancing activity than the alkyl ester side chain series.

AB - The present study examined the enhancement effect of two series of compounds derived from 3-(2-oxo-1-pyrrolidine)hexahydro-1H-azepine-2-one. One series possessed alkyl side chains (series I) and the other alkyl ester side chains (series II). An in vitro diffusion study was performed to investigate the effect of variation in alkyl/alkyl ester side chain length of two series of compounds on the permeation of hydrocortisone (HC) across hairless mouse skin. The permeability coefficient (P), 24 h receptor concentration (Q24) and skin content (SC), as well as the enhancement ratios (ER) for each parameter were recorded. A parabolic relationship was observed between the ERP, and the alkyl side chain length of the enhancers. The relationship between the length of ester side chains and ERP appeared to be relatively linear with R2 of 0.9676. The relationship between the calculated lipophilicity (CL) and enhancement activity of the enhancers showed that for CL 5-9, series I showed higher P values compared with Azone®, but this was not observed with series II. For CL values 4.57-7.75, a significant correlation existed between P of HC and CL of series II compounds (R2 = 0.9967). 1-Tetradecyl-3-(2-oxo-1-pyrrolidine)-ε-caprolactam showed the highest P and Q24, with 40.5- and 18.6-fold increases over the control. In conclusion, the alkyl side chain series of compounds showed more enhancing activity than the alkyl ester side chain series.

KW - Enhancer

KW - Hydrocortisone

KW - Lipophilicity

KW - Skin

KW - Transdermal

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