Intranasal fosphenytoin: The promise of phosphate esters in nose-to-brain delivery of poorly soluble drugs

Pires, Patrícia C.; Santos, Liliana T.; Rodrigues, Márcio; Falcão, Amı́lcar; Santos, Adriana O.

doi:10.1016/j.ijpharm.2020.120040

Cited by 15 publications

(14 citation statements)

References 22 publications

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“…In addition, a combination of these strategies can also be employed. Nanometric emulsions 3 Curcumin 0.006 5 [23] Polymer-coated nanometric emulsions 4 Curcumin 0.006 1.9 [24] Drug molecule modification Salts and hydrophilic prodrugs Phenytoin (used as fosphenytoin) 0.07 34.8 (equivalent to 50 mg/mL fosphenytoin) [25] Diazepam (avizafone) 0.05…”

Section: Overview Of Intranasal Formulation Strategies For Drugs With...mentioning

confidence: 99%

“…Having these results in mind, Pires et al [ 25 ] developed simple aqueous-based formulations containing the prodrug fosphenytoin, the mucoadhesive and viscosifying polymer HPMC, and albumin to increase nose-to-brain transport. The achieved drug strength for an isotonic solution was around 34.8 mg/mL of phenytoin equivalents (50 mg/mL of fosphenytoin), which is 489 times higher than phenytoin’s aqueous solubility.…”

Section: Drug Molecule Modificationmentioning

confidence: 99%

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Strategies to Improve Drug Strength in Nasal Preparations for Brain Delivery of Low Aqueous Solubility Drugs

et al. 2022

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Intranasal administration is a promising route for brain drug delivery. However, it can be difficult to formulate drugs that have low water solubility into high strength intranasal solutions. Hence, the purpose of this work was to review the strategies that have been used to increase drug strength in intranasal liquid formulations. Three main groups of strategies are: the use of solubilizers (change in pH, complexation and the use cosolvents/surfactants); incorporation of the drugs into a carrier nanosystem; modifications of the molecules themselves (use of salts or hydrophilic prodrugs). The use of high amounts of cosolvents and/or surfactants and pH decrease below 4 usually lead to local adverse effects, such as nasal and upper respiratory tract irritation. Cyclodextrins and (many) different carrier nanosystems, on the other hand, could be safer for intranasal administration at reasonably high concentrations, depending on selected excipients and their dose. While added attributes such as enhanced permeation, sustained delivery, or increased direct brain transport could be achieved, a great effort of optimization will be required. On the other hand, hydrophilic prodrugs, whether co-administered with a converting enzyme or not, can be used at very high concentrations, and have resulted in a fast prodrug to parent drug conversion and led to high brain drug levels. Nevertheless, the choice of which strategy to use will always depend on the characteristics of the drug and must be a case-by-case approach.

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Section: Overview Of Intranasal Formulation Strategies For Drugs With...mentioning

confidence: 99%

Section: Drug Molecule Modificationmentioning

confidence: 99%

Strategies to Improve Drug Strength in Nasal Preparations for Brain Delivery of Low Aqueous Solubility Drugs

et al. 2022

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“…Microemulsions and gels have been formulated for the purpose of intranasal drug delivery. Recent preclinical advances in this field include the development of thermo-, pH-, and ion-sensitive hydrogels and polymeric gels, microemulsions, and nanoemulsions for intranasal drug delivery in AD, PD, epilepsy, GBM, depression, schizophrenia, and sleep disorders [ 50 , 146 , 147 , 148 , 149 , 150 , 151 , 152 , 153 , 154 , 155 , 156 , 157 ]. Intranasal delivery of these drug carriers improved nose-to-brain delivery and the safety profile of the drug compared to solution and enhanced drug efficacy in animal models of CNS disease.…”

Section: Intranasal Drug Deliverymentioning

confidence: 99%

Intranasal Polymeric and Lipid-Based Nanocarriers for CNS Drug Delivery

et al. 2023

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Nanomedicine is currently focused on the design and development of nanocarriers that enhance drug delivery to the brain to address unmet clinical needs for treating neuropsychiatric disorders and neurological diseases. Polymer and lipid-based drug carriers are advantageous for delivery to the central nervous system (CNS) due to their safety profiles, drug-loading capacity, and controlled-release properties. Polymer and lipid-based nanoparticles (NPs) are reported to penetrate the blood–brain barrier (BBB) and have been extensively assessed in in vitro and animal models of glioblastoma, epilepsy, and neurodegenerative disease. Since approval by the Food and Drug Administration (FDA) of intranasal esketamine for treatment of major depressive disorder, intranasal administration has emerged as an attractive route to bypass the BBB for drug delivery to the CNS. NPs can be specifically designed for intranasal administration by tailoring their size and coating with mucoadhesive agents or other moieties that promote transport across the nasal mucosa. In this review, unique characteristics of polymeric and lipid-based nanocarriers desirable for drug delivery to the brain are explored in addition to their potential for drug repurposing for the treatment of CNS disorders. Progress in intranasal drug delivery using polymeric and lipid-based nanostructures for the development of treatments of various neurological diseases are also described.

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“…Although the exact mechanisms by which the molecules are transported directly from the nasal cavity to the CNS remain unclear, the involvement of cerebrospinal fluid, neuronal pathways, and nasal lymphatics has been evidenced through plenty of studies ( Alam et al, 2010 ; Crowe et al, 2018 ; Gänger and Schindowski, 2018 ). Given the importance of intranasal delivery technique in CNS diseases, it has gained significant interest for brain targeting and numerous exciting studies have been performed in recent years ( Gonçalves et al, 2019 ; Pires et al, 2021 ). In the meantime, some scientific researchers have focused on reviewing relevant published literature to summarize the characteristics and status of intranasal delivery research.…”

Section: Introductionmentioning

confidence: 99%

Current State and Future Directions of Intranasal Delivery Route for Central Nervous System Disorders: A Scientometric and Visualization Analysis

Zhou

Wang

et al. 2021

Front. Pharmacol.

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Background: The management of various central nervous system (CNS) disorders has been challenging, due to highly compact blood-brain barrier (BBB) impedes the access of most pharmacological agents to the brain. Among multiple strategies proposed to circumvent this challenge, intranasal delivery route has sparked great interest for brain targeting in the past decades. The aim of this study was to apply scientometric method to estimate the current status and future trends of the field from a holistic perspective.Methods: All relevant publications during 1998–2020 were retrieved from the Web of Science Core Collection (SCIE, 1998-present). Two different scientometric software including VOS viewer and CiteSpace, and one online platform were used to conduct co-authorship, co-citation, and co-occurrence analysis of journals, countries, institutes, authors, references and keywords.Results: A total of 2,928 documents, including 2,456 original articles and 472 reviews, were retrieved. Our analysis revealed a significant increasing trend in the total number of scientific publications over the past 2 decades (R2 = 0.98). The United States dominated the field, reflecting in the largest amount of publications (971), the highest H-index (99), and extensive international collaboration. Jamia Hamdard contributed to most publications. Frey WH and Illum L were key researchers with the highest number of publications and citations, respectively. The International Journal of Pharmaceutics was the most influential academic journal, and Pharmacology/Pharmacy and Neurosciences/Neurology were the hottest research categories in this field. Based on keywords occurrence analysis, four main topics were identified, and the current research focus of this field has shifted from cluster 4 (pathways and mechanisms of intranasal delivery) to cluster 2 (the study of nasal drug delivery systems), especially the nanostructured and nano-sized carrier systems. Keywords burst detection revealed that the research focus on oxidative stress, drug delivery, neuroinflammation, nanostructured lipid carrier, and formulation deserves our continued attention.Conclusion: To the authors’ knowledge, this is the first scientometric analysis regarding intranasal delivery research. This study has demonstrated a comprehensive knowledge map, development landscape and future directions of intranasal delivery research, which provides a practical and valuable reference for scholars and policymakers in this field.

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Intranasal fosphenytoin: The promise of phosphate esters in nose-to-brain delivery of poorly soluble drugs

Cited by 15 publications

References 22 publications

Strategies to Improve Drug Strength in Nasal Preparations for Brain Delivery of Low Aqueous Solubility Drugs

Strategies to Improve Drug Strength in Nasal Preparations for Brain Delivery of Low Aqueous Solubility Drugs

Intranasal Polymeric and Lipid-Based Nanocarriers for CNS Drug Delivery

Current State and Future Directions of Intranasal Delivery Route for Central Nervous System Disorders: A Scientometric and Visualization Analysis

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