Kinetics of degradation of cinnarizine in aqueous solution.

Tokumura, Tadakazu; Ichikawa, Takaharu; Sugawara, Nobuyuki; Tatsuishi, Kimio; Kayano, Masanori; Machida, Yoshiharu; Hoshida, Haruhiko; Nagai, Tsuneji

doi:10.1248/cpb.33.2069

Cited by 26 publications

(12 citation statements)

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“…vehicle comprised 5.3% (v/v) DMSO in 0.4% (w/v) Tween® 80 (Sigma Chemical Company) in phosphate buffer at pH 4 (36 mM disodium hydrogen orthophosphate and 22 mM potassium dihydrogen orthophosphate, adjusted to pH 4 with glacial acetic acid). To minimise degradation of CZ in the formulation at low pH,24 the i.v. formulation was made within 24 h of administration.…”

Section: Methodsmentioning

confidence: 99%

The Effect of Administered Dose of Lipid-Based Formulations on the In Vitro and In Vivo Performance of Cinnarizine as a Model Poorly Water-Soluble Drug

Lee

Porter

Boyd

2013

Journal of Pharmaceutical Sciences

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Section: Methodsmentioning

confidence: 99%

The Effect of Administered Dose of Lipid-Based Formulations on the In Vitro and In Vivo Performance of Cinnarizine as a Model Poorly Water-Soluble Drug

Lee

Porter

Boyd

2013

Journal of Pharmaceutical Sciences

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“…The N-phosphonooxymethyl prodrugs of two drugs, cinnarizine [3][4][5][6][7] and loxapine, 8 were selected for the in vivo evaluation of this prodrug strategy. Both drugs are sparingly water soluble.…”

Section: Introductionmentioning

confidence: 99%

A novel prodrug approach for tertiary amines. 3. In vivo evaluation of two N‐phosphonooxymethyl prodrugs in rats and dogs

Krise¹,

Charman²,

Charman³

et al. 1999

Journal of Pharmaceutical Sciences

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N-phosphonooxymethyl derivatives of tertiary amine containing drugs have been identified as a novel prodrug approach for improving aqueous solubility. The in vivo reversion of two prodrugs to the corresponding parent compounds following iv and im administration to rats and dogs was investigated. Equimolar doses of parent drugs (loxapine or cinnarizine) and the corresponding prodrugs were each administered via a rapid iv infusion to rats and dogs. Equimolar doses of loxapine and its prodrug were each administered im to rats only. Blood samples were collected over 12 h, and plasma was assayed for both parent drug and intact prodrug by HPLC. Comparison of the plasma AUC for the parent drugs following administration of the parent drugs and prodrugs allowed estimation of the apparent bioavailability of parent drug from prodrug dosing. Plasma levels of the prodrugs fell below the limit of detection 5 min after iv infusion with an approximate half-life of 1 min. The mean AUCs following iv and im dosing of parent drugs were not statistically different from the parent drug AUCs obtained after prodrug dosing. The results are consistent with rapid and quantitative prodrug to parent drug reversion following administration of the phosphonooxymethyl prodrugs to the rats and dogs. This information, together with previous studies on the synthesis and physicochemical evaluation of the prodrugs, suggests that this novel prodrug strategy is a very promising approach for overcoming solubility limitations seen with many tertiary amine containing drugs at physiological pH values.

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“…As previous reported, cinnarizine exhibits poor stability in an acidic environment (pH < 4) . Hence, we hypothesised that the oral bioavailability of cinnarizine would be limited by its low stability in acidic gastric juice and the low solubility in intestinal fluid.…”

Section: Resultsmentioning

confidence: 77%

Influence of lipid composition on the oral bioavailability of cinnarizine sub‐microemulsions

Yin-rong

Wei

et al. 2016

Euro J Lipid Sci & Tech

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The oral bioavailability of cinnarizine is usually limited by its poor solubility in the gastrointestinal tract. In this study, two kinds of cinnarizine sub‐microemulsions (SMEs) were prepared using medium (MCT) and long (LCT) chain triglycerides, respectively, and the effect of the lipid composition on the oral bioavailability of SMEs was investigated in terms of stability, in vitro lipolysis, in situ single‐pass intestinal perfusion, and in vivo pharmacokinetics. The SMEs increased cinnarizine stability in simulated gastrointestinal fluid and in vitro lipolysis products of LCT‐SMEs showed better cinnarizine solubilization capacity than that of MCT‐SMEs. In addition, the absorption rate (Ka) and the effective permeability coefficient (Peff) of LCT‐SMEs were significantly improved compared with MCT‐SMEs. The AUC0‐t value of LCT‐SMEs was 4132.6 ± 673.4 ng/mL · h, which was 1.94‐fold higher than that of the aqueous suspension. Moreover, the AUC0‐t value of LCT‐SMEs was also significantly greater than that of MCT‐SMEs (2490.7 ± 685.3 ng/mL · h), owing to the better drug solubilization capacity of the complex colloidal mixtures formed from digestion of LCT. Hence, LCT‐SMEs was successful in improving the oral bioavailability of cinnarizine and it was a superior drug vehicle for oral administration. Practical applications: Owing to poor solubility of cinnarizine in the gastrointestinal tract, its commercially available dosage forms including tablets and capsules exhibit low oral bioavailability. Here we propose SMEs to improve oral bioavailability of cinnarizine. In addition, the influence of lipid composition on the oral absorption of SMEs was investigated, and LCT‐SMEs significantly increased the oral bioavailability of cinnarizine compared with MCT‐SMEs. So, in this study we show that LCT‐SMEs is a promising drug vehicle for oral administration of cinnarizine. The colloidal structures generated from digested long chain triglycerides (LCT) have a better cinnarizine solubilisation ability than that generated from medium chain triglycerides (MCT) digestion, resulting in increased oral absorption for the LCT formulation compared with MCT.

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Kinetics of degradation of cinnarizine in aqueous solution.

Cited by 26 publications

References 0 publications

The Effect of Administered Dose of Lipid-Based Formulations on the In Vitro and In Vivo Performance of Cinnarizine as a Model Poorly Water-Soluble Drug

The Effect of Administered Dose of Lipid-Based Formulations on the In Vitro and In Vivo Performance of Cinnarizine as a Model Poorly Water-Soluble Drug

A novel prodrug approach for tertiary amines. 3. In vivo evaluation of two N‐phosphonooxymethyl prodrugs in rats and dogs

Influence of lipid composition on the oral bioavailability of cinnarizine sub‐microemulsions

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