Drug Deliv. 2014 Mar;21(2):75-86. doi: 10.3109/10717544.2013.838713. Epub 2013 Oct 9.

Insights into direct nose to brain delivery: current status and future perspective.
Mittal D1, Ali A, Md S, Baboota S, Sahni JK, Ali J. Author information Abstract
Abstract Now a day's intranasal (i.n) drug delivery is emerging as a reliable method to bypass the bloodbrain barrier (BBB) and deliver a wide range of therapeutic agents including both small and large molecules, growth factors, viral vectors and even stem cells to the brain and has shown therapeutic effects in both animals and humans. This route involves the olfactory or trigeminal nerve systems which initiate in the brain and terminate in the nasalcavity at the olfactory neuroepithelium or respiratory epithelium. They are the only externally exposed portions of the central nervous system (CNS) and therefore represent the most direct method of noninvasive entry into the brain. This approach has been primarily used to explore therapeutic avenues for neurological diseases. The potential for treatment possibilities with olfactory transfer of drugs will increase as more effective formulations and delivery devices are developed. Recently, the apomorphine hydrochloride dry powders have been developed for i.n. delivery (Apomorphine nasal, Lyonase technology, Britannia Pharmaceuticals, Surrey, UK). The results of clinical trial Phase III suggested that the prepared formulation had clinical effect equivalent to subcutaneously administered apomorphine. In coming years, intranasal delivery of drugs will demand more complex and automated delivery devices to ensure accurate and repeatable dosing. Thus, new efforts are needed to make this noninvasive route of delivery more efficient and popular, and it is also predicted that in future a range of intranasal products will be used in diagnosis as well as treatment of CNS diseases. This review will embark the existing evidence of nose-to-brain transport. It also provides insights into the most relevant pre-clinical studies of direct nosebrain delivery and delivery devices which will provide relative success of intranasal delivery system. We have, herein, outlined the relevant aspects of CNS drugs given intranasally to direct the brain in treating CNS disorders like Alzheimer's disease, depression, migraine, schizophrenia, etc.

Sci Pharm. 2013 Apr 14;81(3):843-54. doi: 10.3797/scipharm.1208-18. eCollection 2013.

Intranasal delivery of chitosan nanoparticles for migraine therapy.

Gulati N1, Nagaich U, Saraf SA.
Author information

Erratum in
Sci Pharm. 2013;81(4):1167-9.

Abstract
OBJECTIVE: The objective of the research was to formulate and evaluate sumatriptan succinate-loaded chitosan nanoparticles for migraine therapy in order to improve its therapeutic effect and reduce dosing frequency.

MATERIAL AND METHODS: The Taguchi method design of experiments (L9 orthogonal array) was applied to obtain the optimized formulation. The sumatriptan succinate-loaded chitosan nanoparticles (CNPs) were prepared by ionic gelation of chitosan with tripolyphosphate anions (TPP) and Tween 80 as surfactant. RESULTS: The CNPs had a mean size of 306.8 3.9 nm, a zeta potential of +28.79 mV, and entrapment efficiency of 75.4 1.1%. The in vitro drugrelease of chitosan nanoparticles was evaluated in phosphate buffer saline pH 5.5 using goat nasal mucosa and found to be 76.7 1.3% within 28 hours. DISCUSSION: The release of the drug from the nanoparticles was anomalous, showing non-Fickian diffusion indicating that drug release is controlled by more than one process i.e. the superposition of both phenomena, a diffusion-controlled as well as a swelling-controlled release. This is clearly due to the characteristics of chitosan which easily dissolves at low pH, thus a nasal pH range of 5.5 0.5 supports it very well. The mechanism of pH-sensitive swelling involves protonation of the amine groups of chitosan at low pH. This protonation leads to chain repulsion, diffusion of protons and counter ions together with water inside the gel, and the dissociation of secondary interactions. CONCLUSION: The results suggest that sumatriptan succinate-loaded chitosan nanoparticles are the most suitable mode of drug delivery for promising therapeutic action.

eadache. 2013 Sep;53 Suppl 2:72-84. doi: 10.1111/head.12186.

Breath powered nasal delivery: a new route to rapid headache relief.

Djupesland PG1, Messina JC, Mahmoud RA.
Author information

Abstract
The nose offers an attractive noninvasive alternative for drug delivery. Nasal anatomy, with a large mucosal surface area and high vascularity, allows for rapid systemic absorption and other potential benefits. However, the complex nasal geometry, including the narrow anterior valve, poses a serious challenge to efficient drug delivery. This barrier, plus the inherent limitations of traditional nasal delivery mechanisms, has precluded achievement of the full potential of nasal delivery. Breath Powered bi-directional delivery, a simple but novel nasal delivery mechanism, overcomes these barriers. This innovative mechanism has now been applied to the delivery of sumatriptan. Multiple studies of drug deposition, including comparisons of traditionalnasal sprays to Breath Powered delivery, demonstrate significantly improved deposition to superior and posterior intranasal target sites beyond thenasal valve. Pharmacokinetic studies in both healthy subjects and migraineurs suggest that improved deposition of sumatriptan translates into improved absorption and pharmacokinetics. Importantly, the absorption profile is shifted toward a more pronounced early peak, representing nasalabsorption, with a reduced late peak, representing predominantly gastrointestinal (GI) absorption. The flattening and "spreading out" of the GI peak appears more pronounced in migraine sufferers than healthy volunteers, likely reflecting impaired GI absorption described in migraineurs. In replicated clinical trials, Breath

Powered delivery of low-dose sumatriptan was well accepted and well tolerated by patients, and onset of pain relief was faster than generally reported in previous trials with noninjectable triptans. Interestingly, Breath Powered delivery also allows for the potential of headache-targeted medications to be better delivered to the trigeminal nerve and the sphenopalatine ganglion, potentially improving treatment of various types of headache. In brief, Breath Powered bi-directional intranasal delivery offers a new and more efficient mechanism for nasal drug delivery, providing an attractive option for improved treatment of headaches by enabling or enhancing the benefits of current and future headache therapies. 2013 The Authors. Headache: The Journal of Head and Face Pain published by Wiley Periodicals, Inc. on behalf of American Headache Society.

KEYWORDS: absorption, drug delivery, migraine, nasal, powder, sumatriptan

Headache. 2013 Sep;53(8):1323-33. doi: 10.1111/head.12167. Epub 2013 Aug 28.

Improved pharmacokinetics of sumatriptan with Breath Powered nasal delivery of sumatriptan powder.
Obaidi M1, Offman E, Messina J, Carothers J, Djupesland PG, Mahmoud RA.
Author information

Abstract
OBJECTIVES: The purpose of this study was to directly compare the pharmacokinetic (PK) profile of 22-mg sumatriptan powder delivered intranasally with a novel Breath Powered device (11mg in each nostril) vs a 20 -mg sumatriptan liquid nasal spray, a 100-mg oral tablet, and a 6-mg subcutaneous injection. BACKGROUND: A prior PK study found that low doses of sumatriptan powder delivered intranasally with a Breath Powered device were efficiently and rapidly absorbed. An early phase clinical trial with the same device and doses found excellent tolerability with high response rates and rapid onset of pain relief, approaching the benefits of injection despite significantly lower predicted drug levels. METHODS: An open-label, cross-over, comparative bioavailability study was conducted in 20 healthy subjects at a single center in the USA. Following randomization, fasted subjects received a single dose of each of the 4 treatments separated by a 7-day washout. Blood samples were taken pre-dose and serially over 14 hours post-dose for PK analysis. RESULTS: Quantitative measurement of residuals in used Breath Powered devices demonstrated that the devices delivered 80.9mg (meanstandard deviation) of sumatriptan powder in each nostril (total dose 16mg). Although the extent of systemic exposure over 14 hours was similar following Breath Powered delivery of 16-mg sumatriptan powder and 20-mg liquid nasal spray (area under the curve [AUC]0- 64.9ng*hour/mL vs 61.1ng*hour/mL), sumatriptan powder, despite a 20% lower dose, produced 27% higher peak exposure (Cmax 20.8ng/mL vs 16.4ng/mL) and 61% higher exposure in the first 30 minutes compared with the nasal spray (AUC0-30minutes 5.8 ng*hour/mL vs 3.6ng*hour/mL). The magnitude of

difference is larger on a per-milligram basis. The absorption profile following standard nasal spray demonstrated bimodal peaks, consistent with lower early followed by higher later absorptions. In contrast, the profile following Breath Powered delivery showed higher early and lower late absorptions. Relative to the 100-mg oral tablet (Cmax 70.2ng/mL, AUC0-, 308.8ng*hour/mL) and 6-mg injection (Cmax 111.6ng/mL, AUC0- 128.2ng*hour/mL), the peak and overall exposure following Breath Powered intranasal delivery of sumatriptan powder was substantially lower. CONCLUSIONS: Breath Powered intranasal delivery of sumatriptan powder is a more efficient form of drug delivery, producing a higher peak and earlier exposure with a lower delivered dose than nasal spray and faster absorption than either nasal spray or oral administration. It also produces a significantly lower peak and total systemic exposure than oral tablet or subcutaneous injection. 2013 OptiNose AS. Headache published by Wiley on behalf of the American Headac

Drugs. 2013 Sep;73(13):1483-90. doi: 10.1007/s40265-013-0104-5.

Sumatriptan iontophoretic transdermal system: a review of its use in patients with acute migraine.
Garnock-Jones KP. Author information Abstract
The sumatriptan iontophoretic transdermal system (ZECUITY()) [hereafter referred to as sumatriptan TDS] is the first transdermal treatment formigraine to be approved by the US FDA. This article reviews the available pharmacologic properties of sumatriptan TDS and its clinical efficacy and tolerability for the acute treatment of adult patients with migraine with or without aura. Sumatriptan, a selective 5-hydroxytryptamine receptor subtype 1 (5-HT1) agonist, is presumed to exert its therapeutic effect on migraine patients by binding to the 5-HT1B/1D receptors on intracranial blood vessels and sensory nerves of the trigeminal system, resulting in cranial vessel constriction and the inhibition of the release of pro-inflammatory neuropeptides and plasma extravasation. In a well designed, phase III clinical trial, sumatriptan TDS was shown to be more effective than placebo at treating a singlemigraine attack, with significantly more sumatriptan TDS than placebo recipients being headache pain free and nausea free at 2 hours. These data were supported by a long-term, repeat-use study over 12 months. Additionally, sumatriptan TDS was generally well tolerated in clinical trials; the most common adverse events were application-site reactions. The sumatriptan TDS formulation avoids the gastrointestinal tract, and has a controlled, sustained delivery, allowing for patients with migraine-associated nausea and vomiting to receive treatment without the risk of inconsistent absorption or avoidance of tablet use (associated with oral delivery of the drug in these patients). Moreover, it may offer a useful alternative to the nasal spray or subcutaneous sumatriptan formulations. However, definitive conclusions on the comparative efficacy and tolerability of sumatriptan TDS versus other sumatriptan formulations or other migraine drugs are not as yet possible, and data from comparative trials would be of great interest. Sumatriptan TDS is a useful addition to the treatment options available to migraine patients.

CNS Drugs. 2013 May;27(5):385-94. doi: 10.1007/s40263-013-0061-2.

Dihydroergotamine: a review of formulation approaches for the acute treatment of migraine.

Silberstein SD1, Kori SH. Author information Abstract
Dihydroergotamine (DHE) was first used to treat migraine in 1945 and is currently included among migraine-specific treatments for moderate-severemigraine. DHE may be administered through several routes of delivery, with efficacy and tolerability varying among formulations. We review DHE formulation approaches for the acute treatment of migraine, reviewing pharmacokinetics/dynamics and comparing clinical response among various formulations. Pharmacokinetic properties vary among DHE formulations, with peak concentration occurring in 6 min with intravenous, 34 min with intramuscular, 56 min with intranasal, 12 min with oral inhalation and 75 min with oral administration. DHE is a potent agonist at serotonin 5-HT1B and 5-HT1D receptors. Adverse effects due to binding to select adrenergic and dopaminergic receptors are significantly less with orally inhaled than intravenous DHE when comparing therapeutically effective doses. Among parenteral formulations (including subcutaneous, intramuscular, intravenous and nasal spray), efficacy is superior with injectable dosing. Nasal spray DHE is generally more effective than placebo, but less effective than sumatriptan. Orally inhaled DHE is likewise more effective than placebo, but there are no head-to-head comparisons with triptans available for review. Adverse effects, particularly nausea, may limit use of parenteral DHE. Nausea is generally less frequent with non-injectable dosing.

Iran J Pharm Res. 2012 Spring;11(2):513-21.

Freeze-dried Xanthan/Guar Gum Nasal Inserts for the Delivery of Metoclopramide Hydrochloride.
Dehghan MH1, Girase M. Author information Abstract
Prolonged residence of drug formulation in the nasal cavity is important for the enhancing intranasal drug delivery. The objective of the present study was to develop a mucoadhesive in-situ gelling nasal insert which would enable the reduced nasal mucociliary clearance in order to improve the bioavailability of metoclopramide hydrochloride. Metoclopramide hydrochloride is a potent antiemetic and effective for preventing emesis induced by cancer chemotherapy, migraine, pregnancy and gastroparesis. It undergoes hepatic first pass metabolism and both the absolute bioavailability and the plasma concentrations are subjected to wide inter-individual variation showing values between 32% and 98%. Oral antiemetic often gets vomited out before the systemic absorption compelling parenteral administration which results in low patient compliance. Adverse effect of metoclopramide HCL on CNS caused by high plasma peaks can be avoided through sustained formulation. A novel combination of xanthan gum and guar gum was used to prepare the nasal inserts and the effect of blend ratio of xanthan gum and guar gum on drug release from in-situ gelling nasal inserts and on other insert properties such as bioadhesion potential and water uptake was studied. PXRD was used to determine the effect of freeze-drying on crystalline nature of formulation. The viscosities of xanthan gum in combination with guar gum were observed to be higher than that of single polymer solutions. This is because of the synergistic

rheological interaction between xanthan and guar gum. There is a substantial loss in crystalline nature of the formulation after freeze-drying. The best nasal inserts formulation containing xanthan gum and guar gum ratio 1:5, showed good release (91.83%) as well as bioadhesion which may result in an increase in the nasal residence time.

Drug Deliv. 2011 Nov;18(8):578-85. doi: 10.3109/10717544.2011.600784. Epub 2011 Aug 12.

Evaluation of submicron emulsion as vehicles for rapid-onset intranasal delivery and improvement in brain targeting of zolmitriptan.
Yu C1, Gu P, Zhang W, Cai C, He H, Tang X. Author information Abstract
This study was to evaluate submicron emulsion as a drug carrier for intranasal delivery of zolmitriptan (ZT). Since the drug distribution in submicron emulsion might influence the nasal absorption, two different formulations separately incorporating the drug in oily phase (ZTSE-1) and aqueous phase (ZTSE-2) were assessed. To find the better formulation for rapid-onset intranasal delivery and improvement in brain targeting of ZT, the in vivo nasalabsorption of these two formulations was evaluated. The blood and cerebrospinalfluid (CSF) pharmacokinetics of ZTSE-1, ZTSE-2 and ZT solution (ZTS) were evaluated after intranasal administered to anesthetized Wistar rats. The results demonstrated that ZT from ZTSE-1 and ZTSE-2 had better brain targeting efficiency than the ZTS. In plasma and CSF, the ZTSE-2 reached peak concentration much faster than ZTSE-1 and ZTS. The ZTSE-2 also presented significantly higher initial ZT levels in CSF compared with the ZTSE-1 and ZTS. The results indicated that incorporation of ZT in the aqueous phase of submicron emulsion was effective for rapid intranasal delivery of drug to blood and brain, which would offer patients the benefits of rapid relief from migraine.

J Microencapsul. 2009 Dec;26(8):711-21. doi: 10.3109/02652040802685241.

Formulation and evaluation of nasal mucoadhesive microspheres of sumatriptan succinate.

Jain SA1, Chauk DS, Mahajan HS, Tekade AR, Gattani SG. Author information Abstract
The purpose of present research work was to develop mucoadhesive microspheres for nasal delivery with the aim to avoid hepatic first-pass metabolism, improve therapeutic efficacy and enhance residence time. For the treatment of migraine, hydroxypropyl methylcellulose (HPMC) K4M and K15M based microspheres containing sumatriptan succinate (SS) were prepared by spray-drying technique. The microspheres were evaluated with respect to the yield, particle size, incorporation efficiency, swelling property, in vitro mucoadhesion, in vitro drug release, histological study and stability. Microspheres were characterized by differential scanning calorimetry, scanning electron microscopy and X-ray diffraction study. It was found that the particle size, swelling ability and incorporation efficiency of microspheres increases with increasing drug-to-polymer ratio. HPMC-based microspheres show adequate mucoadhesion and do not have any destructive effect on nasal mucosa. On the basis of these results, SS microspheres based on HPMC may be considered as a promising nasal delivery system

AAPS PharmSciTech. 2006 Jan 20;7(1):E8.

Preliminary brain-targeting studies on intranasal mucoadhesive microemulsions of sumatriptan.

Vyas TK1, Babbar AK, Sharma RK, Singh S, Misra A. Author information Abstract
The aim of this investigation was to prepare microemulsions containing sumatriptan (ST) and sumatriptan succinate (SS) to accomplish rapid deliveryof drug to the brain in acute attacks of migraine and perform comparative in vivo evaluation in rats. Sumatriptan microemulsions (SME)/sumatriptan succinate microemulsions (SSME) were prepared using titration method and characterized for drug content, globule size and size distribution, and zeta potential. Biodistribution of SME, SSME, sumatriptan solution (SSS), and marketed product (SMP) in the brain and blood of Swiss albino rats following intranasal and intravenous (IV) administrations were examined using optimized technetium-labeled ((99m)Tc-labeled) ST formulations. The pharmacokinetic parameters, drug targeting efficiency (DTE), and direct drug transport (DTP) were derived. Gamma scintigraphy imaging of rat brain following IV and intranasal administrations were performed to ascertain the localization of drug. SME and SSME were transparent and stable with mean globule size 38 +/- 20 nm and zeta potential between -35 to -55 mV. Brain/blood uptake ratios at 0.5 hour following IV administration of SME and intranasal administrations of SME, SMME, and SSS were found to be 0.20, 0.50, 0.60, and 0.26, respectively, suggesting effective transport ofdrug following intranasal administration of microemulsions. Higher DTE and DTP for mucoadhesive microemulsions indicated more effective targeting following intranasal administration and best brain targeting of ST from mucoadhesive microemulsions. Rat brain scintigraphy endorsed higher uptake of ST into the brain. Studies conclusively demonstrated rapid and larger extent of transport of microemulsion of ST compared with microemulsion of SS, SMP, and SSS into the rat brain. Hence, intranasal delivery of ST microemulsion developed in this investigation can play a promising role in the treatment of acute attacks of migraine. Drug Target. 2005 Jun;13(5):317-24.

Intranasal mucoadhesive microemulsions of zolmitriptan: preliminary studies on brain-targeting.

Vyas TK1, Babbar AK, Sharma RK, Misra A. Author information Abstract
The aim of this investigation was to prepare microemulsions containing zolmitriptan (ZT) for rapid drug delivery to the brain to treat acute attacks ofmigraine and to characterize microemulsions and evaluate biodistribution in rats. Zolmitriptan microemulsions (ZME) were prepared using the titration method and were characterized for globule size distribution and zeta potential. ZT was radiolabeled using (99m)Tc (technetium) and radiolabeled-drugformulations of ZT were used to carry out biodistribution of drug in the brain of Swiss albino rats after intranasal and intravenous administration. The pharmacokinetic parameters, drug targeting efficiency (%DTE) and direct nose-to-brain drug transport (%DTP) were calculated. Brain scintigraphy imaging in rats were also performed to ascertain the uptake of drug into the brain. ZME were transparent and stable with mean globule size of 35 +/- 25 nm and zeta potential of - 38- 52 mV. (99m)Tc-labeled-drug formulations of ZT were found to be stable and suitable to perform in vivo studies. Following intranasal administrations of zolmitriptan mucoadhesive microemulsion (ZMME), ZME, Zolmitriptan solution (ZS) and intravenous administration of ZS, brain/blood uptake ratios at 0.50 h were

found to be 0.70, 0.56, 0.27 and 0.13, respectively, indicating effective brain-targeting following intranasal administration of ZMME. Comparing intranasal administration of ZMME with intravenous administration of ZME, the %DTE and %DTP were found higher indicating effective drug transport following intranasal administration and highest brain-targeting following ZMME administration. Rat brain scintigrams showed substantial uptake of drug into the brain after intranasal administration of ZMME. Studies of this investigation conclusively demonstrated rapid and larger extent of transport into the rat brain following intranasal administration of ZMME and can play a promising role in the treatment of acute attacks of migraine.

Arq Neuropsiquiatr. 2003 Jun;61(2A):313-20. Epub 2003 Jun 9.

The triptan formulations: a critical evaluation.

Bigal ME1, Bordini CA, Antoniazzi AL, Speciali JG. Author information Abstract
The migraine-specific triptans have revolutionized the treatment of migraine and are usually the drugs of choice to treat a migraine attack in progress. Different triptans are available in different strengths and formulations including oral tablets, orally disintegrating tablets, nasal sprays and subcutaneous injections. In Europe, sumatriptan is also available as a suppository. Specific differences among the triptans exist as evidenced by different pharmacological profiles including T1/2, Tmax, Cmax, AUC, metabolism, drugdrug interaction profiles, amongst other parameters. How or whether these differences translate to clinical efficacy and tolerability differences is not well differentiated. Clinical distinctions among these agents are subtle and proper choice of triptan requires attention to the specific characteristics of each individual patient, knowledge of patient preference, accurate history of the efficacy of previous acute care medications as well as individual features of the drug being considered. Delivery systems may play an important role in the onset of action of triptans. The selection of an acute antimigraine drug for a patient depends upon the stratification of the patient's migraine attack by peak intensity, time to peak intensity, level of associated symptoms such as nausea and vomiting, time to associated symptoms, comorbid diseases, and concomitant treatments that might cause drug-drug interactions. The clinician has in his armamentarium an ever-expanding variety of medications, available in multiple formulations and dosages, with good safety and tolerability profiles. Continued clinical use will yield familiarity with the various triptans, and it should become possible for the interested physician to match individual patient needs with the specific characteristics of a triptan to optimize therapeutic benefit.