Category: Formulation and Quality
Purpose: Aprepitant is an antiemetic drug which is classified as NK1 (neurokinin 1) antagonist. It effectively prevents acute and delayed chemotherapy induced nausea and vomiting (CINV) and also prevents postoperative nausea and vomiting (PONV).
The solubility of aprepitant in water is very limited so it has been commercialized (Emend® capsule) using nanotechnology to enhance solubility and bioavailability.
In this work, aprepitant was developed in the form of a double-layer coated solid dispersion to improve solubility and bioavailability without the nanonization process, and various characteristics were compared with the conventional product in vitro and in vivo.
Methods: Double-layer coated solid dispersion of aprepitant (SYO-1906) was prepared by bottom spray coating of water soluble polymer (1st layer) and gastric soluble polymer (2nd layer) with aprepitant on inactive spherical microcrystalline cellulose. The morphology and crystalline structure of samples were investigated with electronic microscope, DSC (Differential Scanning Calorimetry) and pXRD (powdered X-ray diffraction). In vitro release test was carried out using USP dissolution apparatus 2 (PTWS 610, PharmaTest, Germany) with 50 rpm in four media of 900 mL (hydrochloric acid buffer (pH1.2), acetate buffer (pH4.0), phosphate buffer solution (pH6.8), and distilled water) at 37℃.
The pharmacokinetics study was evaluated in male beagle dogs. Eight beagle dogs were randomly divided into two groups (n=8). Capsules with the dose of 125mg as aprepitant were prepared for the reference formulation and for the test formulation and orally administered to the dogs in each group, respectively. Blood samples were collected from Jugular vein with a heparinized syringe at the predetermined interval to 48 hours after administration, and the plasma samples were stored frozen at -70℃ after centrifuge until analysis. The concentration of drug in plasma was determined with LC/MS/MS (HPLC; HP1100 series, US, MS; Quattro Ultima-Pt, UK) system.
Results: Double-layer coated solid dispersion of aprepitant (SYO-1906) was developed sucessfully by bottom spray coating without aggregation. It was proved by DSC and pXRD that the active pharmaceutical ingredient existed in an amorphous form among the polymers. The dissolution rates of test formulation were superior to those of reference formulation in pH1.2 media, however, in the pharmacokinetics study in beagle dogs, both value of AUClast and Cmax were comparable to the reference formulation and the test formulation. AUClast were 68,511.4 ± 29,706.0 and 64,459.8 ± 44,590.5, and Cmax were 2,973.7 ± 1,161.6 and 2,898.1 ± 1,505.9 for test formulation and reference formulation, respectively. The relative magnitude of AUClast and Cmax of test drug to those of reference drug were 106.3% and 102.6%, respectively, that regarded as being bioequivalent.
Conclusion: Poorly soluble aprepitant were formulated by double layer coated solid dispersion to make bioequivalent product with nanonized reference drug. Aprepitant was maintained in an amorphous state by the polymer, thereby obtaining a relatively high dissolution rate in pH1.2. In vivo pharmacokinetics study conducted on beagle dogs confirmed that SYO-1906 was equivalent to the nanonized formulations (Emend® capsule). Therefore, it is expected that the two agents could be prescribed interchangeably.
Sang Yeob Park– Seongnam-si, Kyonggi-do, Republic of Korea
Nam Hyuck Kim– Seongnam-si, Kyonggi-do, Republic of Korea
Jaeyoung Lee– Researcher, Samyang Biopharmaceuticals Corporation, Seongnamsi, Kyonggi-do, Republic of Korea
Minhyuk Yun– Principal researcher, Samyang Biopharmaceuticals Corporation, Seongnamsi, Kyonggi-do, Republic of Korea
Sangwoo Jo– Seongnamsi, Kyonggi-do, Republic of Korea
Jiyeong Kim– Deputy Senior Manager, Instrument analysis/ R&D center/ Samyang Biopharmaceuticals corp., Seongnamsi, Kyonggi-do, Republic of Korea
Yoojeong Yoon– Samyang Biopharmaceuticals Corporation, Seongnam-si, Kyonggi-do, Republic of Korea
Junehee Lee– Seongnam-si, Kyonggi-do, Republic of Korea
kyujin Kyung– Seongnam-si, Kyonggi-do, Republic of Korea
Seungwei Jeong– Samyang Biopharmaceuticals Corporation, Seongnamsi, Kyonggi-do, Republic of Korea
Sukyen Ko– Samyang Biopharmaceuticals Corporation, Seongnam, Kyonggi-do, Republic of Korea
Sawon Lee– Team manager, Samyang Biopharmaceuticals Corporation, Seongnamsi, Kyonggi-do, Republic of Korea