Studies On The Rapid-onset Intranasal Delivery System For Zolmitriptan

Zolmitriptan (ZT) is a 5-HT1B/1D receptor partial agonist for use in the acute treatment of migraine and related vascular headaches. ZT is commercially available on the market in the form of oral tablets (conventional and orodispersible) and nasal spray. However, the current oral therapies have some drawbacks. ZT undergoes first-pass metabolism and has poor bioavailability (40%). In addition, an oral formulation may not be suitable for the treatment of some kinds of migraine attacks, particularly those associated with nausea and vomiting which make it difficult for migraine patients to take tablets. Furthermore, gastric stasis is a common feature of migraine attacks, and this can limit the absorption of orally administered medications. Consequently, a nasal spray formulation of ZT has been developed that demonstrates good efficacy, high tolerability and a very fast onset of action. However, although absorption of ZT is initially more rapid after intranasal administration than oral administration, pharmacokinetic parameters for ZT such as plasma concentration-time curve (AUC) or Cmax values were similar for nasal spray and oral formulations. The bioadhesive microspheres and submicron emulsion of ZT were studied in this paper, aiming to offer benefits of highly effective and rapid relief from migraine for patients.High pressure homogenizer was used to prepare ZT submicron emulsion. Taking physical appearance, particle size distribution, zeta potential, entrapment efficiency as index, main formulation and preparation factors were systemically studied. Two different formulations was prepared, one had ZT incorporating the drug in oily phase of the negatively charged submicron emulsion (NCSE). The other was prepared using stearylamine as the positive charge inducer and had ZT dispersing in the aqueous phase of the positively charged submicron emulsion (PCSE).To find the better formulation for rapid-onset intranasal delivery and improvement in brain targeting of ZT, the in vivo nasal absorption of these two formulations was evaluated. The blood and cerebrospinalfluid pharmacokinetics of NCSE, PCSE and ZT solution (ZTS) were evaluated after intranasal administered to anesthetized Wistar rats by microdialysis method. After i.n. administration of ZTS, NCSE and PCSE, the absolute biological availability calculated was 84.0±11.1%,84.3±12.0% and 85.0±30.5%, respectively. The mean value of Tmax of PCSE (0.3h) group was obviously shorter than that of ZTS (1.0±0.6h) and NCSE (1.2±0.9h) groups after i.n. administration. Compared with ZTS and NCSE, the intranasal absorption of ZT from PCSE to plasma was much faster. In CSF, The Tmax of PCSE (2.0±0.9h) was significantly shorter than that of ZTS (4.0±1.1h) or NCSE (4.0±1.4h) after i.n. administration (P<0.05). PCSE had higher initial ZT levels in CSF compared with NCSE and ZTS after i.n. administration. Comparing i.n. administration of NCSE and PCSE with i.v. administration of ZTS, significantly higher AUCCSF/AUCPlasma value was obtained (P<0.05). The results demonstrated that ZT from NCSE and PCSE had better brain targeting efficiency than the ZTS. The results indicated that incorporation of ZT in aqueous phase of submicron emulsion was effective for rapid intranasal delivery drug either to plasma or to brain and, thus, will offer patients the benefits of rapid relief from migraine. The nasal ciliotoxicity of the preparations was evaluated by using in situ toad palate model which indicated that the submicron emulsion of ZT did not exhibit any obvious nasal ciliotoxicity.The absolute biological availability (about 80%) of all the ZT preparation described above was significantly higher than that in human (40% in report). The surgically prepared anesthetized rats were used in this study resulted in a relatively high biological availability of ZT. Pharmacokinetic study was carried out after the PCSE and ZTS were intranasally administrated to awake beagle dogs. In addition, surfactants acting as penetration enhancers can improve transcellular transport of drugs across nasal mucosa. To study the effect of surfactants in on nasal absorption of ZT alone, a control preparation was prepared by dissolving ZT in water with the same amount of surfactants as that in PCSE. The absolute bioavailability of PCSE group (80.68±16.84%) was significantly higher than that of ZTS group (53.23±19.86%) and the ZT in surfactants control preparation group (62.70±5.06%)(P<0.05). The pharmacokinetic studies demonstrated that ZT from PCSE was absorbed much more rapidly and effectively. The enhanced nasal absorption of ZT in PCSE was not mainly caused by the egg lecithin and poloxamer. These results demonstrated that the submicron emulsion preparation of ZT was a relatively safe dosage form for rapid and effective intranasal delivery of ZT.The most commonly reported adverse events for the ZT nasal spray were unusual taste and throat discomfort and this is likely to be due to the absolute quantity of drug passing from the nasal cavity via the nasopharynx to the gastrointestinal tract. As a result, the nasal solid preparation has some potential advantages over the fluild preparation. Nasally administered bioadhesive preparations are capable to enhance drug absorption by increasing the contact time between the dosage form and mucosal layers. The chitosan hydrochloride (CH), carboxylation chitosan (CPCTS) and carbopol 974 P (CP) microspheres were prepared by emulsification solvent evaporation technique. Taking the yields and physical appearance as the main index, the formulation and preparation factors were optimized. The yields of the CH、CPCTS and CP microspheres were 52.8%、77.6% and 55.9% respectively. The content was 8.04%、5.67% and 7.29%. The angle of repose were 37.7±1.6°45.4±1.9°and 57.1±1.2°. The particle size was 39.3±15.1μm and 21.4±10.1±m for CH and CPCTS microspheres. The particle size was within 10μm-70μm range for CP microspheres. The in vitro release of ZT from CH microsphres was fast. However, CPCTS and CP microsphres exhibited slow release of drug. After the three microspheres preparations were hydrated, the rheological analysis was carried out to study the viscoelasticity. The results demonstrated that viscoelasticity of CH and CP microsphres were significantly higher than that of CPCTS microspheres. Chitosan hydrochloride microspheres were probably a suitable mucoadhesive preparation for nasal administration of ZT because of its high mucoadhesivity and fast drug release property.Pharmacokinetic was studied after inintransal admininistration of CH and CP microspheres to awake beagle dogs. The absolute biological availability of CH microspheres was higher than that of ZTS and CP microspheres, but no significanlly different differences was found (P>0.05) Absoption of CP microspheres was slower than CH microspheres and the T1/2 got longer(P<0.05). The initial ZT levels of ZT in plasma after i.n. administration of CH microspheres were higer than that of ZTS. The absorption of ZT was faster than ZTS nasal spray.