Development and formulation of a 0.2% oral solution of midazolam containing γ-cyclodextrin

Marçon, Fréderic; Mathiron, David; Pilard, Serge; Lemaire-Hurtel, Anne-Sophie; Dubaele, Jean-Marc; Djedaïni‐Pilard, Florence

doi:10.1016/j.ijpharm.2009.05.029

Cited by 33 publications

(32 citation statements)

References 21 publications

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“…Saturation solubility studies were carried out as described by Higuchi & Connors 4 . Briefly, excess amount of midazolam was added to flask containing different solvents and samples were continuously agitated at 100 rpm for 24 h at 25°C.…”

Section: Saturation Solubility Studiesmentioning

confidence: 99%

“…2,21 . Since midazolam has short half-life and delay of action, it is commonly employed in children pre-anesthesia 4 . It is generally used sublingually and orally by dose of 0.2 mg/kg and 0.4 mg/kg, respectively.…”

Section: Hpmc Effectmentioning

confidence: 99%

“…It is generally used sublingually and orally by dose of 0.2 mg/kg and 0.4 mg/kg, respectively. However, in oral administration midazolam undergoes extensive first pass metabolism in the liver (bioavailability of 15-27% in children) 21 -and also its strong bitterness may be repulsive for children 4 .…”

Section: Hpmc Effectmentioning

confidence: 99%

“…It is also administered in status epilepticus in children 1,2 . Midazolam is a weak acid (pKa 6.2) in pH>4 and exists in un-ionized form 3 , with hydrophobic properties in neutral and physiological pH 4 therefore, it is commercially formulated in acidic pH (approximately 3) for better solubility, which cause pain and irritation in administration site 2,5 .…”

Section: Introductionmentioning

confidence: 99%

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2017

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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: Saturation Solubility Studiesmentioning

confidence: 99%

Section: Hpmc Effectmentioning

confidence: 99%

Section: Hpmc Effectmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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2017

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“…1b), whereas other derivatives did not provide significant enhancement of drug solubility in combination with HPMC (data not shown). γ-CD being less toxic than other derivatives (25) was, therefore, used as a complexing agent in the proposed formulation.…”

Section: Solubility Studiesmentioning

confidence: 99%

Bioadhesive Microspheres for Bioavailability Enhancement of Raloxifene Hydrochloride: Formulation and Pharmacokinetic Evaluation

2011

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Abstract. Raloxifene hydrochloride (R-HCl), a BCS class II drug, remains a mainstay in the prevention and pharmacologic therapy of osteoporosis. Its absolute bioavailability, however, is 2% due to poor solubility and extensive first pass metabolism. The present study describes two simultaneous approaches to improve its bioavailability, complexation of R-HCl with cyclodextrin(s), and formulation of mucoadhesive microspheres of the complex using different proportions of carbopol and HPMC. Microspheres were pale yellow in color, free-flowing, spherical, and porous in outline. The particle size ranged between 3 and 15 μm, and entrapment efficiency was found to be within 81.63% to 87.73%. A significant improvement in the solubility of R-HCl was observed, and it differed with the combination of excipients used. X-ray diffraction and differential scanning calorimetry studies revealed that enhancement in drug solubility was resulted due to a change in its crystallinity within the formulation. Microspheres possessed remarkable mucoadhesion and offered controlled drug release, lasting up to 24 h. They produced a sharp plasma concentration-time profile of R-HCl within 30 min postadministration to Wistar rats.[AUC] 0-24 h was found to be 1,722.34 ng h/ml, and it differed significantly to that of pure drug powder (318.28 ng h/ml). More than fivefold increase in AUC and more than twofold increase in MRT were observed. FT-IR studies evidenced no interaction among drug and excipients. The results of this study showed that mucoadhesive microspheres could be a viable approach to improve the pharmacokinetic profile of R-HCl.

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