Studies On Diazepam Microemulsion For Intranasal Delivery

Status epilepticus is a serious neurological disorder,which requires quick treatment to avoid the risk of brain damage and minimize mortality.The preferred drugs for the treatment of epileptic seizures are diazepam(DZ),intravenously administered.These administrations are effective for hospitalized or institutionalized patients,since the application cannot be performed by an untrained person and treatment may be associated with hypotension,cardiac dysrhytmias or central nervous systemic depression.In recent years,intranasal administration has received a lot of attention,because it offers some advantages including rapid absorption, avoidance of hepatic first-pass metabolism,and a practical,noninvasive route for rapid drug delivery to the brain.Nasal application of diazepam is a potential alternative to intravenous injections or rectal administration in treatment of acute seizures.For nasal delivery of DZ,a challenge existing in formulation development is the solubilization of poorly water-soluble DZ(about 0.05 mg·ml^-1in water),and the formulation should be designed so as to provide rapid transport of drug across nasal cavity.Microemulsions,by virtue of their lipophilic nature and having low globule size,are widely explored as a delivery system to enhance uptake across mucosa.But few studies have reported the use of microemulsion for the intranasal drug delivery.Therefore,a rapid brain-targeted diazepam microemulsion(DZME)was prepared to increase solubility and promote absorption of diazepam.During the preformulation study,the drug solubility and oil/water partition coefficient were determined.Two methods,UV spectrophotometry and HPLC,were developed for in vitro assay.HPLC could eliminate the disturbance of excipients on analysis.A novel microemulsion was prepared for intranasal delivery to increase the solubility of DZ. For the microemulsions,Miglyol 812(812)was chosen as oil phase,Tween80 as surfactants (S),PEG400 as cosurfactant(CoS)and the double-distilled water as water phase. Pseudo-ternary phase diagrams were constructed to obtain the concentration range of each component for the microemulsion formation.The effects of structure and different weight ratios of surfactant to cosurfactant(S/CoS)on the Pseudo-ternary phase diagrams was investigated.The microemulsion region reached a biggest area of microemulsion region when the ratio of S/CoS was 2∶1.Hence,the ratio of 2∶1(Tween80 to PEG400)was used.For further studies,five potential microemulsions vehicles were prepared at K_m=2 along two cuts through the phase triangle with different surfactant to oil ratios(S-CoS/O of 80∶20 and 70∶30), and the physicochemical properties of these MEs were studied by measuring surface tension, viscometry,electric conductivity,droplet size and the solubilization of DZ.Rat situ nasal perfusion methods were used as an experimental model to investigate the regulation of nasal absorption.DZ is good absorbed across the nasal mucosa in DZME1, DZME2,DZME3,DZME4 and DZME5.The nasal ciliotoxicity studies were carried out using toad palate model by determining the ciliary movement time following administration, which was reported to a good method for studying the ciliotoxicity of nasal formulation.The results suggested that both of the drug and excipient showed no severe toxicity.The toxicity of the DZMEs are very little and the preparation can be used in nasal delivery system.All results brought us a best DZME2 formulation.The concentrations of DZ in blood and brain following nasal administration of DZME2 were also measured,compared with i.v.administration of DZ solution with the same dose of 2.0 mg·kg^-1.The maximum drug plasma concentration(0.1194μg·ml^-1)was arrived within 10 min,and the bioavailability after nasal administration compared with intravenous injection was about 44.83%.The ratio of AUC in brain to that in plasma obtained after nasal administration was significantly higher than those after i.v.administration.These results suggest that the microemulsion system is a promising approach for intranasal delivery of DZ for the treatment of status epilepticus.