Cyclodextrin solubilization of benzodiazepines: formulation of midazolam nasal spray

Loftsson, Þorsteinn; Guðmundsdóttir, Hlíf; Sigurjónsdóttir, Jóhanna F; Sigurđsson, Hákon Hrafn; Sigfússon, Sigurdur Dadi; Másson, Már; Stefánsson, Einar

doi:10.1016/s0378-5173(00)00580-9

Cited by 103 publications

(47 citation statements)

References 19 publications

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“…The aqueous solubility of midazolam is a function of both the ionization of the drug molecule and the ring-opening of the diazepine ring. The ring-opening of the benzodiazepine ring is pHdependent and fully reversible 9,23 . Midazolam low aqueous solubility is a problem in formulations design.…”

Section: Hpmc Effectmentioning

confidence: 99%

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Untitled

2017

IJPSR

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ABSTRACT:Midazolam is used as short-acting pre-anesthetic benzodiazepine with solubility of <0.1mg/mL at neutral-pH, which increases considerably in acidic media. Midazolam commercial acidic aqueous parenteral formulation (pH~3.3) causes pain and inflammation at administration site, which induces low patientcompliance. According to the absence of non-parenteral formulation, available parenteral dosage-form administered orally that showed bitter-taste with low bioavailability. Alternatively, intranasally administration was rapidly absorbed, with improved bioavailability. However, not only causes nasal mucosa irritation due to acidic media, but also needs large solution amount because of midazolam low solubility. On contrary of previous studies, which focused on solubility improvement in acidic pH, the aim of this study is to compare solubility enhancement techniques at nasal physiological pH (6). Different techniques evaluated including buffer solutions (Britton-Robinson, citrate and phosphate), inclusion-complexation (β-CD), polymeric-micellar-solubilization(HPMC) and co-solvency (PEG400 and P.G) separately in mentioned buffers. Ternary-diagram with the best-selected system examined in different ratios. As a result, phosphate buffer in combination with applied techniques indicated solubility enhancement ratio of 17.9, 22

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Section: Hpmc Effectmentioning

confidence: 99%

“…Various studies examined one or two solubility enhancement techniques separately or in combination in acidic pH (pH<4) for midazolam 9 .…”

Section: Introductionmentioning

confidence: 99%

Untitled

2017

IJPSR

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“…[25][26][27][28][29][30][31][32][33][34] The main considerations from these data might be whether maximum plasma concentrations represented by C max are within ranges known to produce pharmacologic effects, and the second consideration is whether the concentrations are achieved rapidly enough to be appropriate for treating a seizure. Well-designed nasal preparations may demonstrate a pharmacokinetic profile in which the rate and extent of drug exposure is superior to intramuscular injection and approximates IV infusion (FIG.…”

Section: Pharmacokinetics and Pharmacodynamics Of Nasal Benzodiazepinmentioning

confidence: 99%

Intranasal Delivery of Antiepileptic Medications for Treatment of Seizures

Wermeling

2009

Neurotherapeutics

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Summary: Acute isolated seizure, repetitive or recurrent seizures, and status epilepticus are all deemed medical emergencies. Mortality and worse neurologic outcome are directly associated with the duration of seizure activity. A number of recent reviews have described consensus statements regarding the pharmacologic treatment protocols for seizures when patients are in pre-hospital, institutional, and home-bound settings. Benzodiazepines, such as lorazepam, diazepam, midazolam, and clonazepam are considered to be medications of first choice. The rapidity by which a medication can be delivered to the systemic circulation and then to the brain plays a significant role in reducing the time needed to treat seizures and reduce opportunity for damage to the CNS. Speed of delivery, particularly outside of the hospital, is enhanced when transmucosal routes of delivery are used in place of an intravenous injection.Intranasal transmucosal delivery of benzodiazepines is useful in reducing time to drug administration and cessation of seizures in the pre-hospital setting, when actively seizing patients arrive in the emergency room, and at home where caregivers treat their dependents. This review summarizes factors to consider when choosing a benzodiazepine for intranasal administration, including formulation and device considerations, pharmacology and pharmacokinetic/pharmacodynamic profiles. A review of the most relevant clinical studies in epilepsy patients will provide context for the relative success of this technique with a number of benzodiazepines and relatively less sophisticated nasal preparations. Neuropeptides delivered intranasally, crossing the blood-brain barrier via the olfactory system, may increase the availability of medications for treatment of epilepsy. Consequently, there remains a significant unmet medical need to serve the pharamcotherapeutic requirements of epilepsy patients through commercial development and marketing of intranasal antiepileptic products.

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“…For that purpose, various nasal midazolam formulations were developed like solutions and sprays (20,21). However, these systems suffer from a number of disadvantages.…”

Section: Introductionmentioning

confidence: 99%

“…Parenteral solution of midazolam for intranasal administration caused irritation that is produced by its acidic pH and the relatively large volume that has to be administered. These problems could be reduced by using aerosols containing a solution of midazolam in cyclodextrin, which accomplishes a greater concentration with a pH that is less acidic (21). It has been reported that nasal spray prepared by Knoester et al (20) caused nasal irritation, lacrimation and irritation in throat of almost all the subjects.…”

Section: Introductionmentioning

confidence: 99%

Development and Characterization of Mucoadhesive In Situ Nasal Gel of Midazolam Prepared with Ficus carica Mucilage

Basu

Bandyopadhyay

2010

AAPS PharmSciTech

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Abstract. The objective of the present study was to prepare mucoadhesive in situ nasal gels with mucilage isolated from fig fruits (Ficus carica, family: Moraceae) containing midazolam hydrochloride. Nasal gels of midazolam were prepared using three different concentrations (0.5%, 1.0% and 1.5% w/v) of F. carica mucilage (FCM) and synthetic polymers (hydroxypropylmethyl cellulose and Carbopol 934). Evaluation of FCM showed that it was as safe as the synthetic polymers for nasal administration. In situ gels were prepared with mixture Pluronic F127 and mucoadhesive agents. Evaluation of the prepared gels was carried out, including determination of viscosity, texture profile analysis and mucoadhesive strength. In vitro drug permeation study was conducted with the gels prepared with and without permeation enhancer (0.5% w/v sodium taurocholate) using excised goat nasal mucosa. In vitro permeation profiles were evaluated, and histological study of nasal mucosae before and after permeation study was also conducted to determine histological change, if any. In vivo experiments conducted in rabbits further confirmed that in situ nasal gels provided better bioavailability of midazolam than the gels prepared from synthetic mucoadhesive polymers. It was observed that the nasal gel containing 0.5% FCM and 0.5% sodium taurocholate exhibited appropriate rheological, mechanical and mucoadhesive properties and showed better drug release profiles. Moreover, this formulation produced no damage to the nasal mucosa that was used for the permeation study, and absolute bioavailability was also higher compared to gels prepared from synthetic polymers.

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Cyclodextrin solubilization of benzodiazepines: formulation of midazolam nasal spray

Cited by 103 publications

References 19 publications

Untitled

Untitled

Intranasal Delivery of Antiepileptic Medications for Treatment of Seizures

Development and Characterization of Mucoadhesive In Situ Nasal Gel of Midazolam Prepared with Ficus carica Mucilage

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