"Wanjin oil" Cabotini repeatedly broke through.

(S) - Malic acid cabotinib is a new multi-target broad-spectrum anti-cancer drug that inhibits a variety of tumor-related kinase receptors and was approved by the U.SFood and Drug Administration (FDA) in 2012 for the treatment of thyroid myelin, advanced kidney and liver cancerreview the therapeutic effect of cabotinib and the prospect of studying known dosage forms as well as new dosage forms and viscose crystalsDrug Overview Cabozantinib S-Malate, a pyridine compound developed by Exelixis Biopharmaceuticals in the United States, was first approved for sale in the United States in 2012 for the treatment of myelin cancercabotinib is a multi-target molecular target drug, at present, has been in kidney cancer, thyroid cancer, liver cancer, soft tissue sarcoma, non-small cell lung cancer, prostate cancer, breast cancer, ovarian cancer, bowel cancer and other solid tumors, confirmed a better therapeutic effect, especially for bone metastasis control effectbecause of its wide range of cancer seisks, cabotinib is known as the "golden oil" in the targeted drug, with broad-spectrum anti-cancer capabilitieswas approved by the European Medicines Agency (EMA) on 21 March 2014 for the listing of a ®, come, and on April 25, 2016, approved a first-line treatment for patients with advanced kidney cancer, which is available in Ipson for sale in Europe, with products called Cometriq ® and Cabometyx ®January 2019, fda approval for hepatocellular carcinoma was approved by the FDA based on the results of the THIRD phase of THE CELESTIAL clinical trial1Treatment of thyroid myelin cancer (MTC) Cabotinib showed better efficacy through multi-target function, and experiments showed that the survival of cabotinib seis no progress was extended by 75% compared to the placebo group, while adverse reactions such as diarrhea, stomatitis, loss of appetite, etccan be controlled by adjusting the dose of the drug and become the star drug for the treatment of MTC2Treatment of advanced renal cancer (renal cell carcinoma, RCC) Cabotinib as a new molecular target anti-cancer drug in patients with advanced kidney cancer in clinical applications to obtain good results: using the clinically used drug ivemos as a control group, cabotinib can extend the total survival of patients by 29.7%used the first-line treatment drug sunitinib as a control group with an efficiency of 46% VS 18%, a progression-free survival of 8.2 VS5.6 months, and, more importantly, a total survival of 30.3 VS21.8 monthsit shows that Cabotinib has shown better clinical results in the treatment of patients with advanced kidney cancer 3 Patients with advanced liver cancer treated with cabotinib for treatment of liver cancer (cellularhepato carcinoma, HCC) had a significantly longer survival, with a 37 per cent decrease in the risk of death and an objective efficiency of about 5 per cent , Cabotinib has become one of the drugs used to treat advanced liver cancer, along with drugs such as rigofeni and PD-1 antibodies patients with advanced HCC who had treatment for sorafini, the median survival of the cabotinib group reached 11.3 months, compared with 7.2 months for the placebo group, with significant effects in September 2018, CHMP provided positive advice on cabotinib as a monodrug treatment for HCC in adults who had previously received sorafenib treatment Cabozanib, the world's first generic drug, cabotinib produced in Bangladesh, , is on the market and is clinically consistent with the original drug in terms of active ingredients, pathways of administration, dosage form, dosage terms and bioequisability Cabotini original drug priceist is very expensive, in Hong Kong, the price in the monthly 55,000 or so, its Bangladeshi imitation version of about 7,500 yuan per box, about 10,000 per month, in the price has a certain advantage at present, there are Beijing Selintai Medicine, Zhengda Tianqing, Nanjing Warwick Pharmaceuticals, Jiangsu Osaykang Pharmaceuticals, Shanghai Huilun Jiangsu Pharmaceuticals, Sui Langrui Pharmaceutical Technology and other companies applied for the Cabotini clinical trial, Zhengda Tianqing has completed the Cabotini biological equivalence experiment, but the imitation advantage is not obvious Cabotinib spent more than 8 years from research and development to market, with total research and development costs of nearly US$2 billion, and sales revenue totaled approximately US$250 million to 2017, accounting for only 12.5% of research and development investment, which is low in relation to other target tumor-targeted inhibitors because of cabotini's apparent role, Cabotini's sales growth is clear, so it is very optimistic about its prospects Listed Dosage and New Dosage Form Study 1 In the initial development experiments, Cabotinib was found to be a BCS CLASS II compound with low solubility and high permeability the low solubility in water and was initially not considered suitable for the development of solid oral preparations, the focus of drug development was on finding salts with appropriate water absorption, thermal stability, chemical stability, lysozyme stability and solubility, taking into account the high-quality combination of the medicinal properties of The S-Apple acid cabotinib, No changes shown in determining purity, humidity and solubility, and its crystal and amorphous form outperformed Cabozantinb's free alkalis and other salts, and Exelixis chose Cabotinib's apple acid as the active ingredient in the development of solid formulations cabotinib solid oral preparations of the existing tablets and capsules of two dosage forms, different specifications can adjust the dosage according to the adverse reactions that occur, but it is prohibited to substitute the capsule dosage form and the tablet dosage form treatment for thyroid cancer with cabotini capsules, the treatment of kidney cell cancer tablets cabotinib tablets are supplied with 20mg, 40mg or 60mg cabotini in thin film, respectively, equivalent to 25mg, 51mg or 76mg cabotini S-appleacid, including the following inactive ingredients: microcrystalline cellulose, aqueous lactose, hydroxyl cellulose, methyl sodium cellulose, colloidal silica, and magnesium sclerotic acid coating contains sodium pylcellulose, titanium dioxide, triacetyl glycerin, and iron oxide cabotini capsules 20 mg and 80 mg, containing 20 mg and 80 mg of malic acid cabotini, respectively, the FDA recommended daily dose of cabotini is 140 mg (one 80 mg, three 20 mg capsules), not mixed with food 1.1 Prescription Design Select patented CN103221035A 5, a pharmaceutical composition containing the compound cabotinib (S)-apple acid of 30-32 weight percent; 50-70% filler; 2-4% adhesive; 4-8% disintegrating agent; and 0.2-0.6% flux and 0.5-1% lubricant drug composition, the filler comprises lactose and microcrystalline cellulose, the adhesive is hydroxypropyl cellulose, the disintegrating agent is cross-linked methyl cellulose sodium, the flux is colloidal silicon dioxide, the lubricant is magnesium stearate, and also contains a thin film coating obadelicanxelione made tablets Table 1 Example of a pharmaceutical composition of cabotinib tablets 1.2 The production process of cabotinib tablets will be premixed with the crushed cabotenini (S) - cider and microcrystalline cellulose, aqueous lactose and cross-linked sodium methyl cellulose The formation of adhesive solution, high shear wet legal particles to produce wet particles wet method screening by the fluidized bed drying, grinding, and colloidal silicon dioxide and cross-linked methyl cellulose mixed, and then added steagin magnesium lubrication mixed, tablets, film coating 2.2 New Dosage Form Research With cabotinib sauors showing extensive clinical effects, resulting in new approved treatment options for a wide range of tumor types, there is interest in evaluating new formulations of multi-target tyrosine kinase kinase inhibitors that are provided when used in combination with checkpoint inhibitors in search of further possible collaborative anti-cancer clinical effects taking into account the difficulty of swallowing oral solid preparations in pediatric patients and elderly patients, the preference for liquid oral preparations is easy to ingest, and drug compliance is improved Patent WO2018227119A, reports mixing Cabozantinib and its pharmaceutically acceptable salts (e.g., (L)-apple acid, also known as (S)-apple rate) with one or more carriers Prepare oral preparations containing approximately 85% OF PEG-400 (w/w), and/or about 10% Of TPGS (w/w), and/or about 5% ethanol (w/w) to form a solution or suspension Table 2 Examples of liquid preparations containing cabotinib (S) -applecelate2.3 Viscose and crystal-type According to crystal cloud technology viscose type patent CN104961681A, the study shows that cabotinib viscotes are easy to obtain, generally cabotini and The viscosis is dissolved in solvents (acetylene, alcohol, ketones, ethers and the above-mentioned solvents and water mixed solvent system, respectively, (10-20): 1), so that the reaction of the two is to obtain cabotinib viscose, no recrystallization operation, crystal analysis can be a stable salt type obtained cabotinib muscous solubility is high, is conducive to improve the biological utilization and efficacy of the drug, has good stability, only a single crystal type, can reduce the polycrystalline drug due to the change of drug efficacy and safety due to the recrystalline, has a low wetting, preparation process does not need special drying conditions, simplifies the preparation and reprocessing process of the drug, easy to industrial production and the crystal in different humidity conditions, the moisture content is basically the same, easy to long-term storage of drugs, greatly reduce the storage of materials and quality control costs, with strong economic value the X-ray powder diffraction (XRPD) spectrum of the viscotate crystal siftography is shown in Figure 1, which comprises peaks at 13.4, 17.3, 19.6, 21.8, 22.5, 23.1, and 25.5 (2 x 2 s 2 s 2 s Weightlessness was not found in TG/DTA analysis, indicating that it is a crystalless type Figure 1 The X-ray powder diffraction (XRPD) spectral map of the viscotate crystal type, derived from the reference 7 summary At present, "Wanjin oil" Cabotini has shown obvious therapeutic effect in kidney cancer, thyroid cancer, liver cancer, prostate cancer, breast cancer and other solid tumors, with broad spectrum anti-cancer ability, and with good specific target drug with a more significant advantage Inevitably, , Cabotini has relatively more side effects Exelixis has applied for cabotini metabolite patents, salt patents, crystal patents, composition patents, preparation patents, application patents, and preparation method patents in China , salt patents (apple acid patents) and metabolite senile patents limit the means to apply for new drugs such as Cabotinib Suzhou Jingyun Pharmaceutical Technology also has cabotini crystal patent, viscotate-type patent, preparation method patent, use patent, its advantage is more than a salt patent, but Cabotinib original research drug metabolites in 2019 has been licensed, Cabotinib in China may still have to wait until the patent expires to market, and then strive for market share in general, given the huge advantages of cabotinib treatment, if domestic pharmaceutical companies can successfully market at a lower cost than patents, will occupy the main market, follow-up cancer treatment will continue to be optimistic References FDA grants regular approval to cabometyx for first-linetreatment of advanced renal cell carcinoma (EB/OL) (2019-01-19) 2019-05-19: fda.gov/drugs/ informationondrugs/approveddrugs/ucm589842 Htm THE FDA'S OFFICIAL WEBSITE NDA 203756 approval letter (EB/OL) (2012-11-29) [2018-05-19] https:// Aeesdata Fda Gov/drugsatfda_docs/appletter/2012/203756Orig1s00ltr Pdf The FDA's official website NDA 208692 approval letter (EB/OL) (2016-04-25) [2018-05-19] https:// Aeesdata Fda Gov/drugsatfda_docs/appletter/2016/208692Orig1s000ltr Pdf Cabometyx ™ (cabozantinib) tablets USprescribing information Exelixis, Inc April 2016 Axeli Axis, Inc C-MET Regulator Drug Compositions .P.China: CN103221035A, 2013-07-24 EXELIXIS INC LIQUID DOSAGE FORMS TOTREAT CANCER .P US: WO2018227119A, 2018-12-13 Suzhou Jingyun Pharmaceutical Technology Co., Ltd Cabotini's viscosis and its crystals China: CN104961681A, 2014-11-13.