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.

RESULTS: The CNPs had a mean size of 306. showing non-Fickian diffusion indicating that drug release is controlled by more than one process i. The flattening and "spreading out" of the GI peak appears more pronounced in migraine sufferers than healthy volunteers. the absorption profile is shifted toward a more pronounced early peak. Breath powered nasal delivery: a new route to rapid headache relief. doi: 10. diffusion of protons and counter ions together with water inside the gel. demonstrate significantly improved deposition to superior and posterior intranasal target sites beyond thenasal valve. DISCUSSION: The release of the drug from the nanoparticles was anomalous. This is clearly due to the characteristics of chitosan which easily dissolves at low pH.4 ± 1.7 ± 1. representing predominantly gastrointestinal (GI) absorption. allows for rapid systemic absorption and other potential benefits. Djupesland PG1. Importantly. with a large mucosal surface area and high vascularity.1111/head.5 supports it very well. has precluded achievement of the full potential of nasal delivery. Breath . Mahmoud RA.79 mV. a diffusion-controlled as well as a swelling-controlled release. poses a serious challenge to efficient drug delivery. CONCLUSION: The results suggest that sumatriptan succinate-loaded chitosan nanoparticles are the most suitable mode of drug delivery for promising therapeutic action. a zeta potential of +28.12186. the complex nasal geometry. The in vitro drugrelease of chitosan nanoparticles was evaluated in phosphate buffer saline pH 5. In replicated clinical trials.5 using goat nasal mucosa and found to be 76.53 Suppl 2:72-84. The mechanism of pH-sensitive swelling involves protonation of the amine groups of chitosan at low pH. Pharmacokinetic studies in both healthy subjects and migraineurs suggest that improved deposition of sumatriptan translates into improved absorption and pharmacokinetics. eadache.3% within 28 hours. 2013 Sep. representing nasalabsorption. Messina JC.1%. likely reflecting impaired GI absorption described in migraineurs. the superposition of both phenomena.e. However.8 ± 3. and the dissociation of secondary interactions. The sumatriptan succinate-loaded chitosan nanoparticles (CNPs) were prepared by ionic gelation of chitosan with tripolyphosphate anions (TPP) and Tween 80 as surfactant. Nasal anatomy.5 ± 0. including comparisons of traditionalnasal sprays to Breath Powered delivery. Breath Powered bi-directional delivery. a simple but novel nasal delivery mechanism. This protonation leads to chain repulsion.MATERIAL AND METHODS: The Taguchi method design of experiments (L9 orthogonal array) was applied to obtain the optimized formulation. overcomes these barriers. This barrier. Author information Abstract The nose offers an attractive noninvasive alternative for drug delivery. Multiple studies of drug deposition. thus a nasal pH range of 5.9 nm. This innovative mechanism has now been applied to the delivery of sumatriptan. with a reduced late peak. including the narrow anterior valve. plus the inherent limitations of traditional nasal delivery mechanisms. and entrapment efficiency of 75.

4 ng/mL) and 61% higher exposure in the first 30 minutes compared with the nasal spray (AUC0-30 minutes 5. migraine. KEYWORDS: absorption.9 mg (mean±standard deviation) of sumatriptan powder in each nostril (total dose 16 mg). and a 6-mg subcutaneous injection. sumatriptan powder.8 ng*hour/mL vs 3. fasted subjects received a single dose of each of the 4 treatments separated by a 7-day washout. The magnitude of .8 ng/mL vs 16. nasal. BACKGROUND: A prior PK study found that low doses of sumatriptan powder delivered intranasally with a Breath Powered device were efficiently and rapidly absorbed.12167. comparative bioavailability study was conducted in 20 healthy subjects at a single center in the USA. on behalf of American Headache Society. cross-over. Inc.6 ng*hour/mL). despite a 20% lower dose. Carothers J. 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-∞ 64.9 ng*hour/mL vs 61. sumatriptan Headache. Interestingly. 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 (11 mg in each nostril) vs a 20 -mg sumatriptan liquid nasal spray. powder. 2013 Sep. Headache: The Journal of Head and Face Pain published by Wiley Periodicals.1 ng*hour/mL). potentially improving treatment of various types of headache. Breath Powered bi-directional intranasal delivery offers a new and more efficient mechanism for nasal drug delivery. Improved pharmacokinetics of sumatriptan with Breath Powered™ nasal delivery of sumatriptan powder. drug delivery. doi: 10. Messina J. In brief. Mahmoud RA. providing an attractive option for improved treatment of headaches by enabling or enhancing the benefits of current and future headache therapies. Blood samples were taken pre-dose and serially over 14 hours post-dose for PK analysis. Djupesland PG. Offman E. a 100-mg oral tablet. © 2013 The Authors. produced 27% higher peak exposure (Cmax 20. Epub 2013 Aug 28. and onset of pain relief was faster than generally reported in previous trials with noninjectable triptans. Obaidi M1.1111/head.53(8):1323-33. 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. Following randomization.Powered delivery of low-dose sumatriptan was well accepted and well tolerated by patients. RESULTS: Quantitative measurement of residuals in used Breath Powered devices demonstrated that the devices delivered 8±0. Breath Powered delivery also allows for the potential of headache-targeted medications to be better delivered to the trigeminal nerve and the sphenopalatine ganglion. METHODS: An open-label.

with significantly more sumatriptan TDS than placebo recipients being headache pain free and nausea free at 2 hours. © 2013 OptiNose AS. Relative to the 100-mg oral tablet (Cmax 70. Moreover. The sumatriptan TDS formulation avoids the gastrointestinal tract.2 ng*hour/mL). the profile following Breath Powered delivery showed higher early and lower late absorptions. AUC0-∞. CONCLUSIONS: Breath Powered intranasal delivery of sumatriptan powder is a more efficient form of drug delivery. The absorption profile following standard nasal spray demonstrated bimodal peaks. doi: 10. phase III clinical trial. Additionally. definitive conclusions on the comparative efficacy and tolerability of sumatriptan TDS versus other sumatriptan formulations or other migraine drugs are not as yet possible. It also produces a significantly lower peak and total systemic exposure than oral tablet or subcutaneous injection. and has a controlled. the most common adverse events were application-site reactions. 308. resulting in cranial vessel constriction and the inhibition of the release of pro-inflammatory neuropeptides and plasma extravasation.6 ng/mL. However.1007/s40265-013-0104-5. . AUC0-∞ 128. 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. sustained delivery. the peak and overall exposure following Breath Powered intranasal delivery of sumatriptan powder was substantially lower. In contrast. Sumatriptan iontophoretic transdermal system: a review of its use in patients with acute migraine. and data from comparative trials would be of great interest. 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). Sumatriptan TDS is a useful addition to the treatment options available to migraine patients. These data were supported by a long-term. 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.73(13):1483-90.difference is larger on a per-milligram basis. Sumatriptan.2 ng/mL. consistent with lower early followed by higher later absorptions. a selective 5-hydroxytryptamine receptor subtype 1 (5-HT1) agonist. 2013 Sep. 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.8 ng*hour/mL) and 6-mg injection (Cmax 111. 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. Headache published by Wiley on behalf of the American Headac Drugs. sumatriptan TDS was shown to be more effective than placebo at treating a singlemigraine attack. In a well designed. sumatriptan TDS was generally well tolerated in clinical trials. repeat-use study over 12 months. it may offer a useful alternative to the nasal spray or subcutaneous sumatriptan formulations.

particularly nausea. 2012 Spring. Iran J Pharm Res. DHE may be administered through several routes of delivery.1007/s40263-013-0061-2. Dihydroergotamine: a review of formulation approaches for the acute treatment of migraine. with efficacy and tolerability varying among formulations. 12 min with oral inhalation and 75 min with oral administration. pregnancy and gastroparesis. doi: 10. 56 min with intranasal. We review DHE formulation approaches for the acute treatment of migraine.CNS Drugs. Adverse effects. Dehghan MH1. intramuscular. Pharmacokinetic properties vary among DHE formulations. The viscosities of xanthan gum in combination with guar gum were observed to be higher than that of single polymer solutions. Author information Abstract Prolonged residence of drug formulation in the nasal cavity is important for the enhancing intranasal drug delivery. Nausea is generally less frequent with non-injectable dosing.27(5):385-94.11(2):513-21. Author information Abstract Dihydroergotamine (DHE) was first used to treat migraine in 1945 and is currently included among migraine-specific treatments for moderate-severemigraine. 2013 May. Silberstein SD1. 34 min with intramuscular. DHE is a potent agonist at serotonin 5-HT1B and 5-HT1D receptors. Girase M. efficacy is superior with injectable dosing. but less effective than sumatriptan. Adverse effect of metoclopramide HCL on CNS caused by high plasma peaks can be avoided through sustained formulation. Metoclopramide hydrochloride is a potent antiemetic and effective for preventing emesis induced by cancer chemotherapy. PXRD was used to determine the effect of freeze-drying on crystalline nature of formulation. with peak concentration occurring in 6 min with intravenous. but there are no head-to-head comparisons with triptans available for review. This is because of the synergistic . intravenous and nasal spray). may limit use of parenteral DHE. Orally inhaled DHE is likewise more effective than placebo. Freeze-dried Xanthan/Guar Gum Nasal Inserts for the Delivery of Metoclopramide Hydrochloride. Kori SH. Among parenteral formulations (including subcutaneous. migraine. 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. Nasal spray DHE is generally more effective than placebo. reviewing pharmacokinetics/dynamics and comparing clinical response among various formulations. 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. 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%. 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. Oral antiemetic often gets vomited out before the systemic absorption compelling parenteral administration which results in low patient compliance.

the ZTSE-2 reached peak concentration much faster than ZTSE-1 and ZTS. in vitro drug release. ZTSE-2 and ZT solution (ZTS) were evaluated after intranasal administered to anesthetized Wistar rats. J Microencapsul. 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. 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. Gu P. 2011 Nov. Evaluation of submicron emulsion as vehicles for rapid-onset intranasal delivery and improvement in brain targeting of zolmitriptan. 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. The blood and cerebrospinalfluid (CSF) pharmacokinetics of ZTSE-1. doi: 10.3109/10717544. histological study and stability. Yu C1. two different formulations separately incorporating the drug in oily phase (ZTSE-1) and aqueous phase (ZTSE-2) were assessed. improve therapeutic efficacy and enhance residence time. 2009 Dec. swelling ability and incorporation efficiency of microspheres increases with increasing drug-to-polymer ratio.83%) as well as bioadhesion which may result in an increase in the nasal residence time. To find the better formulation for rapid-onset intranasal delivery and improvement in brain targeting of ZT. particle size. Epub 2011 Aug 12. The results demonstrated that ZT from ZTSE-1 and ZTSE-2 had better brain targeting efficiency than the ZTS. showed good release (91. Since the drug distribution in submicron emulsion might influence the nasal absorption. In plasma and CSF. which would offer patients the benefits of rapid relief from migraine.600784. For the treatment of migraine. Gattani SG. Drug Deliv. Chauk DS. the in vivo nasalabsorption of these two formulations was evaluated. On the basis of these results. incorporation efficiency. Author information Abstract This study was to evaluate submicron emulsion as a drug carrier for intranasal delivery of zolmitriptan (ZT).3109/02652040802685241.rheological interaction between xanthan and guar gum. It was found that the particle size. Formulation and evaluation of nasal mucoadhesive microspheres of sumatriptan succinate. Zhang W.18(8):578-85. SS microspheres based on HPMC may be considered as a promising nasal delivery system . Tang X. HPMC-based microspheres show adequate mucoadhesion and do not have any destructive effect on nasal mucosa. The ZTSE-2 also presented significantly higher initial ZT levels in CSF compared with the ZTSE-1 and ZTS. Cai C. He H.26(8):711-21. The best nasal inserts formulation containing xanthan gum and guar gum ratio 1:5. Microspheres were characterized by differential scanning calorimetry. Jain SA1. There is a substantial loss in crystalline nature of the formulation after freeze-drying. in vitro mucoadhesion.2011. Mahajan HS. scanning electron microscopy and X-ray diffraction study. swelling property. doi: 10. Tekade AR.

Zolmitriptan microemulsions (ZME) were prepared using the titration method and were characterized for globule size distribution and zeta potential. 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.50 h were . Following intranasal administrations of zolmitriptan mucoadhesive microemulsion (ZMME). 0. 0. Rat brain scintigraphy endorsed higher uptake of ST into the brain. Babbar AK. Intranasal mucoadhesive microemulsions of zolmitriptan: preliminary studies on brain-targeting. ZME. Brain/blood uptake ratios at 0. Drug Target.50. Preliminary brain-targeting studies on intranasal mucoadhesive microemulsions of sumatriptan.20 nm and zeta potential between -35 to -55 mV. The pharmacokinetic parameters. and direct drug transport (DTP) were derived. globule size and size distribution. Sharma RK. sumatriptan solution (SSS). Sumatriptan microemulsions (SME)/sumatriptan succinate microemulsions (SSME) were prepared using titration method and characterized for drug content.38. SMP. Singh S. Misra A. 2005 Jun. 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.AAPS PharmSciTech. The pharmacokinetic parameters. SMME. Babbar AK. Zolmitriptan solution (ZS) and intravenous administration of ZS. ZME were transparent and stable with mean globule size of 35 +/. Biodistribution of SME. 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. Hence.7(1):E8.60. Vyas TK1. SME and SSME were transparent and stable with mean globule size 38 +/. Studies conclusively demonstrated rapid and larger extent of transport of microemulsion of ST compared with microemulsion of SS.52 mV. 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. 2006 Jan 20. intranasal delivery of ST microemulsion developed in this investigation can play a promising role in the treatment of acute attacks of migraine. (99m)Tc-labeled-drug formulations of ZT were found to be stable and suitable to perform in vivo studies. Higher DTE and DTP for mucoadhesive microemulsions indicated more effective targeting following intranasal administration and best brain targeting of ST from mucoadhesive microemulsions. drug targeting efficiency (DTE). SSME.13(5):317-24. 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. suggesting effective transport ofdrug following intranasal administration of microemulsions.26. Sharma RK.20. Misra A. and SSS were found to be 0. and 0. Gamma scintigraphy imaging of rat brain following IV and intranasal administrations were performed to ascertain the localization of drug. and SSS into the rat brain. brain/blood uptake ratios at 0.25 nm and zeta potential of . respectively. and zeta potential. Vyas TK1.5 hour following IV administration of SME and intranasal administrations of SME.

How or whether these differences translate to clinical efficacy and tolerability differences is not well differentiated. Bordini CA. nasal sprays and subcutaneous injections. Rat brain scintigrams showed substantial uptake of drug into the brain after intranasal administration of ZMME. The selection of an acute antimigraine drug for a patient depends upon the stratification of the patient's migraine attack by peak intensity. orally disintegrating tablets. comorbid diseases.27 and 0. Bigal ME1. available in multiple formulations and dosages. . Epub 2003 Jun 9. 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. Different triptans are available in different strengths and formulations including oral tablets. accurate history of the efficacy of previous acute care medications as well as individual features of the drug being considered. the %DTE and %DTP were found higher indicating effective drug transport following intranasal administration and highest brain-targeting following ZMME administration. Speciali JG. metabolism. Delivery systems may play an important role in the onset of action of triptans. Tmax. drugdrug interaction profiles.61(2A):313-20.13.70. sumatriptan is also available as a suppository. The triptan formulations: a critical evaluation. level of associated symptoms such as nausea and vomiting. and concomitant treatments that might cause drug-drug interactions. In Europe. with good safety and tolerability profiles. Cmax. Arq Neuropsiquiatr. The clinician has in his armamentarium an ever-expanding variety of medications. Clinical distinctions among these agents are subtle and proper choice of triptan requires attention to the specific characteristics of each individual patient. respectively. 2003 Jun. 0.56. AUC. Continued clinical use will yield familiarity with the various triptans. Comparing intranasal administration of ZMME with intravenous administration of ZME.found to be 0. Antoniazzi AL. 0. 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. time to peak intensity. time to associated symptoms. 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. indicating effective brain-targeting following intranasal administration of ZMME. Specific differences among the triptans exist as evidenced by different pharmacological profiles including T1/2. knowledge of patient preference. amongst other parameters.