| Migraine is a common headache which is recurrent and intermittent. There are 9%-16% people suffered from migraine with varying degrees of symptoms. The disease incidence among female is higher than that among male. Some of them have been last for several decades. With the rapid development of social economy, accelerating the pace of life, increasing individual stress, an ascendant trend of the incidence of migraine is evident. In recent years, the neurotransmitter serotonin (5-HT, a potent vasoconstrictor factor) is considered to play a major role in the pathogenesis of migraine. Triptans were selective 5-HT1B/1D agonists, which exhibited a good therapeutic effect of migraine. Nasal Drug Delivery System (NDDS) has been given more focus in recent years. It has the advantages of rapidly absorption, no first-pass effect, convenient administration, and good patient compliance. In addition, it also can provide another route for brain-targeting.An HPLC method was established for in vitro analysis of sumatriptan succinate (SMS). The analysis method was proved to be precise, simple and reliable. The solubility of SMS in different kinds of oil phase with addition of various amount of lecithin was determined. It was found that the solubility of SMS in the oil phase is poor. The addition of lecithin could increase the solubility of SMS in the oil.The in situ rat nasal perfusion technique is used in the study of nasal absorption of drugs with addition of different absorption enhancers and preservatives. The enhance effect of studied addition agents could be arranged in the following decreasing order:0.5% Sodium Deoxycholate (SDC)≈5% RAMEB> 5% HP-β-CD≈Control> 0.01% Benzalkonium Bromide (BAB). The pH and osmolarity had little effect on the nasal uptake of SMS. A biochemical method was employed to evaluate the potential mucosa perturbation. The results of the irritation obtained from the release of total protein and LDH is found to be in the following order:0.5% SDC> 5% RAMEB> 0.01% BAB≈5% HP-β-CD≈Saline. As a result,5% RAMEB was considered to be the best absorption enhancer for SMS nasal spray.High pressure homogenizer was used to prepare SMS loaded positively charged submicron emulsions (SMS-PCSE) and negatively charged submicron emulsions (SMS-NCSE). Taking physical appearance, particle size distribution, zeta potential, entrapment efficiency as index, the main formulation and preparation factors were systemically studied. The final formulation and procedure of SMS-PCSE were developed:3% egg lecithin and 0.75% stearylamine were added to the 15% MCT, stirred at 75℃until totally dispersed to obtain the oil phase,0.5%SMS,2.25% glycerol and 0.5% F68 were heated and dissolved into double-distilled water to obtain the water phase. Coarse emulsion was achieved by mixing the oil and aqueous phases for 5 min using a high-shear mixer at a speed of 10000 rpm. After adjusting the pH to about 7.5, final emulsion were obtained by passing the coarse emulsion through a high pressure homogenizer (70 MPa,8 cycles). The final product was gassed with nitrogen gas before being sealed in glass bottles. The final formulations of SMS-NCSE were as follows:15% MCT,3% egg lecithin,0.5%SMS, 2.25% glycerol,0.5%F68,0.5% sodium oleate. Preparation procedure is the same as above.The viscosity of SMS submicron emulsion was higher than SMS solution, regardless of the charge of emulsion. In vitro drug release experiment revealed that SMS-PCSE has the same drug release rate as SMS solution, but SMS-NCSE showed a slower in vitro drug release compared to the above two.To assess the ciliary toxicity of nasal preparations of SMS, the hoptoad in situ maxilla mucosa method was used by determining the ciliary movement time. It was showed that no significant ciliary toxicity was observed.A simultaneous blood and brain microdialysis coupled with UPLC-MS/MS method was established for in vivo analysis of SMS. The recovery and delivery of probe detected by gain and loss method didn’t show any statistical difference. The in vivo recovery decreased with increasing time, a protein sheath may occur and hinder the membrane permeability.The pharmacokinetics and brain-targeting was evaluated after intranasal administration of SMS nasal spray and two different charged submicron emulsions. The data were analyzed with DAS 2.0 pharmacokinetic program. After i.v. administration of SMS solution, the drug concentration in the plasma fitted a three-compartment model, while in CSF fitted a two-compartment model. The MRTs of SMS in brain and blood were 130.72 min,104.1 min, AUCs were 1682.856,6885.062 ng-min-mL-1, respectively. After intranasal administration, there exist a plateau period for a relatively long time. This could be attributed to the intrinsic property of SMS, relatively small volume of rat nasal cavity and relatively large intranasal dose.After intranasal administration of different SMS preparations, it was showed that the addition of absorption enhancer (5%RAMEB) can significantly decrease the time to reach the plateau level and increase the drug concentration in plasma. The time to reach the plateau level of NSCE is longer than PCSE. This could be attributed to the slower in vitro release profile of NCSE. There still existed a plateau period after intranasal administration of SMS-PCSE, which could not eliminate completely after 6 hours. AUCs of SMS in blood and brain were 5543.298±194.965,1214.421±499.785ng-min-mL-1 and 6266.724±1205.713,1920.383±380.601 ng-min-mL-1 after intranasal administration of SMS-NCSE and SMS-PCSE. The bioavailability of SMS nasal spray and two SMS submicron emulsions is better than SMS saline solution, which is as better as 91% when intranasal administration of SMS-PCSE.Drug targeting index (DTI) and direct transport percentage (DTP) were introduced in our research for a better understanding the direct transportation between nose and brain. After intranasal administration SMS saline solution, the DTI and DTP values were 3,67%, respectively, which indicate a good brain-targeting profile. However, compared with i.v. injection, the brain-targeting profiles of SMS nasal spray, SMS-PCSE and SMS-NCSE didn’t show any significant difference, which is less than the saline group. |
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