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Pharmacokinetic profiles of midazolam after intranasal (0.4 mg/kg) administrations of three formulations to rabbits (n = 4)—a comparison between microemulsion, macroemulsion (both containing 20% aqueous phase) and surfactants mixture (without water). All formulations contain same components' ratios and 25 mg/g (2.5% by weight) of the drug. mucosa and transport. The possible entrapment and the surfactant-accompanying drug diffusion may explain why this method of nasal administration is apparently non-irritable.
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Nasal application of benzodiazepines might be an alternative to intravenous administration in acute clinical situations such as seizures emergencies. However, irritation and pain as well as symptoms like teary eyes, dizziness, discomfort, nasal drainage and bad taste usually accompany subject received midazolam and diazepam via the nasal route. The...
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Objective-This study aimed to compare sedation efficacy in intranasal administration of xylazine, diazepam and midazolam with or without ketamine in Chough. Design-To determine the sedation efficacy, an experimental in vivo study was employed. Animals-Seven healthy Choughs were examined in the current study. Procedures-With an interval of one week,...
Citations
... The intranasal alcohol-free microemulsion of diazepam and midazolam was developed by Botner et al. for the emergency treatment of epilepsy [25]. The nasal absorption of the drugs from the same formulation was found to be fairly rapid after the administration of 0.4 mg/kg to rabbits. ...
Background:
Epilepsy is one of the major neurological disorders, affecting about 50 million people globally. Oral, intravenous, and rectal delivery systems are available for the management of epileptic seizures. However, intranasal delivery serves beneficial for delivering anti-epileptic drugs owing to the advantages it offers.
Objective:
Various approaches have been developed over the years aiming to attain either a safer or faster brain delivery; a nasal delivery system proposes significant outcomes. The non-invasiveness and high vascularity contribute to the high permeability of the nasal mucosa, allowing rapid drug absorption. This review highlights some of the promising novel approaches delivering antiepileptic drugs efficiently employing the nasal route.
Methods:
The method includes a collection of data from different search engines like PubMed, ScienceDirect, SciFinder for obtaining appropriate and relevant literature regarding epilepsy, intranasal delivery of antiepileptic agents, and novel therapeutics.
Results:
The present review underlines the majority of work related to intranasal delivery in the treatment of epilepsy, aiming to draw the attention of the researchers towards the easiest and efficient ways of formulation for the delivery of antiepileptics during seizures.
Conclusion:
This review intends to provide understanding about the delivery aspects of anti-epileptic drugs, the benefits of intranasal delivery, and the novel approaches employed for the treatment of epilepsy.
... Some researchers have also addressed a problem regarding the poor solubility of Dzp. 3 Despite being lipophilic, Dzp is rapidly redistributed out of the brain. 2,4 Dzp is poorly soluble in water, and its intravenous formulation has to be prepared using co-solvents such as propylene glycol (40%) and ethanol (10%) which, in turn, may result in adverse effects. Considering this issue, lipid nanoparticles could be applied as an interesting solution; 2,5 as Đorđević et al 6 formulated Dzp nanoemulsion with the aim of tackling the mentioned side effects. ...
Purpose: To overcome the side effects of repetitive administration of diazepam (Dzp) besidesgaining benefits from sustaining release of the drug, which contributes to patient compliance,we concentrated on designing and preparing Dzp solid lipid nanoparticles (SLNs).
Methods: Using cholesterol (CHOL), stearic acid (SA), and glycerol monostearate (GMS), SLNswere prepared by high shear homogenization technique coupled with sonication. Polysorbate80 (Tween 80) was used as a nonionic surfactant. After modification of prepared SLNs, particlesize, zeta potential, drug-loading efficiency, morphology, and scanning calorimetry, as well asrelease studies were conducted. To increase the stability of desired particles, freeze-drying bycryoprotectant was carried out. In the final stage, In vivo studies were performed by oral (PO)and intraperitoneal (IP) administrations to Wistar male rats.
Results: Results indicated that optimized prepared particles were on average 150 nm diameterin spherical shape with 79.06 % loading efficiency and release of more than 85% of the loadeddrug in 24 hours. In vivo investigations also illustrated differences in blood distribution of Dzpafter loading this drug into SLNs.
Conclusion: Based on the findings, it seems that drug delivery using SLNs could be anopportunity for solving complications of Dzp therapy in the future.
... There are many studies in the literature in favor of the i.n. route as the most effective route, in which they have mentioned that Lamotrigine, Clonazepam, Diazepam, and Midazolam loaded with mucoadhesive nanoformulation increased their effective treatment of the mentioned drugs for anticonvulsant activity [59][60][61]. ...
To formulate novel chitosan (CS)-coated–PLGA–nanoparticles (NPs) using a central composite design approach and use them in order to improve brain bioavailability for catechin hydrate (CH) through direct nose-to-central nervous system (CNS) delivery for the evaluation of a comparative biodistribution study of CH by the newly developed ultra high performance liquid chromatography mass spectroscopy and mass spectroscopy (UHPLC-MS/MS) method in the treatment of epilepsy. For PLGA–NPs’ preparation, a double emulsion-solvent evaporation method was used, where a four-factor, three-level central composite design was used to obtain the best nanoformulation. For the optimization, four independent variables were chosen, that is, PLGA, polyvinyl alcohol (PVA), sonication time, and temperature. The optimized PLGA–NPs were further coated with chitosan and assessed for drug release, nasal permeation study, as well as a comparative pharmacokinetic and pharmacodynamic study. Independent and dependent variables helped to optimize the best nanoformulation based on the composition of PLGA (50.0 mg), PVA (1.10%), sonication time (90.0 s), and temperature (25.0 °C). The values of dependent variables were observed, such as polydispersity index (PDI), particle size, and zeta potential (ZP)—that is, 0.106 ± 0.01, 93.46 ± 3.94 nm, and −12.63 ± 0.08 mV, respectively. The ZPs of CS-coated PLGA–NPs were changed from negative to positive value with some alteration in the distribution of particle size. Excellent mucoadhesive-nature of CS–CH–PLGA–NPs as compared with CH–S and CH–PLGA–NPs was seen, with a retention time of 0.856 min and m/z of 289.23/245.20 for CH, together with a retention time of 1.04 min and m/z of 301.21/151.21 for Quercetin as an internal standard (IS). For a linear range (1–1000 ng mL−1), % accuracy (93.07–99.41%) and inter- and intraday % precision (0.39–4.90%) were determined. The improved Cmax with area under curve (AUC)0–24 was found to be highly significant (p < 0.001) in Wistar rats’ brain as compared with the i.n. and i.v. treated group based on the pharmacokinetics (PK) results. Furthermore, CS–CH–PLGA–NPs were found to be more significant (p < 0.001) for the treatment of seizure threshold rodent models, that is, increasing current electroshock and pentylenetetrazole-induced seizures. A significant role of CS–CH–PLGA–NPs was observed, that is, p < 0.001, for the enhancement of brain bioavailability and the treatment of epilepsy.
... route has showed more effectiveness than pother routes, it supports reported literatures whereas same as improved anticonvulsant effect of drugs (Lamotrigine, Clonazepam, Diazepam, and Table 4 Pharmacokinetic parameters of THQ-PLGA-NPs after i.n. and i.v. administration to rats at the dose of 10 mg kg −1 in brain, lungs and plasma (n = 6, mean ± SD) Midazolam) in nanoformulation or mucoadhesive nanoformulation was observed [43][44][45]. The activity enhanced for nanoformulation based THQ-PLGA-NPs is distributed because of ability of nano-carrier across BBB. ...
Abstract To formulate a nanoformulation (PLGA-NPs) and to improve brain bioavailability for thymoquinone (THQ) through intranasal (i.n.) drug delivery, using a newly UHPLC-PDA developed the method and validated. Five different THQ-PLGA-NPs (THQ-N1 to THQ-N5) were prepared by emulsion solvent evaporation method. A new UHPLC method developed and validated for biodistribution studies in the rat’s brain, lungs and plasma. Optimized-THQ-N1-NPs showed a particle size of 97.36 ± 2.01 nm with a low PDI value of 0.263 ± 0.004, ZP of − 17.98 ± 1.09, EE of 82.49 ± 2.38% and DL of 5.09 ± 0.13%. THQ-N1-NPs showed sustained release pattern via in vitro release profile. A bioanalytical method was developed by UHPLC-PDA and validated for the evaluation of pharmacokinetics parameters, biodistribution studies, brain drug-targeting potential (89.89 ± 9.38%), and brain-targeting efficiency (8075.00 ± 113.05%) studies through intranasal administration which showed an improved THQ-brain- bioavailability, compared to i.v. Moreover, THQ-PLGA-NPs improved the seizure threshold treatment i.e. epilepsy increasing current electroshock (ICES) rodent models induced seizures in rats. A significant role of THQ-PLGA-NPs with high brain targeting efficiency of the nanoformulations was established. The reported data supports the treatment of epilepsy.
... The dosage forms currently available on the market are oral tablets, oral syrups, oromucosal solutions (only available in Europe), and solutions for intravenous or intramuscular injection.127,128 Several intranasal (IN) formulations have been investigated35,[129][130][131][132][133][134] or are under development,135 but a dosage form specifically designed for IN delivery has not yet become commercially available.IN delivery of MDZ is attractive because it offers many important advantages over other routes of administration, especially in emergency situations. 14 A therapeutic plasma concentration can be attained quickly due to the large absorptive surface area, high vascularization, and thin epithelium of the nasal mucosa. ...
A seizure emergency occurs when an individual experiences a seizure that lasts for more than five minutes (status epilepticus) or multiple distinct seizures with incomplete recovery between them (acute repetitive seizures). A patient experiencing a seizure emergency must be treated as quickly as possible to avoid lasting neurological damage and other life-threatening complications. Benzodiazepines are the primary rescue medications used to treat seizure emergencies, the most commonly used being intravenous lorazepam or rectal diazepam. Despite the effectiveness of these drugs, the delivery routes are not ideal for first-line, outpatient treatments. A skilled caregiver must be present to administer drugs intravenously, and the social stigma associated with rectal administration results in low compliance. Intranasal delivery is an attractive alternative because it requires little training, is easily performed by non-medical personnel, carries a low risk of injury to the patient, and can provide a rapid therapeutic effect. However, formulating a benzodiazepine nasal spray is challenging because these drugs have very low aqueous solubilities.
One strategy to circumvent solubility issues relies on in situ production of drug from co-administration of soluble reactants. Herein, we describe how a prodrug/enzyme reaction or an acid/base reaction can be used to deliver a benzodiazepine in an aqueous vehicle with a volume and pH appropriate for intranasal administration. When the soluble components of these two-part reactive formulations are mixed at the time of administration, a metastable supersaturated solution of the benzodiazepine is produced. The supersaturated state of the benzodiazepine provides a large chemical activity gradient for rapid absorption across the nasal mucosa and into systemic circulation. In vitro characterization of the reaction kinetics and supersaturation behaviors for diazepam prodrug/enzyme reactions, midazolam prodrug/enzyme reactions, and midazolam acid/base reactions demonstrated that these two-part formulations generate predictable levels of supersaturated drug. An in vivo pharmacokinetic study in rats showed that rapid absorption and high bioavailability of diazepam results from intranasal administration of a diazepam prodrug/enzyme formulation. Furthermore, a dual chamber nasal spray device capable of mixing and atomizing the components of a two-part formulation was designed, prototyped, and tested. These two-part reactive formulations, coupled with the specialized nasal spray device, exemplify a new intranasal drug delivery strategy that may be applicable to a variety of other drugs with poor stability or low solubility.
... Pharmacokinetic parameters [32,33] were calculated from plasma concentration-time profiles and are shown in Fig. 8. Values of C max , T max , AUC 0−6 (ng.h/ml), and ratio of (AUC brain tissue /AUC plasma ) % are shown in Table 6. The C max attained by frovatriptan in plasma by nasal ME was 2 times greater than the oral solution. ...
Objective: The main objective of the present research work was to develop, optimize, and characterize microemulsion (ME) of frovatriptan succinate to improve brain transport. Methods: The pseudoternary phase diagrams were constructed for ME formulations composed of Capmul MCM, Cremophor EL, and propylene glycol. Frovatriptan succinate-loaded ME was optimized by simplex lattice design having the concentration of oil, surfactant, and cosurfactant representing three apex points on the triangle. These were taken as independent variables and percentage drug release as a response variable. All developed batches of ME were characterized for in vitro tests, histopathology study, and pharmacokinetics in Swiss albino rats. Results: Clear MEs were obtained. F5 having particle size – 142.0 nm, zeta potential – 17.7–−7.8 mv, refractive index – 1.38±0.20, drug content – 98.24±0.20%, and drug diffused through dialysis membrane – 85% was the optimized batch. Drug permeation through the nasal mucosa of F5 in the ex vivo study was found to be 82.32%. Histopathology microscopic study has shown that F5 does not cause any irritation and structural changes in sheep nasal mucosa. The pharmacokinetic parameters were determined after nasal and oral administration of F5. For brain tissue, after nasal administration were Cmax181±1.51 ng/ml, Tmax – 2±1.01, area under curve (AUC)0−6 – 390.0±2.08 ng.h/ml. The AUC0−6 attained by nasal ME was 3.29 times greater than oral solution. Drug targeting index of frovatriptan succinate was 2.06. This was found satisfactory. Conclusion: Microemulsion of said composition was found to be enhancing delivery of frovatriptan succinate to brain tissues through nasal route.
... The supportive evidence for more effectiveness of i.n. route may be found in the previous literatures where an enhanced anticonvulsant effect of drugs (Clonazepam, Lamotrigine, Midazolam and Diazepam) in nanoemulsion or mucoadhesive formulation was observed [43][44][45]. The enhanced activity for nanoemulsion based Amiloride formulation is imparted due to ability of nano-carrier across BB. ...
We, the Editors and Publishers of Artificial Cells, Nanomedicine, and Biotechnology have retracted the following article:
Niyaz Ahmad, Rizwan Ahmad, Md Aftab Alam, Farhan Jalees Ahmad & Mohd Amir. (2018). Impact of ultrasonication techniques on the preparation of novel Amiloride-nanoemulsion used for intranasal delivery in the treatment of epilepsy. Artificial Cells, Nanomedicine, and Biotechnology, 46:sup3, S192–S207. DOI: 10.1080/21691401.2018.1489826
This article is retracted due to reuse of images from other articles by the same authors, representing results of different experiments. This includes a section of Figure 6(d) which can also be found in:
Ahmad et al. (2018). Ultrasonication techniques used for the preparation of novel Eugenol-Nanoemulsion in the treatment of wounds healings and anti-inflammatory. Journal of Drug Delivery Science and Technology, https://doi.org/10.1016/j.jddst.2018.06.003
As well as Figure 4(b), which can also be found in:
Ahmad et al. (2018). Journal of Drug Delivery Science and Technology, https://doi.org/10.1016/j.jddst.2018.06.003
In addition, concerns were raised regarding the integrity of other Figures in the article, including Figure 1.
When asked for an explanation, the authors were unable to provide raw data that would support the integrity of their research.
As the authors were unable to provide the original images, the Editors agreed the findings of the study are no longer valid and advised for the article to be retracted.
The authors do not agree with the retraction.
We have been informed in our decision-making by our policy on publishing ethics and integrity and the COPE guidelines on retractions.
The retracted article will remain online to maintain the scholarly record, but it will be digitally watermarked on each page as “Retracted”.
... Spraying this formulation into rabbit nostrils (0.4 mg/ kg) yielded a t max of < 10 min with 34% absolute bioavailability for both drugs. In this study, it was also observed that MDZ was better absorbed from W/O ME (20% water) compared to O/W ME (50% water) [96]. ...
Epileptic seizure emergencies are life-threatening conditions, which in their most severe form, status epilepticus, have a high mortality rate if not quickly terminated. Treatment requires rapid delivery of anti-epileptics such as benzodiazepines to the brain. The nasal route is attractive due to its non-invasiveness, potential for direct nose to brain delivery, high vascularity, relatively large absorptive surface area, and avoidance of intestinal/liver metabolism. However, the limited volume of the nasal cavity and poor water solubility of anti-epileptics restrict absorption, leading to insufficient therapeutic brain levels. This review covers various formulation approaches adopted to improve nasal delivery of drugs, especially benzodiazepines, used to treat seizure emergencies. Other general topics such as nasal anatomy, challenges to nasal delivery, and drug/formulation considerations for nose to brain delivery are also discussed.
... It could be administered intramuscularly, intravenously, intranasally as well buccally. Intranasal Midazolam route can go through the blood-brain barrier and reach the central nervous system biophase quickly 7,8 . Wermeling found some of the advantages of IN; no fi rst-pass metabolism, more rapid absorp on, faster onset of ac on, good bioavailability 9 . ...
Rectal diazepam is reputed as the gold-standard management of childhood seizures. Otherwise, intranasal (IN) midazolam has no first-pass metabolism and faster onset of action. The effectiveness and easier route of these drugs are important choices for faster seizure cessation. The aim of this study was to clarify the effectiveness of intranasal midazolam compared with rectal diazepam for seizure termination.Material and Methods: The children, one month until 18 years of age, presented with acute seizures. Patients were randomly classified into two groups with either received intranasal midazolam or rectal diazepam for seizure termination. Interval time of drug administration to cease seizure was compared. The log-rank analysis was used for statistical analysis. Side effect of both drugs were evaluated.Results: There were 60 patients enrolled the study, 30 in each group. The median time interval for seizures cessation with intranasal midazolam was 42 seconds, otherwise in rectal diazepam group was 180 seconds. There was statistically significant difference interval time between two groups (p<0.01). None of the both groups had any significant side effects statistically.Conclusion: Intranasal midazolam is effective to terminate a seizure in children. It can be used as an alternative treatment for seizures in patients with intravenous or rectal route difficulties.J Nepal Paediatr Soc 2015;35(2):117-122
... Similarly 11.53 times (51.1 ± 2.8 v/s 4.4 ± 1.1) and 9.4 times (23.6 ± 1.1 v/s 2.5 ± 0.41) increment of Curcumin concentration in OB following intranasal and intravenous delivery at the time points 30 and 360 min as shown in Fig. 7b, c respectively. Following intranasal administration, 89.9 % of Curcumin was transported to the brain via the olfactory pathway at 6 h (Tian et al. 2011;Botner and Sintov 2011) and hence can be concluded that nasal route of administration and mucoadhesive formulation may help Curcumin to enhance its brain uptake. ...
This study was aimed at designing mucoadhesive microemulsion gel to enhance the brain uptake of curcumin through intranasal route. Suitable oil, surfactant and cosurfactant for the development of microemulsion were selected based on maximum curcumin solubility, drug excipients compatibility through FTIR study and non-toxicity to sheep nasal mucosa. Curcumin loaded mucoadhesive microemulsion (CMME) was developed by incorporating polycarbophil as mucoadhesive polymer into Capmul MCM based optimal microemulsion (CME) and was subjected to characterization, stability, mucoadhesion and naso-ciliotoxicity study. Brain uptake of Curcumin via nasal route was studied by performing biodistribution study in Swiss albino rats. CME was found to be transparent, stable and non ciliotoxic with 57.66 nm ± 3.46, −16.28 mV ± 4.11 and 98.08 % ± 1.01 as average globule size, zeta potential and drug content respectively. PdI and TEM study depicted the narrow size distribution of CME. Following single intranasal administration of CMME and CME at dose of 2.86 mg/kg, Maximum Curcumin uptake in the olfactory bulb was more than 11 fold (51.1 ± 2.8) than that of intravenous injection of Curcumin solution (4.4 ± 1.1). AUC ratio of brain tissues to that in plasma obtained after nasal administration of CMME were significantly higher than those after intravenous administration of Curcumin solution. Findings of the present study revealed that optimal CMME and intranasal route may be considered to be promising and an alternative approach for brain targeting of Curcumin.
