Recent development of Nose-to-Brain delivery as inhalable dry nanoparticles for the treatment of Migraine

Joysa Ruby Joseph¹*, Venkatesh Dinneker Puttegowda², Selvakumar Kanthiah³,

Ajay Pankajbhai Lunagariya⁴, Jeevan Kumar Mishra⁵, Ashly Merin George⁶

^1,2,4,5,6Department of Pharmaceutics, Acharya and BM Reddy College of Pharmacy,

Rajiv Gandhi University of Health Sciences, Bangalore 560107, Karnataka, India.

³Department of Pharmaceutical Quality Assurance, Acharya and BM Reddy College of Pharmacy,

Rajiv Gandhi University of Health Sciences, Bangalore 560107, Karnataka, India.

*Corresponding Author E-mail: joysarubyj@acharya.ac.in, joysaruby2010@gmail.com

ABSTRACT:

Headache serves as a prevalent symptom across various diseases and disorders, with migraines notably exerting a substantial impact on an individual's daily well-being and occupational functionality. Immediate management of migraines assumes pivotal significance due to the prolonged and debilitating nature of associated symptoms. Migraines commonly manifest in two forms: migraine with aura and migraine without aura. Afflicted individuals often contend with enduring symptoms such as phonophobia, photophobia, and manifestations akin to vomiting. Traditional medications necessitate a protracted timeframe, often exceeding 1-2 hours, for alleviating pain induced by migraines. The innovative approach of nose-to-brain drug delivery emerges as a promising strategy in addressing neurological conditions, offering the advantage of mitigating undesired side effects compared to conventional pharmaceutical interventions. By specifically targeting the olfactory and trigeminal nerves, this method circumvents the Blood-Brain-Barrier (BBB), thereby yielding more favorable therapeutic outcomes. Although diverse nano formulations have been developed, the concept of nano inhalable dry powder stands out as an optimal modality for migraine treatment. This comprehensive review encapsulates the existing pharmacotherapeutic landscape for migraine treatment, delving into the diverse modalities employed in the development of dry powder formulations, elucidating their inherent advantages, and contemplating the future trajectory of nano-inhalable dry powder applications in migraine therapeutics.

KEYWORDS: Migraine, Nose-to-brain delivery, Blood-Brain-Barrier, Nano inhalable dry powder.

INTRODUCTION: 

Migraine, characterized as a intricate neurological disorder, exhibits a prolonged duration spanning several days. Traditionally delineated into four distinct stages, namely premonitory, aura, headache, and postdrome, this condition manifests as a multifaceted and protracted brain ailment with a comprehensive temporal trajectory.¹ Migraines stand among the foremost contributors to global work impairment, representing a frequently incapacitating neurological disorder.

Individuals grappling with migraines may endure headache pain persisting for a minimum duration of 4 to 72 hours, characterized by two distinctive features: unilateral presentation and a pulsating nature of moderate to severe intensity, exacerbated or triggered by routine physical activities. In the course of a migraine episode, prevalent symptoms encompass nausea, vomiting, as well as heightened sensitivity to sound (phonophobia) and light (photophobia).² Migraine constitutes a distressing physiological ailment characterized by an intense, pulsating headache localized to one hemisphere of the head. Within the throes of a migraine episode, the cerebral blood vessels undergo dilation and constriction, a response triggered by the stimulation of nerve endings proximal to the affected vascular structures.³ The International Classification of Headache Disorders (ICHD) employs the designation "chronic migraine" to delineate individuals experiencing recurrent headaches deemed biologically migrainous. Those afflicted with chronic headaches have historically encountered insufficient education regarding headache management and have been subjected to therapeutic nihilism.⁴ Numerous investigations have indicated the potential significance of genetic factors in the etiology of migraines. A total of 28 genes associated with the onset of headaches have been identified, and researchers have also detected genetic mutations contributing to this phenomenon.⁵ Migraine patients have been observed to exhibit diminished levels of serotonin and reduced salivary magnesium. This occurrence triggers the release of neuropeptides by the trigeminal nerves, ultimately culminating in the manifestation of migraine pain.⁶ Presently, pharmaceutical interventions such as opium, non-steroidal anti-inflammatory drugs (NSAIDs), triptans, and neuroleptics constitute the therapeutic arsenal for managing migraines. Additionally, magnesium has been employed as a secondary treatment modality for individuals suffering from migraines. The impact of magnesium extends to its modulation of the nervous system, involving inhibition of NMDA receptors, voltage-gated calcium channels, connexin channels, and various other ion channels.⁷ Lately, Lasmiditan, categorized within the class of ditans, has garnered approval from the FDA for its role in the acute treatment of migraines.⁸ The potential integration of gepants into migraine therapy has been hindered by premature cessation of research activities due to apprehensions regarding liver toxicity. However, a subsequent generation of gepants, including Rimegepant, Atogepant, and Ubrogepant, has emerged, exhibiting distinct chemical compositions from their predecessors and demonstrating both efficacy and safety. Furthermore, a novel class of drugs known as calcitonin gene-related peptide (CGRP) antagonists has received approval for migraine prophylaxis in adults. Among these, Erenumab, Fremanezumab, and Galcanezumab stand as noteworthy representatives.^9,10 Several pharmacological agents extensively employed in the treatment of migraines are outlined in Table 1.

Nose-to-brain delivery:

Globally, migraine ranks as the second leading cause of mortality and constitutes the primary contributor to disability-adjusted life years (DALYs).¹² The Blood-Brain Barrier (BBB) serves as a restrictive barrier, impeding the transit of a majority of substances from the bloodstream into the brain. Comprising tight junctions among endothelial capillary cells, astrocyte foot processes, and endothelial capillary cell connections with limited transcytosis capability, in addition to degradative enzymes, the BBB imposes stringent criteria for medication permeation.

Table 1: Drugs Available for Migraine treatment^10,11

Drug	Drug category	Route/Dosage common	Common Adverse effect
ASA (acetyl salicylic acid)	NSAID	Oral (650-1,000) mg	Epigastric discomfort, Nausea, Heartburn, Dyspepsia
Naproxen sodium	NSAID	Oral (50-100) mg	Constipation, Increased sweating, Diarrhea, Nausea, Itching, Dizziness, Headache, Vomiting, Burning or stinging in the eyes, Increased blood pressure.^12
Paracetamol+ ASA+ caffeine	NSAID /stimulant/ analgesic	Oral (500/500) mg/130 mg	Insomnia, Vomiting, Nervousness, Nausea
Almotriptan	Triptan	Oral (6.25-12.5) mg (Maximum dose=25mg/day)	Blood pressure, Dry mouth, Dizziness, Nausea, Feeling of heaviness, Vomiting
Eletriptan	Triptan	Oral 20-40mg (maximum dose=80mg/day)	Dry mouth, Nausea, Mild headache, Flushing, Paraesthesia, Vomiting, High blood pressure
Frovatriptan	Triptan	Oral2.5mg (maximum dose =7.5mg/day)	Dry mouth, Mild headache, Dizziness, Nausea, High blood pressure, Drowsiness, Vomiting, Feeling of heaviness.
Naratriptan	Triptan	Oral 1–2.5 mg (Maximum dose =5 mg/day)	Flushing, Vomiting, Dry Mouth, Feeling of heaviness, Vomiting, Mild headache, Nausea, High blood pressure
Sumatriptan	Triptan	Oral 20-100mg (Maximum dose =200mg/day) Subcutaneous 1-6 mg (Maximum dose = 12mg/day)	Feeling of heaviness, Dry mouth, Flushing, Dizziness, Mild headache, Nausea, Paraesthesia, Vomiting.
Zolmitriptan	Triptan	Oral 1.25–2.5 mg (maximum dose =10 mg/day)	High blood pressure, Vomiting, Mild headache, Dry mouth, Nausea, Feeling of heaviness, Flushing, Dizziness.
Lasmiditan	Ditan	Oral 50–100 mg (maximum dose =200 mg/day)	Dizziness, Fatigue, paraesthesia, Muscle weakness, Drowsiness.^9

Effectively crossing the BBB necessitates medications to exhibit a molecular weight below 400 Dalton, predominately polar characteristics, and a non-multicyclic nature. Consequently, approximately 98% of drug molecules encounter impediments in traversing the BBB.

An alternative strategy for delivering substances to the brain involves the nasal-to-brain route, circumventing the blood-brain barrier (BBB). Both preclinical investigations and studies involving human subjects indicate a growing popularity for the nasal-to-brain route. The nasal cavity is anatomically divided into three distinct regions: (i) the respiratory region, (ii) the vestibular region, and (iii) the olfactory region.¹³ The abundant blood arteries in the respiratory region facilitate the absorption of numerous drugs into the systemic circulation. The presence of the trigeminal neuron transporter further aids the transportation of drugs into the pons and cerebrum of the brain, with additional transit to the olfactory and frontal brains, albeit to a lesser extent.^13,14 The most straightforward and direct method for brain targeting involves a nose-to-brain injection, offering the advantage of bypassing invasive procedures and circumventing circulatory clearance.

Olfactory Route and Trigeminal neurons:

The primary conduit for direct medication delivery to the brain involves the olfactory (olfactory epithelium) and trigeminal nerve pathways. The nasal cavity comprises four distinct segments: the nasal atrium, nasal vestibule, respiratory epithelium, and olfactory epithelium. Within the olfactory route, the respiratory epithelium has the capacity to generate mucus or nasal secretions, thereby facilitating mucociliary clearance (MCC). MCC plays a pivotal role in regulating the duration of the drug's presence in the nasal mucus. Basal cells, serving as progenitor (supporting cell) cells, also provide mechanical support to other cells through anchoring mechanisms. Each knob's basal bodies exhibit approximately 10–23 cilia, each extending up to 200 m in length.¹⁵ Nonetheless, numerous molecules face limitations in the feasibility of nose-to-brain delivery attributed to factors such as elevated molecular weight, restricted diffusion across the mucus barrier, interaction with mucin, and susceptibility to mucociliary clearance. Consequently, the distribution of drugs through the nose-to-brain route is predominantly restricted to those with optimal efficacy, a characteristic frequently associated with a prolonged half-life.¹⁶

Mechanism of drug transport through the Olfactory Region:

The pathway for drug transport is contingent upon various factors, including the specific nature of the medication, formulation attributes, physiological conditions, the type of delivery device employed, and other relevant considerations. A schematic representation of the human olfactory system is presented in Figure 1.

Figure 1: Illustrates a schematic representation of the human olfactory system.

The preeminent routes for delivering medications from the nose to the brain remain the olfactory nerve pathway and the trigeminal nerve pathway. In intranasal delivery, the olfactory nerve pathways play a pivotal role, wherein fluorescent tracers associated with olfactory nerves traverse the cribriform plate. Consequently, drug concentrations in the olfactory bulbs typically rank among the highest concentrations observed within the central nervous system (CNS). There exists a robust and positive correlation between concentrations in the olfactory epithelium and the olfactory bulbs. Olfactory ensheathing cells (OECs), specialized Schwann cell-like entities, envelop the axons of olfactory receptor neurons (ORNs), playing a crucial role in axonal regeneration, regrowth, and remyelination. Furthermore, the absorption of drug molecules by the nasal vasculature is contingent upon the relative volume of distribution. However, it is noteworthy that the medication may be retained within the venous supply of the nasal tube rather than entering the systemic circulation in its entirety. This selective retention allows for the swift access of the drug to the brain and CNS arteries, a process commonly referred to as the counter-current procedure.^17,18

Drugs available in powder form to treat migraine:

A concise examination of various nanoformulations and their corresponding research outcomes is presented in Table 2.

Table 2: Drug formulations and their study outcome

Drug	Formulation	Study outcome
Sumatriptan	Polymeric Nanoparticle	Polymeric nanoparticles have undergone assessment for their neuropharmacokinetic potential, substantiated by the notably high Drug Targeting Index (DTI) values exhibited by these nanoparticles, affirming their efficacy as a robust mechanism for brain delivery.^18
Zolmitriptan	Polymeric Nanoparticle	Experiments on ex vivo drug permeation demonstrate a regulated drug release extending over a duration of 24 hours, suggesting a potential intranasal drug delivery approach for targeting the migraine-affected brain.
Eletriptan Hydrobromide	Polymeric Nanoparticle	It diminishes the impact of first-pass metabolism and enhances bioavailability following the administration of medication through the nasal route.
Rizatriptan Benzoate	Solid-lipid nanoparticles (SLN)	The Nasal Solid Lipid Nanoparticle (SLN) exhibited superior pharmacokinetic parameters, with a Cmax of 473.56 ng/ml, Tmax of 1 hour, AUC of 3706.95 ng/ml, and T1/2 of 5.7 hours, surpassing the performance of approved oral formulations and intravenously administered drug solutions.^19
Almotriptan	Solid-lipid nanoparticles (SLN)	The drug reached the brain within a span of 10 minutes, and toxicological investigations affirmed the safety of the nano-formulation for nasal administration.
Rizatriptan Benzoate	Nanoemulsion	Intranasal nano-emulsions exhibited superior brain targeting with an AUC of 302.52 g min/g, surpassing the brain targeting observed with intranasal gels (AUC=115 g min/g) and intravenous delivery (AUC=109.63 g min/g).
Flunarizine Dihydrochloride	Nanoemulsion	In the context of nasal medication delivery for migraine treatment, nanoemulsions demonstrated reduced droplet size, favorable zeta potential, and substantial drug loading, all contributing to a consistent and reproducible drug release profile.^20
Flunarizine Dihydrochloride	Solid-lipid nanoparticles (SLN)	Within a simulated nasal fluid environment, nanoemulsion enhances both the solubility and release characteristics of the medication.
Zolmitriptan	Micellar nanocarriers	In vivo biodistribution experiments revealed the superior brain targeting efficacy of the nanocarrier when juxtaposed with intravenous and nasal solutions of the drug.^21
Sumatriptan	Nanostructured lipid carriers (NLCs)	Sufficient drug deposition in the brain was achieved, with calculated values for Drug Targeting Efficiency (DTE) and Drug Targeting Percentage (DTP) of intranasally delivered Nanostructured Lipid Carriers (NLCs) amounting to 258.02% and 61.23%, respectively.

Sumatriptan, the inaugural triptan authorized for nasal administration by the FDA in 1997, is presently accessible in both nasal spray and nasal powder formulations. Primarily, it is dispensed via inhalation as a nasal breath powder.²¹ Nasal Zolmitriptan is accessible in a singular liquid spray dosage under two brand names (AscoTop®, Zomig®), with unit packaging containing doses of 2.5 mg and 5 mg. This formulation received approval in 2003. In the 1990s, limited investigations were conducted on the nasal administration of dihydroergotamine utilizing powder-based formulations. Fransén et al. (2007) explored a combination powder incorporating micronized dihydroergotamine particles and sodium starch glycolate.²²

Nanotechnology:

Nanotechnology represents a valuable advancement facilitating the diminution of medication sizes to nanoscales in practical applications. In clinical contexts, nanoparticles (NPs) are defined as particulate materials with dimensions less than 100 nanometres, exhibiting various attributes such as high permeability, heightened reactivity, expansive surface area, and quantum characteristics.²¹ Nanoparticles have the potential to enhance drug delivery from the nasal route to the brain. This improvement is achieved through heightened bioadhesion to the nasal mucosa, safeguarding the encapsulated drug from biological degradation, and mitigating extracellular transport facilitated by P-gp efflux proteins. The nose-to-brain approach, particularly employing novel drug delivery systems like lipidic carriers, presents an innovative avenue for target discovery in the context of various neurodegenerative disorders. ^23,24

Polymeric nanoparticles, solid lipid nanoparticles, nano-emulsions, nanostructured lipid carriers, micellar nanocarriers, and various other nanoparticulate systems have recently undergone exploration for their potential in nose-to-brain administration for migraine treatment. The nano-powder formulation emerges as a potentially superior option compared to other available nano-formulations, attributed to its enhanced stability and prolonged residence time.^25,26

Dry Powder Inhalers:

The preparation of dry powder for inhalation, particularly within the optimal particle size range of 1–5 µm, presents a significant challenge. Researchers have investigated various techniques to attain this desired size range, including milling, freeze-drying, spray-drying, spray-freeze-drying, and supercritical fluid-drying. In recent times, innovative technologies such as Particle Replication in Non-Wetting Templates (PRINT), inkjet printing (IJP), thin-film freezing (TFF), and hot-melt extrusion (HME) have emerged as promising methodologies for the development of enhanced dry powder formulations for inhalation.^27,28 In addition to formulation considerations, the clinical literature underscores the necessity of incorporating knowledge into the design and functionality of inhalers. Aspects encompassing the prescribing practices of inhalers, patient preferences, and challenges associated with inhaler technique are integral facets of asthma management, demanding substantial attention and resolution.²⁹

The dry-powder inhaler containing mometasone furoate is distinctive in its approach to administering a topical corticosteroid through a straightforward three-step process. Employing a stabilized agglomeration formulation, this breath-actuated inhaler ensures precise dosage measurement and delivery across a broad spectrum of inspiratory flow rates.³⁰ Predominantly, dry powder inhaler (DPI) solutions in the market adhere to carrier-based formulations. AVP-825 is comprised of a breath-powered exhalation device and a low-dose dry powder formulation of sumatriptan (22 mg). It is furnished with a reusable mouthpiece and two disposable nosepieces, each containing a capsule filled with 11 mg of sumatriptan nasal powder, demonstrating notable efficacy.^31,32 While this formulation technique has gained attention, it has been reported to exhibit certain drawbacks, including dosage variability and limited efficacy. To address these issues, contemporary Dry Powder Inhalers (DPIs) have been devised, employing methods such as spray drying, spray freeze drying, and thin film freezing. These techniques yield porous particles, enhancing delivery efficacy and the bioavailability of the drug.³³

Different techniques used to prepare DPI:

Various methods exist for the preparation of dry powder, with spray drying being a prevalent process commonly utilized for microparticle formation. Notably, spray-freeze-drying (SFD) has emerged as a widely employed technique for the preparation of inhalable nanoparticles in dry powder form. Subsequently, the techniques of atmospheric spray freeze drying (ASFD) and atmospheric spray fluidized bed freeze drying (ASFBFD) have been developed. This methodology has found extensive application in pharmaceutical research, as well as in the fields of food science and technology.³⁴

Spray Drying:

From the early twentieth century onward, spray drying has found extensive application in the pharmaceutical industry. It has been employed in the manufacturing of amorphous solid dispersions, the dry spraying of biopharmaceuticals, and the production of inhalation particles. Kurt D. Ristroph et al. developed stable, water-dispersible powders containing OZ439 nanoparticles through spray drying for oral application, specifically for malaria therapy.^35,36

SFD (Spray Freeze Drying):

Freezing technology is extensively employed in the food and pharmaceutical sectors. In particular, Spray-Freeze-Drying (SFD), depicted in Figure 2, is preferred over traditional methods like spray-drying (SD) or freeze-drying (FD) for the formulation of dosage forms intended for alternative distribution routes, owing to several considerations.

Figure 2: illustrates a schematic diagram of a spray freeze dryer.

Spray-Freeze-Drying (SFD) methodologies enhance the apparent solubility of poorly water-soluble pharmaceuticals, a prevalent issue encountered with newly developed active medicinal compounds. The unique morphology achieved through SFD technology is attributed to the utilization of distinct nozzles or technology, coupled with precise quantities of solvent and dissolving agent in a specific ratio. This approach is instrumental in formulating well-coated Dry Powder Inhalers (DPI).^37,38

Electrospray Technology:

Electrospray is a technique involving the atomization of liquids through the application of electrical forces to a liquid jet emanating from a capillary nozzle. The findings indicate that electrospraying is a versatile and cost-effective method capable of generating droplets smaller than 10 micrometers.³⁹ Electrospray technology exhibits superior loading efficiency and a more constrained particle size distribution compared to particles produced through alternative methods.^40,41 The methodology of electrospray technology is elucidated below through the representation provided in Figure 3.

Figure 3: Schematic diagram of electrospray

Recent progress on the Preparation of inhalable dry powder for Nose-To-Brain delivery:

In 2022 Clement Rigaut et al., studied on parameters influencing the olfactory deposition especially instillation of dry powder in nasal casts. As per the study, aiming the spray nozzle directly at the olfactory area is more effective in targeting. ⁴²

In 2021 Laura Nizic Nodil et al., developed a device for nose-to-brain delivery of Dexamethasone and they also developed a formulation which was blended with mannitol and lactose for targeting the brain, which has increased the mucoadhesive property of the drug and also increased permeability on the epithelial model barrier. ⁴³

In 2019 Kuldeep Nigam et al., formulated lamotrigine-loaded PLGA nanoparticles by ultra-sonication and 22.81% DTP value in the brain. ³⁶ Similarly, a study was conducted by Sahin et al.,in this study antibiotics were coated on the surface of chitosan nanoparticles and this new coating techniques crossed the blood-brain barrier through macro-pinocytic and receptor-mediated endocytic routes. ⁴⁴

According to various experimental studies, chitosan-based formulations are prospective solutions for targeted delivery to the brain. There are few research reports on the usage of nanocarriers like in situ gels, liposomes, and emulsions. However, the preliminary findings suggest that they could be used to target the brain.^45,46

CONCLUSION:

Presently, addressing neurological diseases such as migraine poses a challenge due to the absence of a dosage form capable of providing prompt relief from symptoms. Patients currently endure a minimum waiting period of 1-2 hours to alleviate headache pain with medications that may entail side effects. In comparison to traditional dosage forms, nose-to-brain delivery presents the potential to directly administer drugs to the brain, bypassing the Blood-Brain Barrier (BBB) and facilitating immediate symptom relief. This underscores the importance of investigating novel formulations like nanotechnology, which exhibits effective targeting and an Enhanced Permeability and Retention (EPR) effect. However, delivering nanocarriers, including solid lipid nanoparticles, liposomes, lipid nanoparticles, nano-emulsions, and nano-suspensions, to the olfactory and trigeminal regions is challenging due to the absence of suitable devices and stability concerns. Inhalable dry powder nanoparticles emerge as a promising formulation for migraine treatment, possessing favorable aerodynamic and flow properties, enabling targeted delivery to the olfactory and trigeminal regions. Therefore, future endeavors may focus on developing a suitable device and inhalable dry powder with optimal particle size and flow properties to enable the immediate management of migraine through facile drug delivery to the olfactory and trigeminal regions.

DECLARATION OF CONFLICTS OF INTEREST:

The authors affirm the absence of conflicts of interest pertaining to the subject matter discussed in the article. The content and conclusions presented herein remain unaffected by any financial or non-financial interests.

ACKNOWLEDGMENTS:

The authors express their gratitude to Acharya and BM Reddy College of Pharmacy for providing generous support and necessary facilities for this study.

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Received on 06.01.2024      Revised on 04.05.2024

Accepted on 12.07.2024   Published on 20.01.2025

Available online from January 27, 2025

Research J. Pharmacy and Technology. 2025;18(1):51-57.

DOI: 10.52711/0974-360X.2025.00008

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