Summary.
It was the aim of this study to evaluate the potential of thiolated polycarbophil for the nasal administration of Leucine-enkephalin (Leu-enkephalin). The enzymatic degradation of Leu-enkephalin on freshly excised bovine nasal mucosa was analysed qualitatively via thin layer chromatography and quantitatively via high performance liquid chromatography (HPLC). The potential of thiolated polycarbophil gels to provide a sustained release for the therapeutic peptide was investigated via diffusion studies. Permeation studies were performed in Ussing-type diffusion chambers with freshly excised bovine nasal mucosa. Results demonstrated that Leu-enkephalin is mainly degraded by the cleavage of tyrosine from the N-terminus of the peptide. Within one hour more than 63.5 ± 2% of this therapeutic peptide are degraded on the nasal mucosa. In the presence of 0.25% thiolated polycarbophil, this degradation process, however, could be significantly lowered. Diffusion studies demonstrated that Leu-enkephalin being incorporated in a 0.5% thiolated polycarbophil gel is sustained released out of it. The appearent permeability coefficient (Papp) for Leu-enkephalin on the nasal mucosa was determined to be 1.9 ± 1.2 × 10−7 cm/sec. Furthermore, in the presence of 0.5% thiolated polycarbophil and 1% glutathione, which is used as permeation mediator for the thiomer, the uptake of Leu-enkephalin from the nasal mucosa was even 82-fold improved. According to these results thiolated polycarbophil might be a promising excipient for nasal administration of Leu-enkephalin.
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References
RU Agu VH Dang M Jorissen R Kinget N Verbeke (2004) ArticleTitleMetabolism and absorption enhancement of methionine enkephalin in human nasal epithelium Peptides 25 563–569 Occurrence Handle15165710 Occurrence Handle1:CAS:528:DC%2BD2cXksVCiurs%3D Occurrence Handle10.1016/j.peptides.2004.02.019
Albrecht K, Zirm EJ, Bernkop-Schnürch A (2005) In vitro evaluation of parameters influencing the mucoadhesive properties of thiomer particles. 32nd Annual Meeting of the Controlled Release Society, Miami
A Bernkop-Schnürch H Zarti GF Walker (2001a) ArticleTitleThiolation of polycarbophil enhances its inhibition of soluble and intestinal brush border membrane bound aminopeptidase N J Pharm Sci 90 1907–1914 Occurrence Handle10.1002/jps.1140
A Bernkop-Schnürch CE Kast MF Richter (2001b) ArticleTitleImprovement in the mucoadhesive properties of alginate by the covalent attachment of cysteine J Control Release 71 277–285 Occurrence Handle10.1016/S0168-3659(01)00227-9
A Bernkop-Schnürch C Paikl C Valenta (1997) ArticleTitleNovel bioadhesive chitosan-EDTA conjugate protects leucine enkephalin from degradation by aminopeptidase N Pharm Res 14 917–922 Occurrence Handle9244150 Occurrence Handle10.1023/A:1012108118670
A Bernkop-Schnürch V Schwarz S Steininger (1999) ArticleTitlePolymers with thiol groups: a new generation of mucoadhesive polymers? Pharm Res 16 876–881 Occurrence Handle10397608 Occurrence Handle10.1023/A:1018830204170
AE Clausen A Bernkop-Schnürch (2000) ArticleTitleIn vitro evaluation of the permeation-enhancing effect of thiolated polycarbophil J Pharm Sci 89 1253–1261 Occurrence Handle10980500 Occurrence Handle1:CAS:528:DC%2BD3cXntlOlsro%3D Occurrence Handle10.1002/1520-6017(200010)89:10<1253::AID-JPS3>3.0.CO;2-8
Greimel A, Del Curto MD, D’Antonio M, Palmberger T, Bernkop-Schnürch A (2006) In vitro evaluation of thiomer microparticles for nasal drug delivery. J Drug Del Sci Tech (in press)
AF Habeeb (1973) ArticleTitleA sensitive method for localization of disulfide containing peptides in column effluents Anal Biochem 56 60–65 Occurrence Handle4797196 Occurrence Handle1:CAS:528:DyaE3sXlsVeqt7w%3D Occurrence Handle10.1016/0003-2697(73)90169-3
ME Imam M Hornof C Valenta A Bernkop-Schnürch (2003) ArticleTitleEvidence for the interpenetration of mucoadhesive polymers into the mucus gel layer STP Pharm Sci 13 171–176 Occurrence Handle1:CAS:528:DC%2BD3sXpsVSjsbs%3D
AH Krauland A Bernkop-Schnürch (2004) ArticleTitleThiomers: development and in vitro evaluation of a peroral microparticulate peptide delivery system Eur J Pharm Biopharm 57 181–187 Occurrence Handle15018973 Occurrence Handle1:CAS:528:DC%2BD2cXhslWltb8%3D Occurrence Handle10.1016/j.ejpb.2003.09.011
Langoth N, Bernkop-Schnürch A, Kurka P (2006a) The inhibitory effect of glutathione towards buccal enzymatic degradation of therapeutic peptides. J Drug Del Sci Tech (in press)
Langoth N, Guggi D, Bernkop-Schnürch A (2006b) Investigation on the cytotoxicity of (thiolated) polyacrylates. Toxicol in vitro (in press)
VM Leitner D Guggi A Bernkop-Schnürch (2004a) ArticleTitleThiomers in noninvasive polypeptide delivery: in vitro and in vivo characterization of a polycarbophil-cysteine/glutathione gel formulation for human growth hormone J Pharm Sci 93 1682–1691 Occurrence Handle1:CAS:528:DC%2BD2cXltlKrsr8%3D Occurrence Handle10.1002/jps.20069
VM Leitner D Guggi AH Krauland A Bernkop-Schnürch (2004b) ArticleTitleNasal delivery of human growth hormone: in vitro and in vivo evaluation of a thiomer/glutathione microparticulate delivery system J Control Release 100 87–95 Occurrence Handle1:CAS:528:DC%2BD2cXosFSktbg%3D Occurrence Handle10.1016/j.jconrel.2004.08.001
MK Marschütz A Bernkop-Schnürch (2002) ArticleTitleThiolated polymers: self-crosslinking properties of thiolated 450 kDa poly(acrylic acid) and their influence on mucoadhesion Eur J Pharm Sci 15 387–394 Occurrence Handle11988400 Occurrence Handle10.1016/S0928-0987(02)00025-8
UA Remigius M Jorissen T Willems R Kinget N Verbeke (2003) ArticleTitleMechanistic appraisal of the effects of some protease inhibitors on ciliary beat frequency in a sequential cell culture system of human nasal epithelium Eur J Pharm Biopharm 55 283–289 Occurrence Handle12754002 Occurrence Handle1:CAS:528:DC%2BD3sXjs1Gjt7s%3D Occurrence Handle10.1016/S0939-6411(03)00023-7
RG Riley KL Green JD Smart J Tsibouklis JA Davis F Hampson PW Dettmar WR Wilber (2001) ArticleTitleThe gastrointestinal transit profile of 14C-labelled poly(acrylic acids): an in vivo study Biomaterials 22 1861–1867 Occurrence Handle11396891 Occurrence Handle1:CAS:528:DC%2BD3MXksVynsr8%3D Occurrence Handle10.1016/S0142-9612(00)00369-0
M Tafaghodi S Abolghasem Sajadi Tabassi MR Jaafari SR Zakavi M Momen-Nejad (2004) ArticleTitleEvaluation of the clearance characteristics of various microspheres in the human nose by gamma-scintigraphy Int J Pharm 280 125–135 Occurrence Handle15265553 Occurrence Handle1:CAS:528:DC%2BD2cXlslGhs7c%3D Occurrence Handle10.1016/j.ijpharm.2004.05.009
C Wadell E Bjork O Camber (2003) ArticleTitlePermeability of porcine nasal mucosa correlated with human nasal absorption Eur J Pharm Sci 18 47–53 Occurrence Handle12554072 Occurrence Handle1:CAS:528:DC%2BD3sXmsFWjuw%3D%3D Occurrence Handle10.1016/S0928-0987(02)00240-3
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Bernkop-Schnürch, A., Obermair, K., Greimel, A. et al. In vitro evaluation of the potential of thiomers for the nasal administration of Leu-enkephalin. Amino Acids 30, 417–423 (2006). https://doi.org/10.1007/s00726-006-0266-5
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DOI: https://doi.org/10.1007/s00726-006-0266-5