Rosuvastatin calcium nanoparticles: Improving bioavailability by formulation and stabilization codesign

Abstract

Purpose: Rosuvastatin calcium (ROSCa) is a poorly soluble drug with bioavailability not exceeding 20%. Decreasing the particle size may enhance its solubility, dissolution rate and bioavailability. Therefore, the aim of the current study is to prepare ROSCa nanoparticles by wet milling technique using planetary ball mill. The codesign between formulation and stabilization of nanoparticles was studied to achieve both high dissolution as well as bioavailability.

Methodology: ROSCa nanosuspensions was prepared by wet milling technique using planetary ball mill, by applying milling ball size of 0.1 mm at speed of 800 rpm for 3 cycles each cycle composed of 10 minutes. HPMC, PVP k-30, pluronic F-127, Tween 80 and PEG 6000 were used as stabilizers. The nanosuspensions were then freeze-dried, and the dried nanoparticles were evaluated for particle size, zeta potential, in-vitro dissolution test, XRPD and in-vivo study.

Results: ROSCa nanoparticles stabilized with 10% PVP (P3) had a good stability with smallest particle size, which in turn enhanced the dissolution rate. The particle size of the leading formula was 461.8 ± 16.68 nm with zeta potential of -31.8 ± 7.22 mV compared to untreated drug that has a particle size of 618μm. The percent of ROSCa dissolved after 1 hour enhanced significantly which reached 72% and 58.25% for leading nanoparticle formula and untreated ROSCa, respectively (P < 0.05). The in-vivo study of ROSCa from the leading nanoparticle formula showed a significant enhancement in the Cmax after 2 h (82.35 ng/ml) compared to 9.2 ng/ml for untreated drug.

Conclusion: Wet milling technique is a successful method to prepare ROSCa nanoparticles. From different stabilizer used, PVP (10%) was able to produce stable nanoparticle with small particle size which significantly enhance the dissolution rate and pharmacokinetics parameters of ROSCa.

Fig 1. Effect of different types and concentrations of stabilizers on the particle size and zeta potential of ROSCa nanosuspensions prepared by planetary ball mill, compared to the untreated ROSCa powder (618 μm).

Fig 2. Effect of different types and concentrations of stabilizer on the particle size of the freeze-dried ROSCa nanoparticles prepared by planetary ball mill compared with untreated ROSCa (618 μm).

Fig 3. Effect of different types and concentrations of polymeric solutions on the particle size of ROSCa non-milled freeze-dried suspensions compared with untreated ROSCa (618 μm).

Fig 4. Effect of different stabilizers types and concentrations on the percent dissolved of ROSCa nanoparticles after 60 minutes compared to untreated ROSCa and non-stabilized ROSCa nanoparticles.

Fig 5

(A) Particle size of ROSCa nanoparticles prepared by planetary ball milling and stabilized by 10% PVP; (B) In vitro dissolution profile of ROSCa from nanoparticle formulation stabilized by 10% PVP, compared to the untreated drug in 0.1 N HCl at 37C°.

Fig 6. XRPD spectrum for ROSCa nanoparticles stabilized by different PVP concentrations compared to the corresponding non-milled freeze-dried suspensions and untreated ROSCa.

Fig 7. Plasma concentration-time curve of ROSCa in rabbits after oral administration of nanoparticle formula stabilized by 10 PVP compared to the raw drug.