Nasal absorption improvements

Another type of absorption enhancer, which has been shown to have a better safety profile, is cyclodextrin (CD) [39]. CDs have been shown to form inclusion complexes with lipophilic drugs, thereby improving their aqueous solubility and stability. A powdered insulin formulation containing dimethyl-(3-cyclodextrin improved the absolute bioavailability of insulin by 13% in rabbits compared to a control liquid formulation (1%) of insulin with dimethyl-(3-cyclodextrin [40]. Recently, hydroxypropyl (3-cyclodextrin has been shown to be more effective for enhancing the nasal absorption of acyclovir than a range of other absorption enhancers in vivo [41]. 

The enhancement of nasal absorption of insulin by hydrophobic bile salts has also been investigated. It was found that minor differences in the number, position, and orientation of the nuclear hydroxyl groups as well as alterations to side-chain conjugation can improve the adjuvant potency of bile salts. Moreover, the absorption of insulin positively correlated with an increase in the hydrophilicity of the steroid nucleus of the bile salts. In the presence of bile salts, nasal absorption of insulin reached peak levels within about lOmin, and some 10-20% of the dose was found to have been absorbed into the circulation. Marked increases in serum insulin levels were seen with sodium deoxycholate, the most lipophilic of the bile salts, whereas the least elevation—as well as least lowering of blood glucose levels—was seen with the most hydrophobic bile salt, sodium ursodeoxycholate [63],... 

Some well-organized reviews are available for details on these topics,although some formulation-related factors will be referred to in Strategies to Improve Nasal Absorption. ... 

Numerous papers have reported on the possible utility of nasal administration of a variety of compounds, including peptide and protein drugs. However, only a small number of products are of clinical use for intranasal systemic delivery, as mentioned earlier. Especially, most peptide and protein drugs show insufficient nasal bioavailability, which may be one of the reasons for difficulties in development. To improve the nasal absorption of peptide and protein drugs, several strategies classified as follows have been intensively investigated and discussed during the last two decades ... 

Classical enzyme inhibitors such as bacitracin, bes-tatin, and amastatin have been found to be effective for improving the nasal absorption of various peptide drugs such as LHRH and calcitonin. These inhibitors having peptide like structures appear to exert their inhibitory effects by a competitive mechanism. In addition, camostat mesilate and nafamostat mesilate, which are clinically used as primary ingredients for pancreatic diseases, have been found to improve the nasal absorption of vasopressin, desmopressin, and calcitonin by inhibiting aminopeptidase and trypsin activity. 

To increase the residence time in the nasal mucosa, a bioadhesive formulation may be one of the most reasonable approaches. In fact, microspheres containing bioadhesive polymers such as starch, albumin, and Sephadex with a particle size of 40-60 pm have been found to be cleared from the nasal cavity much more slowly than solutions. Starch microspheres improved the nasal absorption of insulin, with synergistic effects of some absorption enhancers in sheep. In another paper, dry powder containing starch and Carbopol 974P showed significantly higher bioavailability after nasal administration than the formulation without Carbopol. ° Chitosan, already mentioned above, also has a bioadhesive property and is found to be useful as a potent absorption enhancer for nasal peptide delivery. Other bioadhesive polymer systems,... 

Coating of PLGA nanoparticles with the mucoadhesive CS improves the stability of the particles in the presence of lysozyme and enhanced the nasal transport of the encapsulated tetanus toxoid. Nanoparticles made solely of CS are stable upon incubation with lysozyme. Moreover, these particles are very efficient in improving the nasal absorption of insulin as well as the local and systemic immune responses to tetanus toxoid, following intranasal administration. 

Absorption enhancement Hexetil hydrochloride/a-CD (improvement of oral bioavailability) ketoconazole/p-CD (improvement of oral bioavailability) ethyl 4-biphenylyl acetate /2-HP-P-CD (improvement of rectal absorption) estradiol/DM-P-CD (enhancement of nasal absorption) nifedipine/2-HP-6-CD (improvement of the oral bioavailability). 

Three ways exist to improve limited nasal absorption of systemically acting substances ... 

A range of nasal peptides such as desmopressin, buserelin, nafarelin and oxytocin, have been formulated into licensed nasal products. However, none of them contains a nasal absorption enhancer. Even though these nasal products are characterised by low peptide bioavailability they are efficacious, as low systemic levels are needed to exert a therapeutic effect. However, developing of novel safe and efficient nasal absorption enhancers is of great interest to improve bioavailability of presently marketed peptides and to provide sufficient nasal permeability of less potent biologicals [22]. 

Wang X, Chi N, Tang X. Preparation of estradiol chitosan nanoparticles for improving nasal absorption and brain targeting. Eur J Pharm Biopharm. 2008 70(3) 735-40. 

Nasal Nanoparticles Insuhn Improved nasal absorption [94]... 

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