| Nintedanib was successfully developed by Boehringer Ingelheim and then approved by the Food and Drug Administration(FDA) in 2014 for the first time. It is a triple tyrosine kinase inhibitors and growth factor antagonist medicine. It can be used to treat the idiopathic pulmonary fibrosis diseases which can only be treated through lung transplantation at present. Additionally, nintedanib exhibited poor solubility in the intestinal tract environment, which leaded to the low bioavailability,just 4.7%. In this study, nintedanib solid dispersion was prepared by electrospray technology to improve its solubility. Furthermore, nintedanib sustained-release capsules were also prepared based on the solid dispersion to prolong drug release,improving patient compliance and reduce the frequency of administration. Finally,quality evaluation and bioavailability in SD rats of nintedanib sustained-release formulation were investigated in this study. This paper is divided into five sections as shown in the following.Part one: ReviewsThis part mainly introduced the research progress on solid dispersion,electrospray technology, sustained and controlled release formulation, as well as the progess of model drug-nintedanib. The application of preparations and some pahrmaceutical technologies were also summarized. Together, physical and chemical properties, pharmacological mechanism and pharmacokinetics of the model drug were elucidated in order to lay the foundation for the subsequent studies of preparations.Part two: Rreformulation studiesThe Ultraviolet spectrophotometric(UV) method was established to assay drug release characteristic in vitro. The maximum absorption wavelength of the drug was385 nm, which was determined by UV full wavelength scanning. The different concentration solution was used to establish standard curve. The experimental results of methodology validation showed that the method is stable, reliable and consistent with the methodology. The equilibrium solubility and oil-water partition coefficient of nintedanib in different mediums were all measured respectively. As shown, thesolubility of nintedanib reaches the highest in pH 1.0, lower in the PBS, suggesting that nintedanib is a poorly water soluble compound in intestinal because of their similar environment, which leads to the low biobioavailability. The study on the prescription of nintedanib provided a reference for the study of solid dispersion and sustained release capsules. In this part, the method of the determination of the content and dissolution rate of nintedanib has been verified. The results showed that the content and dissolution determination method were according with the requirements of the methodology.Part three: Preparation and characterization of nintedanib solid dispersionsIn this part, electrospray technology was used to prepare nintedanib solid dispersion with povidone(PVP) K30 as a carrier. In order to enhance drug absorption,Soybean lecithin was added into the solid dispersion. In vitro dissolution and surface morphology of the solid dispersion as the index to investigate the different drug load ratio and electrospray parameters how to affect the nintedanib solid dispersion. Based on which, the optimal compositions were presented as follows: the nintedanib solid dispersion was consisted of nintedanib: PVPK30: Soybean lecithin at the optimized ratio of 1: 5: 0.25. The best operating parameters of voltage was 21 kv, receiving distance was 18 cm, solution flow rate was 0.3 mL/h, pinhole inner diameter was 0.5mm, stable environment(t = 25℃, RH = 30%). Upon these conditions, the characteristic of optimal formulation was evaluated in vitro. The accumulative release rate of the optimized solid dispersion was more than 60% in 30 minutes and 100% in60 minutes in the medium, showing the drug release rate was significantly faster than the raw material. The results of scanning electron microscopy(SEM) and particle size distribution showed that the size distribution is uniform(340nm) and the surface is smooth. The solid dispersion was identified by DSC and X-ray diffraction patterns and the results showed that nintedanib existed in the solid dispersion through amorphous form, which indicated that nintedanib solid dispersion was successfully prepared.Part four: Preparation, quality evaluation and drug release mechanism of nintedanib sustained release capsulesIn this part, nintedanib solid dispersion was used as raw material and HPMC was used as sustained-release matrix material to prepare nintedanib sustained-release capsules. Screening the viscosity and consumption of skeleton material and the type of fillers through single factor. Eventually, the optimal prescription was determined.HPMC K100 M as skeleton material, MCC as filler. Evaluated the quality of nintedanib sustained-release capsules: the content of nintedanib was between 98% ~102% and the other indicators of sustained release capsules all meet the requirements.The accumulative release rate of the homemade sustained release capsules was35.17%, 54.78%, 70.58% 93.93% in 2 h, 6 h, 8 h, 12 h respectively in the dissolution medium, relatively having better sustained release effect in vitro compared to the solid dispersion. According to the result of model fitting results, the release behaviour of nintedanib sustained-release capsules in vitro was in accordance with Ritger-peppas model. Release mechanism of drug showed that the sustained-release capsule drug release process were diffusion and matrix erosion.Part five: Pharmacokinetics study of nintedanib sustained release capsules in SD ratsIn this part, a high performance liquid chromatography method was established to determine the blood drug concentration of SD rats in vivo for nintedanib soft capsule, nintedanib solid dispersions, nintedanib sustained-release capsules. Through validation, the method was proved be strong specificity, high sensitivity and high recovery rate. It was also accurate and precise enough to meet the requirements. In vivo dynamic experimental results showed that blood drug concentration Tmax of nintedanib soft capsule, nintedanib solid dispersion and nintedanib sustained release capsules were 3h, 2h, 6h respectively. The maximum plasma concentration Cmax were 2.945 μg/ml, 5.32 μg/ml, 3.75 μg/ml respectively, the area under the curve was15.124 μg·h/mL, 23.438 μg·h/mL, 24.584 μg·h/mL respectively. The relevant bioavailability of nintedanib sustained-release capsules was 162.55% compared to nintedanib soft capsule and 104.89% compared to nintedanib solid dispersion. The results of relevant evaluation showed that absorption and dissolution of nintedanib sustained release capsules was in good correlation between in vivo and in vitro. |
PDF Full Text Request