Research Articles
Comparison of the Absorption of Micronized (Daflon 500® mg) and Nonmicronized 14C‐diosmin Tablets After Oral Administration to Healthy Volunteers by Accelerator Mass Spectrometry and Liquid Scintillation Counting

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Abstract

Daflon 500® mg, is a micronized purified flavonoid fraction, containing 90% w/w diosmin and 10% w/w of flavonoids expressed as hesperidin, used clinically in the treatment of chronic venous insufficiency and hemorrhoidal disease. This study was designed to investigate the influence of particle size on the overall absorption of diosmin after oral administration of micronized (mean particle size = 1.79 μm, with 80% of particles having a size lower than 3.45 μm) and nonmicronized diosmin (mean particle size = 36.5 μm, with 80% of particles comprised between 19.9 and 159 μm). In a double blinded, cross‐over study design, 500 mg tablets containing trace amounts (approximately 25 nCi) of 14C‐diosmin were administered to 12 healthy male volunteers as a single oral dose. Accelerator mass spectrometry and liquid scintillation counting were used for the measurement of 14C‐diosmin in urine and feces. Absorption of 14C‐diosmin from the gastrointestinal tract, measured by the urinary excretion of total radioactivity, was significantly improved with the micronized (57.9 ± 20.2%) compared with the nonmicronized material (32.7 ± 18.8%). Statistical comparison of the urinary excretion of the two pharmaceutical formulations showed this difference to be highly significant (p = 0.0004, analysis of variance). The overall excretion of the radiolabeled dose was 100% with mean ± SD of 109 ± 23% and 113 ± 20% for the micronized and nonmicronized forms, respectively. The results of this study show: 1. the impact of a reduction of particle size on the extent of absorption of diosmin, giving a pharmacokinetic explanation to the better clinical efficacy observed with the micronized formulation, and 2. the use of accelerator mass spectrometry in conjunction with liquid scintillation counting in measurement of bioavailability in a human cross‐over study comparing two drug formulations containing trace amounts of radioactivity. © 2002 Wiley‐Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 91:32–40, 2002

Section snippets

INTRODUCTION

Oral absorption is a multifactorial process encompassing not only the in vivo dissolution of the drug, but also the physiological conditions in the gastrointestinal tract such as gastric emptying and the presence of bile acids, as well as the passage of the drug across the intestinal membrane.

The less a drug is absorbed, the more pharmacokinetic variation will occur from one subject to another, and the more it may be influenced by exogenous factors such as diet and dosing regimen.

For highly

Study Drugs and Labeled Compound

Purified flavonoid fraction (S 5682) batch 53879 was supplied by Technologie Servier (Orleans, France). 14C‐labeled diosmin (Fig. 1) was synthesized by Nycomed Amersham Plc. (Buckinghamshire, England). Specific activity was 2.07 GBq/mmol (56 mCi/mmol) with a purity of 98%.

Tablet Preparation

Preparation of the tablet formulations with the radiolabeled drug substance: The tablets were prepared according to a similar process and with the same formulation as that described for the core tablet in the submission file.

Drug Formulation

Manufacture of the tablets was performed to match the specification of the final formulation used in the clinic. The presence of radioactive material, negligible in terms of the individual dose given to the healthy volunteers, still implies formulation on a smaller‐scale machine with adapted safety conditions during the manufacturing process.

The tablets were sampled and tested for purity (radiochemical and nonlabeled drug purity) granulometry, and homogeneity. Radiochemical purity was 98.3% and

CONCLUSIONS

The data reported herein demonstrate that reduction of particle size obtained by a micronization process improves the extent of absorption of diosmin and/or its metabolites, giving a pharmacokinetic explanation to the better clinical efficacy observed with the micronized formulation.

Increasing the absorbed fraction will also lead to lower variability from one patient to another, and less influence of exogenous factors such as diet and dosing regimen.

The results of this study indicate that the

Acknowledgements

CBAMS Ltd. thanks GlaxoSmithKline, Pfizer UK Ltd., Janssen Pharmaceutica Belgium, Novartis Switzerland, the UK Ministry of Agriculture, Fisheries, and Food, and the University of York for their financial assistance in creating our Centre. In addition, we thank Servier, France for giving permission to publish our findings.

REFERENCES (12)

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