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Improved oral absorption of cilostazol via sulfonate salt formation with mesylate and besylate.

Seo JH, Park JB, Choi WK, Park S, Sung YJ, Oh E, Bae SK - Drug Des Devel Ther (2015)

Bottom Line: The dissolution profiles in various pH conditions and pharmacokinetic studies in rats were compared with those of cilostazol-free base.Both cilostazol mesylate and cilostazol besylate showed significantly improved dissolution rate and extent of drug release in the pH range 1.2-6.8 compared to the cilostazol-free base.In addition, after oral administration to rats, cilostazol mesylate and cilostazol besylate showed increases in C max and AUC t of approximately 3.65- and 2.87-fold and 3.88- and 2.94-fold, respectively, compared to cilostazol-free base.

View Article: PubMed Central - PubMed

Affiliation: College of Pharmacy and Integrated Research Institute of Pharmaceutical Sciences, The Catholic University of Korea, Bucheon, South Korea.

ABSTRACT

Objective: Cilostazol is a Biopharmaceutical Classification System class II drug with low solubility and high permeability, so its oral absorption is variable and incomplete. The aim of this study was to prepare two sulfonate salts of cilostazol to increase the dissolution and hence the oral bioavailability of cilostazol.

Methods: Cilostazol mesylate and cilostazol besylate were synthesized from cilostazol by acid addition reaction with methane sulfonic acid and benzene sulfonic acid, respectively. The salt preparations were characterized by nuclear magnetic resonance spectroscopy. The water contents, hygroscopicity, stress stability, and photostability of the two cilostazol salts were also determined. The dissolution profiles in various pH conditions and pharmacokinetic studies in rats were compared with those of cilostazol-free base.

Results: The two cilostazol salts exhibited good physicochemical properties, such as nonhygroscopicity, stress stability, and photostability, which make it suitable for the preparation of pharmaceutical formulations. Both cilostazol mesylate and cilostazol besylate showed significantly improved dissolution rate and extent of drug release in the pH range 1.2-6.8 compared to the cilostazol-free base. In addition, after oral administration to rats, cilostazol mesylate and cilostazol besylate showed increases in C max and AUC t of approximately 3.65- and 2.87-fold and 3.88- and 2.94-fold, respectively, compared to cilostazol-free base.

Conclusion: This study showed that two novel salts of cilostazol, such as cilostazol mesylate and cilostazol besylate, could be used to enhance its oral absorption. The findings warrant further preclinical and clinical studies on cilostazol mesylate and cilostazol besylate at doses lower than the usually recommended dosage, so that it can be established as an alternative to the marketed cilostazol tablet.

No MeSH data available.


Related in: MedlinePlus

Dissolution profiles of cilostazol-free base (•), cilostazol mesylate (○), and cilostazol besylate (▲) in (A) pH 1.2, (B) pH 4.5, and (C) pH 6.8 buffer media at 37°C±0.5°C (mean ± SD, n=3).
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f3-dddt-9-3961: Dissolution profiles of cilostazol-free base (•), cilostazol mesylate (○), and cilostazol besylate (▲) in (A) pH 1.2, (B) pH 4.5, and (C) pH 6.8 buffer media at 37°C±0.5°C (mean ± SD, n=3).

Mentions: In vitro dissolution of cilostazol-free base, cilostazol mesylate, and cilostazol besylate was carried out in HCl buffer (pH 1.2), acetate buffer (pH 4.5), and phosphate buffer (pH 6.8) to simulate the gastrointestinal conditions. Dissolution profiles were presented in Figure 3. For cilostazol-free base, the percent cumulative drug dissolved at 6 hours was 25.4%±3.56%, 8.54%±1.89%, and 2.74%±0.341% in pH 1.2, 4.5, and 6.8, respectively, indicating that cilostazol exhibited a pH-dependent dissolution profiles. The lower drug dissolution obtained at higher pH values was due to the basic nature of cilostazol, which is more soluble at lower pH values.


Improved oral absorption of cilostazol via sulfonate salt formation with mesylate and besylate.

Seo JH, Park JB, Choi WK, Park S, Sung YJ, Oh E, Bae SK - Drug Des Devel Ther (2015)

Dissolution profiles of cilostazol-free base (•), cilostazol mesylate (○), and cilostazol besylate (▲) in (A) pH 1.2, (B) pH 4.5, and (C) pH 6.8 buffer media at 37°C±0.5°C (mean ± SD, n=3).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4524531&req=5

f3-dddt-9-3961: Dissolution profiles of cilostazol-free base (•), cilostazol mesylate (○), and cilostazol besylate (▲) in (A) pH 1.2, (B) pH 4.5, and (C) pH 6.8 buffer media at 37°C±0.5°C (mean ± SD, n=3).
Mentions: In vitro dissolution of cilostazol-free base, cilostazol mesylate, and cilostazol besylate was carried out in HCl buffer (pH 1.2), acetate buffer (pH 4.5), and phosphate buffer (pH 6.8) to simulate the gastrointestinal conditions. Dissolution profiles were presented in Figure 3. For cilostazol-free base, the percent cumulative drug dissolved at 6 hours was 25.4%±3.56%, 8.54%±1.89%, and 2.74%±0.341% in pH 1.2, 4.5, and 6.8, respectively, indicating that cilostazol exhibited a pH-dependent dissolution profiles. The lower drug dissolution obtained at higher pH values was due to the basic nature of cilostazol, which is more soluble at lower pH values.

Bottom Line: The dissolution profiles in various pH conditions and pharmacokinetic studies in rats were compared with those of cilostazol-free base.Both cilostazol mesylate and cilostazol besylate showed significantly improved dissolution rate and extent of drug release in the pH range 1.2-6.8 compared to the cilostazol-free base.In addition, after oral administration to rats, cilostazol mesylate and cilostazol besylate showed increases in C max and AUC t of approximately 3.65- and 2.87-fold and 3.88- and 2.94-fold, respectively, compared to cilostazol-free base.

View Article: PubMed Central - PubMed

Affiliation: College of Pharmacy and Integrated Research Institute of Pharmaceutical Sciences, The Catholic University of Korea, Bucheon, South Korea.

ABSTRACT

Objective: Cilostazol is a Biopharmaceutical Classification System class II drug with low solubility and high permeability, so its oral absorption is variable and incomplete. The aim of this study was to prepare two sulfonate salts of cilostazol to increase the dissolution and hence the oral bioavailability of cilostazol.

Methods: Cilostazol mesylate and cilostazol besylate were synthesized from cilostazol by acid addition reaction with methane sulfonic acid and benzene sulfonic acid, respectively. The salt preparations were characterized by nuclear magnetic resonance spectroscopy. The water contents, hygroscopicity, stress stability, and photostability of the two cilostazol salts were also determined. The dissolution profiles in various pH conditions and pharmacokinetic studies in rats were compared with those of cilostazol-free base.

Results: The two cilostazol salts exhibited good physicochemical properties, such as nonhygroscopicity, stress stability, and photostability, which make it suitable for the preparation of pharmaceutical formulations. Both cilostazol mesylate and cilostazol besylate showed significantly improved dissolution rate and extent of drug release in the pH range 1.2-6.8 compared to the cilostazol-free base. In addition, after oral administration to rats, cilostazol mesylate and cilostazol besylate showed increases in C max and AUC t of approximately 3.65- and 2.87-fold and 3.88- and 2.94-fold, respectively, compared to cilostazol-free base.

Conclusion: This study showed that two novel salts of cilostazol, such as cilostazol mesylate and cilostazol besylate, could be used to enhance its oral absorption. The findings warrant further preclinical and clinical studies on cilostazol mesylate and cilostazol besylate at doses lower than the usually recommended dosage, so that it can be established as an alternative to the marketed cilostazol tablet.

No MeSH data available.


Related in: MedlinePlus