Effect of chitosan structure properties and molecular weight on the intranasal absorption of tetramethylpyrazine phosphate in rats.
The objective of this work was to assess and compare the absorption promoting effect of different molecular-weight chitosans, trimethyl chitosans and thiolated chitosans for intranasal absorption of 2,3,5,6-tetramethylpyrazine phosphate (TMPP). An in situ nasal perfusion technique in rats was utilized to test the rate and extent of TMPP absorption in situ. In vivo studies were carried out in rats and the pharmacokinetic parameters were calculated and compared with that of intravenous injection. All the chitosan derivatives investigated could enhance the intranasal absorption of TMPP significantly. However, thiolation could not improve the absorption-enhancing capacity of chitosan remarkably even when the thiolation ratio was as high as 152 micromol/g. In contrast, trimethylated chitosan exhibited stronger absorption-enhancing ability than the homopolymer chitosan. The permeation enhancing effect of chitosan increased with increasing molecular weight up to M(w) 100 kDa. In vivo studies indicated that chitosan 100 kDa and TMC 50 kDa had comparable absorption-enhancing effect but chitosan 100 kDa functioned for more than 120 min versus 90 min for TMC. A good correlation was found between the in situ absorption data and plasma concentration in vivo for the polymers investigated. This study demonstrated that both chitosan structural features and chitosan molecular weight play a key role on promoting the intranasal absorption of TMPP. Taking safety reason into account, chitosan 100 kDa is the most promising as an intranasal absorption enhancer.
Mei
Dan
D
School of Pharmacy, Shenyang Pharmaceutical University, Shenyang, China.
Mao
Shirui
S
Sun
Wei
W
Wang
Yanjun
Y
Kissel
Thomas
T
D000281:Administration, Intranasal; D000818:Animals; D002626:Chemistry, Pharmaceutical; D048271:Chitosan / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D007275:Injections, Intravenous; D008297:Male; D008745:Methylation; D015394:Molecular Structure; D008970:Molecular Weight; D009297:Nasal Mucosa / Q000187:drug effects* / Q000378:metabolism; D010539:Permeability; D010710:Phosphates / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D011719:Pyrazines / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D051381:Rats; D017208:Rats, Wistar; D012995:Solubility; D013438:Sulfhydryl Compounds / Q000737:chemistry / Q000494:pharmacology*
D010710:Phosphates; D011719:Pyrazines; D013438:Sulfhydryl Compounds; D048271:Chitosan; C017953:tetramethylpyrazine