Performance and toxicity of different absorption enhancers used in the preparation of Poloxamer thermosensitive in situ gels for ketamine nasal administration

Abstract

The purpose of this study was to investigate the nasal absorption rate and nasal mucosal toxicity of thermosensitive ketamine in situ gels containing various absorption enhancers. The optimal composition ratio for the gel matrix was determined to be 17.2% Poloxamer 407 and 2% Poloxamer 188, as this combination resulted in solutions with a gelation point within the range found in the nasal cavity. Ketamine gels containing the tested enhancers, namely, ethylenediaminetetraacetic acid disodium salt, hydroxypropyl-β-cyclodextrin, propylene glycol, or Tween-80, were compared with enhancer-free counterparts to determine the absorption of the drug, in vivo by measuring its plasma levels in rats and in vitro using a Franz diffusion cell. Moreover, the toxicity of each gel type was assessed by microscopic observation of the morphology of rat nasal mucosa as well as by determining the mobility of the mucosal cilia using an established toad model. The results showed that gels containing hydroxypropyl-β-cyclodextrin could promote the absorption of ketamine without added toxicity compared to enhancer-free gels. Thus, we consider hydroxypropyl-β-cyclodextrin as the most promising absorption enhancer for the nasal administration of ketamine using in situ gels.

Keywords:

• Ketamine
• absorption accelerator
• nasal mucosal toxicity
• in situ gel
• ciliotoxicity

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

This work was supported by the National Natural Science Foundation of China [Grant No. 81573357], the National Key Technologies Research and Development Program for New Drugs of China [Grant No. 2018ZX09J18107], and the Military Medical Innovation Project [Grant No. 16CXZ032].