KINETICS, ULTRASTRUCTURAL ASPECTS AND MOLECULAR MODELING OF TRANSDERMAL PEPTIDE FLUX ENHANCEMENT BY N-ALKYLAZACYCLOHEPTANONES

被引:71
作者
HOOGSTRAATE, AJ
VERHOEF, J
BRUSSEE, J
IJZERMAN, AP
SPIES, F
BODDE, HE
机构
[1] LEIDEN UNIV,CTR BIOPHARMACEUT SCI,POB 9502,2300 RA LEIDEN,NETHERLANDS
[2] LEIDEN UNIV,DEPT ORGAN CHEM,2300 RA LEIDEN,NETHERLANDS
[3] LEIDEN UNIV,DEPT ELECTRON MICROSCOPY,2300 RA LEIDEN,NETHERLANDS
关键词
TRANSDERMAL DELIVERY; PEPTIDE; PENETRATION ENHANCEMENT; FREEZE-FRACTURE ELECTRON MICROSCOPY; MOLECULAR MODELING; AZONE; DESGLYCINAMIDE ARGININE VASOPRESSIN;
D O I
10.1016/0378-5173(91)90341-K
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
Transdermal delivery is an attractive route to administer peptide drugs. The stratum corneum, however, is a barrier for peptides; hence there is a need for agents to enhance peptide transport. The aim of this study was to investigate the enhancement properties of azacycloheptan-2-ones (Azones) as a function of hydrocarbon chain length. Their ability to enhance the percutaneous penetration of desglycinamide arginine vasopressin (DGAVP) was taken as a criterion. The flux of DGAVP through human stratum corneum was measured. For control experiments the stratum corneum was either untreated or immersed in propylene glycol (PG). The non-enhanced peptide flux through human stratum corneum was 1.6 +/- 0.1 nmol/cm2 per h (peptide concentration in the donor 6.0 mM). Pretreatment with PG or hexyl- or octyl-Azone did not change the flux significantly. However, the permeability increased 1.9-fold after pretreatment with decyl-Azone, 3.5-fold with dodecyl-Azone, and 2.5-fold with tetradecyl-Azone. Electron micrographs taken from freeze-fracture replicas of skin samples treated with either PG or dodecyl-Azone suggest that these treatments do not drastically change the lamellar appearance of the intercellular lipids. Taken together, the morphological and kinetical data suggest that the enhancing effect of Azone is caused by interference with the packing arrangement of the intercellular lamellar lipids in the stratum corneum, most likely by insertion of Azones into the lipid bilayers. In order to assess the capability of the Azone molecule to perturb the lipid arrangement within the bilayers, the degree of conformational freedom in Azone's polar head group was investigated using computer-aided molecular modelling. These calculations indicated that, upon turning the carbonyl moiety towards the interlamellar hydrophilic domain, a 'soup-spoon' conformation can be obtained, which is only 1 kcal/mol away from the minimum energy conformation. This 'soup-spoon' conformation would be highly favourable in order to accommodate the Azone molecule at the interface between the hydrocarbon and polar head group regions, respectively. This conformation might strongly perturb the lipid structure, making it more permeable to the penetrant. Such an effect apparently optimizes around a chain length of about 12 C-atoms.
引用
收藏
页码:37 / 47
页数:11
相关论文
共 30 条
[1]   SYSTEMIC DELIVERY OF THERAPEUTIC PEPTIDES AND PROTEINS [J].
BANGA, AK ;
CHIEN, YW .
INTERNATIONAL JOURNAL OF PHARMACEUTICS, 1988, 48 (1-3) :15-50
[2]  
BANNERJEE PS, 1989, INT J PHARM, V49, P199
[3]  
BARRY B W, 1987, Journal of Controlled Release, V6, P85, DOI 10.1016/0168-3659(87)90066-6
[4]  
BARRY BW, 1986, DELIVERY SYSTEMS PEP, P265
[5]   TRANSDERMAL PEPTIDE DELIVERY [J].
BODDE, HE ;
VERHOEF, JC ;
PONEC, M .
BIOCHEMICAL SOCIETY TRANSACTIONS, 1989, 17 (05) :943-945
[6]   VISUALIZATION OF NORMAL AND ENHANCED HGCL2 TRANSPORT THROUGH HUMAN-SKIN INVITRO [J].
BODDE, HE ;
KRUITHOF, MAM ;
BRUSSEE, J ;
KOERTEN, HK .
INTERNATIONAL JOURNAL OF PHARMACEUTICS, 1989, 53 (01) :13-24
[7]  
BODDE HE, 1989, CRIT REV THER DRUG, V6, P87
[8]  
BODDE HE, 1989, NOV INT S PRES DEV F
[9]  
BODDE HE, 1990, HAUT ALS TRANSPORTOR, P15
[10]   EFFECT OF N-ALKYL-AZOCYCLOHEPTAN-2-ONES INCLUDING AZONE ON THE THERMAL-BEHAVIOR OF HUMAN STRATUM-CORNEUM [J].
BOUWSTRA, JA ;
PESCHIER, LJC ;
BRUSSEE, J ;
BODDE, HE .
INTERNATIONAL JOURNAL OF PHARMACEUTICS, 1989, 52 (01) :47-54