The nose has it: Opportunities and challenges for intranasal drug administration for neurologic conditions including seizure clusters

Chung, Steve S.; Peters, Jurriaan M.; Detyniecki, Kamil; Tatum, William O.; Rabinowicz, Adrián L.; Carrazana, Enrique

doi:10.1016/j.ebr.2022.100581

Cited by 23 publications

(47 citation statements)

References 85 publications

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“…Intranasal (IN) drug administration is a potential route of delivery for neurological conditions [ 83 ], where CBD has most clinical evidence for efficacy [ 1 ]. Preclinical studies have shown that intranasal delivery of CBD improves symptoms in several behavioural tests of posttraumatic stress disorder [ 29 ] and produces long-lasting antinociceptive effects in neuropathic pain, with a faster onset than oral delivery [ 84 ].…”

Section: Novel Routes Of Cbd Administrationmentioning

confidence: 99%

Strategies to Improve Cannabidiol Bioavailability and Drug Delivery

O’Sullivan,

Jensen,

Kolli

et al. 2024

Pharmaceuticals

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The poor physicochemical properties of cannabidiol (CBD) hamper its clinical development. The aim of this review was to examine the literature to identify novel oral products and delivery strategies for CBD, while assessing their clinical implications and translatability. Evaluation of the published literature revealed that oral CBD strategies are primarily focused on lipid-based and emulsion solutions or encapsulations, which improve the overall pharmacokinetics (PK) of CBD. Some emulsion formulations demonstrate more rapid systemic delivery. Variability in the PK effects of different oral CBD products is apparent across species. Several novel administration routes exist for CBD delivery that may offer promise for specific indications. For example, intranasal administration and inhalation allow quick delivery of CBD to the plasma and the brain, whereas transdermal and transmucosal administration routes deliver CBD systemically more slowly. There are limited but promising data on novel delivery routes such as intramuscular and subcutaneous. Very limited data show that CBD is generally well distributed across tissues and that some CBD products enable increased delivery of CBD to different brain regions. However, evidence is limited regarding whether changes in CBD PK profiles and tissue distribution equate to superior therapeutic efficacy across indications and whether specific CBD products might be suited to particular indications.

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Section: Novel Routes Of Cbd Administrationmentioning

confidence: 99%

Strategies to Improve Cannabidiol Bioavailability and Drug Delivery

O’Sullivan,

Jensen,

Kolli

et al. 2024

Pharmaceuticals

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“…Some studies have shown that most neurophilic viruses (such as rabies, herpetic stomatitis, and equine encephalomyelitis viruses), steroid hormones, metal ions (such as cadmium and nickel), and proteins enter the brain through the olfactory nerve pathway ( Crowe et al, 2018 ). After crossing the olfactory mucosa, these substances are absorbed at the axon terminals of olfactory neurons through pinocytosis, endocytosis, or simple diffusion ( Chung et al, 2022 ). They subsequently flow through the axonal plasma of neurons and are directly transported through the sieve plates to the olfactory bulb, reaching the rhinencephalon ( Chung et al, 2022 ).…”

Section: The Pathways Through Which Drugs Can Enter the Brain Through...mentioning

confidence: 99%

“…After crossing the olfactory mucosa, these substances are absorbed at the axon terminals of olfactory neurons through pinocytosis, endocytosis, or simple diffusion ( Chung et al, 2022 ). They subsequently flow through the axonal plasma of neurons and are directly transported through the sieve plates to the olfactory bulb, reaching the rhinencephalon ( Chung et al, 2022 ). The olfactory nerve pathway is considered to be the most important pathway for the entry of drugs into the brain from the nose, and it represents the most direct pathway for bypassing the BBB ( Ruigrok and de Lange, 2015 ).…”

Section: The Pathways Through Which Drugs Can Enter the Brain Through...mentioning

confidence: 99%

Research progress in brain-targeted nasal drug delivery

Huang,

Chen,

et al. 2024

Front. Aging Neurosci.

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The unique anatomical and physiological connections between the nasal cavity and brain provide a pathway for bypassing the blood–brain barrier to allow for direct brain-targeted drug delivery through nasal administration. There are several advantages of nasal administration compared with other routes; for example, the first-pass effect that leads to the metabolism of orally administered drugs can be bypassed, and the poor compliance associated with injections can be minimized. Nasal administration can also help maximize brain-targeted drug delivery, allowing for high pharmacological activity at lower drug dosages, thereby minimizing the likelihood of adverse effects and providing a highly promising drug delivery pathway for the treatment of central nervous system diseases. The aim of this review article was to briefly describe the physiological structures of the nasal cavity and brain, the pathways through which drugs can enter the brain through the nose, the factors affecting brain-targeted nasal drug delivery, methods to improve brain-targeted nasal drug delivery systems through the application of related biomaterials, common experimental methods used in intranasal drug delivery research, and the current limitations of such approaches, providing a solid foundation for further in-depth research on intranasal brain-targeted drug delivery systems (see Graphical Abstract).

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“…The National Association of School Nurses recommends using the least restrictive medication (e.g., buccal or nasal) [ 40 ], and the FDA states that the intranasal route of administration is less invasive and provides “significantly improved ease of use” compared with rectal administration [ 41 ]. The drug is sprayed into the nasal cavity, where it is deposited on the nasal mucosa, then transported across the nasal epithelium and absorbed into the systemic circulation via the vascular endothelia [ 42 ], avoiding first-pass metabolism. From there, the drug crosses the blood-brain barrier and reaches the central nervous system and the brain, where it exerts its effect [ 42 ].…”

Section: Role Of Nasal Spray Formulationsmentioning

confidence: 99%

“…The drug is sprayed into the nasal cavity, where it is deposited on the nasal mucosa, then transported across the nasal epithelium and absorbed into the systemic circulation via the vascular endothelia [ 42 ], avoiding first-pass metabolism. From there, the drug crosses the blood-brain barrier and reaches the central nervous system and the brain, where it exerts its effect [ 42 ]. However, drug volume is limited to ~ 100 µL to minimize leakage out of the nasal cavity from the back or the front [ 9 ].…”

Section: Role Of Nasal Spray Formulationsmentioning

confidence: 99%

Benzodiazepines for the Treatment of Seizure Clusters

Penovich,

Rao,

Long

et al. 2024

CNS Drugs

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Patients with epilepsy may experience seizure clusters, which are described by the US Food and Drug Administration (FDA) as intermittent, stereotypic episodes of frequent seizure activity that are distinct from a patient’s usual seizure pattern. Untreated seizure clusters may increase the risk for status epilepticus, as well as decrease quality of life and increase burden on patients and care partners. Benzodiazepine therapies are the mainstay for acute treatment of seizure clusters and are often administered by nonmedical care partners outside a healthcare facility. Three rescue therapies are currently FDA-approved for this indication, with diazepam rectal gel being the first in 1997, for patients aged ≥ 2 years. Limitations of rectal administration (e.g., positioning and disrobing the patient, which may affect ease of use and social acceptability; interpatient variation in bioavailability) led to the investigation of the potential for nasal administration as an alternative. Midazolam nasal spray (MDS) was approved by the FDA in 2019 for patients aged ≥ 12 years and diazepam nasal spray (DNS) in 2020 for patients aged ≥ 6 years; these two intranasal therapies have differences in their formulations [e.g., organic solvents (MDS) vs. Intravail and vitamin E for absorption and solubility (DNS)], effectiveness (e.g., proportion of seizure clusters requiring only one dose), and safety profiles. In clinical studies, the proportion of seizure clusters for which only one dose of medication was used varied between the three approved rescue therapies with the highest single-dose rate for any time period for DNS; however, although studies for all three preparations enrolled patients with highly intractable epilepsy, inclusion and exclusion criteria varied, so the three cannot be directly compared. Treatments that have been used off-label for seizure clusters in the USA include midazolam for injection as an intranasal spray (indicated for sedation/anxiolysis/amnesia and anesthesia) and tablet forms of clonazepam (indicated for treatment for seizure disorders) and lorazepam (indicated for anxiety). In the European Union, buccal and intranasal midazolam are used for treating the indication of prolonged, acute convulsive seizures and rectal diazepam solution for the indication of epileptic and febrile convulsions; duration of effectiveness for these medications for the treatment of seizure clusters has not been established. This paper examines the literature context for understanding seizure clusters and their treatment and provides effectiveness, safety, and administration details for the three FDA-approved rescue therapies. Additionally, other medications that are used for rescue therapy in the USA and globally are discussed. Finally, the potential benefits of seizure action plans and candidates for their use are addressed. This paper is intended to provide details about the unique characteristics of rescue therapies for seizure clusters to help clarify appropriate treatment for individual patients. Grap...

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The nose has it: Opportunities and challenges for intranasal drug administration for neurologic conditions including seizure clusters

Cited by 23 publications

References 85 publications

Strategies to Improve Cannabidiol Bioavailability and Drug Delivery

Strategies to Improve Cannabidiol Bioavailability and Drug Delivery

Research progress in brain-targeted nasal drug delivery

Benzodiazepines for the Treatment of Seizure Clusters

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