WO2019218979A1 - 一种hc-1119制剂及其制备方法和用途 - Google Patents

一种hc-1119制剂及其制备方法和用途 Download PDF

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WO2019218979A1
WO2019218979A1 PCT/CN2019/086694 CN2019086694W WO2019218979A1 WO 2019218979 A1 WO2019218979 A1 WO 2019218979A1 CN 2019086694 W CN2019086694 W CN 2019086694W WO 2019218979 A1 WO2019218979 A1 WO 2019218979A1
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receptor inhibitor
androgen receptor
preparation
androgen
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PCT/CN2019/086694
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English (en)
French (fr)
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魏星
齐明
杜武
李兴海
陈元伟
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成都海创药业有限公司
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Priority to CA3105389A priority Critical patent/CA3105389A1/en
Priority to US17/055,862 priority patent/US20210290553A1/en
Priority to AU2019268481A priority patent/AU2019268481A1/en
Priority to KR1020207035068A priority patent/KR102542275B1/ko
Priority to JP2020564111A priority patent/JP7301883B2/ja
Priority to EP19803519.8A priority patent/EP3795153A4/en
Publication of WO2019218979A1 publication Critical patent/WO2019218979A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4858—Organic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4166—1,3-Diazoles having oxo groups directly attached to the heterocyclic ring, e.g. phenytoin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4833—Encapsulating processes; Filling of capsules
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4866—Organic macromolecular compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention specifically relates to an androgen receptor inhibitor HC-1119 formulation, a process for its preparation and use.
  • HC-1119 is an Androgen Receptor (AR) inhibitor that competitively inhibits the binding of androgen to AR and blocks the transmission of AR signaling pathways, including androgen signaling pathway-dependent diseases, including But not limited to prostate cancer, breast cancer.
  • AR Androgen Receptor
  • Its chemical name is: 4- ⁇ 3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-thio-1-imidazolidine ⁇ ]-fluoro-N-tridehypo-methylbenzamide, the structure is as shown in Formula I:
  • HC-1119 was insoluble in water.
  • the results of in vitro experiments showed that the permeability of HC-1119 was evaluated by Caco-2 cell model.
  • the apparent permeability coefficient of -1119 is 11.4 ⁇ 13.6 ⁇ 10 -6 cm/s. Therefore, HC-1119 is a poorly soluble, highly permeable drug, which belongs to the second category of BSC classification. Improving the bioavailability of drugs is the key to drug development.
  • the present invention provides an HC-1119 preparation and a HC-1119 soft capsule containing the same.
  • the HC-1119 preparation of the present invention is prepared from the following raw materials by weight ratio:
  • the androgen receptor inhibitor HC-1119 is from 1 to 100 parts, the solvent is from 100 to 1000 parts, and the antioxidant is from 0.11 to 11 parts.
  • the solvent is a combination of one or more of polyglycolic acid decanoic acid glyceryl glyceride, soybean oil, glycerin, polyethylene glycol, polyethylene glycol glyceride and glyceryl caprylate;
  • the polyethylene glycol glyceride is selected from one or two of polyethylene glycol monoglyceride and polyethylene glycol triglyceride;
  • the caprylic acid glyceride is selected from caprylic acid triglyceride ;
  • the solvent is phthalic acid decanoic acid polyethylene glycol glyceride.
  • the antioxidant is a combination of one or more of butylated hydroxyanisole, butylated hydroxytoluene, and an aromatic amine antioxidant;
  • the antioxidant is a composition of butylated hydroxyanisole and butylated hydroxytoluene; wherein, the butylated hydroxyanisole is 0.1 to 10 parts, and the butylated hydroxytoluene is 0.01 to 1 part.
  • HC-1119 preparation is prepared from the following weight ratio raw materials:
  • HC-1119 preparation is prepared from the following weight ratio raw materials:
  • Androgen receptor inhibitor HC-1119 25-55 parts, 920-980 parts of caprylic acid polyethylene glycol glyceride, 0.5-1.5 parts of butylated hydroxyanisole, 0.05-0.15 parts of butylated hydroxytoluene;
  • HC-1119 preparation is prepared from the following weight ratio raw materials:
  • one preparation is prepared from the following raw materials and auxiliary materials:
  • Androgen receptor inhibitor HC-1119 1 ⁇ 100mg, preferably 80mg;
  • the androgen receptor inhibitor HC-1119 is 25-55 mg, preferably 40 mg;
  • the androgen receptor inhibitor HC-1119 is 15 to 25 mg, preferably 20 mg;
  • the androgen receptor inhibitor HC-1119 is 5 to 15 mg, preferably 10 mg.
  • the preparation is a tablet, a liquid preparation, a soft capsule; preferably, the preparation is a soft capsule.
  • the present invention also provides an androgen receptor inhibitor HC-1119 soft capsule, which is composed of the aforementioned preparation and capsule shell;
  • the capsule shell is composed of the following weight ratio auxiliary materials: 100 parts of gelatin, 20-60 parts of glycerin, 20-60 parts of sorbitol solution or 10-50 parts of sorbitol, 0.5-2 parts of titanium dioxide, and 50-100 parts of purified water. Share.
  • the invention also provides a preparation method of the aforementioned preparation, which comprises the following steps:
  • the HC-1119 bulk drug is pulverized to a particle size of 1-150 ⁇ m, and used;
  • the dissolution temperature in the step (2) is 45 ° C ⁇ 3 ° C.
  • the invention also provides a preparation method of the aforementioned HC-1119 soft capsule, which comprises the following steps:
  • a gelatinized tank is heated to 70 ° C, added to the above weight ratio of water, glycerin, sorbitol solution, stirred for 20 minutes;
  • the thickness of the rubber is controlled to be 0.8mm-1.10mm, and the filling amount of the capsule content is ⁇ 5% of the theoretical capacity, and the capsule is compressed;
  • the B capsule After the B capsule is pressed, it is blown to the drum by cold air, shaped, and added with oil-absorbing cotton for rubbing, and dried at a temperature of 25.0 to 30.0 ° C and a humidity of 25.0% until the content of the water is less than 5.0%.
  • the present invention also provides the use of the aforementioned HC-1119 preparation for the preparation of a medicament for treating an androgen signaling pathway-dependent disease; preferably, the androgen signaling pathway-dependent disease is prostate cancer, breast cancer; preferably The prostate cancer is castration-resistant prostate cancer.
  • the present invention also provides the use of the aforementioned soft capsule for the preparation of a medicament for treating an androgen signaling pathway-dependent disease; preferably, the androgen signaling pathway-dependent disease is prostate cancer, breast cancer; preferably, Prostate cancer is castration-resistant prostate cancer.
  • the present invention also provides an oral preparation of the androgen receptor inhibitor HC-1119, which is an oral preparation prepared by administering an effective dose of HC-1119 as an active ingredient together with a pharmaceutically acceptable adjuvant.
  • the unit contains an androgen receptor inhibitor HC-11191 ⁇ 100mg.
  • the preparation unit refers to a dosage form unit of each tablet of the tablet, each capsule of the capsule, and each bag of the granules.
  • each unit of the formulation contains 80 mg of the androgen receptor inhibitor HC-1119.
  • each preparation unit contains 25 to 55 mg, preferably 40 mg, of the androgen receptor inhibitor HC-1119;
  • each preparation unit contains 15-15 mg of androgen receptor inhibitor HC-1119, preferably 20 mg;
  • each preparation unit contains 5 to 15 mg, preferably 10 mg, of the androgen receptor inhibitor HC-1119.
  • the present invention also provides the use of the aforementioned oral preparation for the preparation of a medicament for treating an androgen signaling pathway-dependent disease; preferably, the androgen signaling pathway-dependent disease is prostate cancer, breast cancer; preferably, Prostate cancer is castration-resistant prostate cancer.
  • the present invention also provides a method for treating an androgen signaling pathway-dependent disease, which is to give a patient the aforementioned HC-1119 preparation, the aforementioned soft capsule or the aforementioned oral preparation;
  • the androgen signaling pathway-dependent disease is prostate cancer, breast cancer; preferably, the prostate cancer is castration-resistant prostate cancer.
  • the invention also provides a method for administering the androgen receptor inhibitor HC-1119, which is 1 to 100 mg of the androgen receptor inhibitor HC-1119 per patient, once a day, or 1 day 2 Times, or once every 2 days, or once every 3 days, or once every 4 days, or once every 5 days, or once every 6 days, or once a week.
  • it is 80 mg of the androgen receptor inhibitor HC-1119 administered to the patient once a day, once a day.
  • it is 25 to 55 mg of the androgen receptor inhibitor HC-1119, preferably 40 mg, administered to the patient each time;
  • the androgen receptor inhibitor HC-1119 is 15 to 25 mg of the androgen receptor inhibitor HC-1119, preferably 20 mg, per patient;
  • the androgen receptor inhibitor HC-1119 is 5 to 15 mg of the androgen receptor inhibitor HC-1119, preferably 10 mg, per patient.
  • the androgen receptor inhibitor HC-1119 is administered by administering the aforementioned HC-1119 preparation, the aforementioned soft capsule.
  • the present invention also provides a method for treating an androgen signaling pathway-dependent disease, which is administered to a patient 1 to 100 mg of the androgen receptor inhibitor HC-1119 once a day, once a day.
  • it is 80 mg of the androgen receptor inhibitor HC-1119 administered to the patient once a day, once a day.
  • it is 25 to 55 mg of the androgen receptor inhibitor HC-1119, preferably 40 mg, administered to the patient each time;
  • the androgen receptor inhibitor HC-1119 is 15 to 25 mg of the androgen receptor inhibitor HC-1119, preferably 20 mg, per patient;
  • the androgen receptor inhibitor HC-1119 is 5 to 15 mg of the androgen receptor inhibitor HC-1119, preferably 10 mg, per patient.
  • the androgen receptor inhibitor HC-1119 is administered by administering the aforementioned HC-1119 preparation, the aforementioned soft capsule.
  • the androgen signaling pathway-dependent disease is prostate cancer or breast cancer; preferably, the prostate cancer is trend-resistant prostate cancer.
  • the HC-1119 preparation of the invention obviously dissolves the solubility of HC-1119 by dissolving the raw material of HC-1119 in polyethylene glycol glyceryl citrate, greatly improves the bioavailability and reduces the concentration of blood plasma. And the difference in exposure between individuals increases the safety of medication.
  • the HC-1119 soft capsule of the invention has good stability.
  • the raw materials and equipment used in the specific embodiments of the present invention are known products and are obtained by purchasing commercially available products.
  • CCMG polyethylene glycol glyceride caprylate
  • BHA butylated hydroxyanisole
  • BHT butylated hydroxytoluene
  • BHT and HC-1119 were crushed through a 100 mesh sieve
  • 1 pressure pellet transfer the contents into the hopper, continue to be filled with nitrogen to protect the pellet.
  • capsules with unqualified appearance should be selected at any time.
  • the thickness of the rubber should be controlled from 0.8mm to 1.10mm, and the filling amount of the capsule contents should be ⁇ 5% of the theoretical capacity.
  • the capsules are transferred to the drying room (temperature 20 ⁇ 25 ° C, humidity RH 28 ⁇ 35%) for secondary drying, sampled every 3h, until the capsule skin moisture is less than 5.0%, the content moisture is less than 5.0% Stop the pill.
  • the prescription of the raw materials of the present invention is shown in Table 2.
  • Rubber thickness adjustment glue, adjust the thickness of the rubber (1.00 ⁇ 1.10mm) and commissioning process parameters;
  • the capsule After the capsule is pressed, it is blown to the drum by cold air and shaped. Add oil-absorbing cotton for rubbing, wipe, and continue to dry, drying conditions: temperature 25.0 ⁇ 30.0 ° C, humidity ⁇ 25.0%, sampling and determination, until the capsule sac moisture is less than 5.0%, the content of water is less than 5.0%, stop dry.
  • Rubber thickness adjustment glue, adjust the thickness of the rubber (1.00 ⁇ 1.10mm) and commissioning process parameters;
  • the capsule After the capsule is pressed, it is blown to the drum by cold air and shaped. Add oil-absorbing cotton for rubbing, wipe, and continue to dry, drying conditions: temperature 25.0 ⁇ 30.0 ° C, humidity ⁇ 25.0%, sampling and determination, until the capsule sac moisture is less than 5.0%, the content of water is less than 5.0%, stop dry.
  • Rubber thickness adjustment glue, adjust the thickness of the rubber (1.00 ⁇ 1.10mm) and commissioning process parameters;
  • the capsule After the capsule is pressed, it is blown to the drum by cold air and shaped. Add oil-absorbing cotton for rubbing, wipe, and continue to dry, drying conditions: temperature 25.0 ⁇ 30.0 ° C, humidity ⁇ 25.0%, sampling and determination, until the capsule sac moisture is less than 5.0%, the content of water is less than 5.0%, stop dry.
  • Stability test protocol The stability test of the soft capsules produced in Example 2 was carried out, and the stability investigations of accelerated June and long-term December were respectively carried out. Three conditions were examined, namely accelerated test (40 °C ⁇ 2 °C, relative humidity (RH) 75% ⁇ 5%); intermediate condition test (30 °C ⁇ 2 °C, RH 65% ⁇ 5%) and long-term test ( 25 ° C ⁇ 2 ° C, RH 60% ⁇ 5%).
  • the package is made of aluminum-plastic blister pack and external medium-sealed bag. The properties, acid value, peroxide value, related substances, dissolution, antioxidant amount, moisture, microbial limit and content of the soft capsule were examined at each time point.
  • the detection method is visual, the standard is white-like oval capsule, the content is light yellow oily liquid, no precipitation.
  • Amount of antioxidant Take the contents of this product and test it according to high performance liquid chromatography (Chinese Pharmacopoeia 2015 edition general rule 0512).
  • Dissolution Take this product, according to the dissolution method (General Rule 0931, second method), with 900% of hydrochloric acid solution containing 0.2% sodium lauryl sulfate as the dissolution medium, the rotation speed is 50 rpm, according to the law, after 30 At the minute, take the appropriate amount of the solution and test it.
  • Peroxide value Take the content of this product and measure it according to the method of measuring the peroxide value under the method of fat and fatty oil determination (General Rule 0713).
  • Acid value Take the content of this product and determine the acid value according to the method of determination of fat and fatty oil (General Rule 0713).
  • Moisture Take the contents of this product and measure according to the moisture measurement method (Chinese Pharmacopoeia 2015 General Regulation 0832 First Law 1).
  • Microbiological Limits Take this product and test it against microbiological limit inspections for non-sterile products (General Rules 1105, 1106 and 1107).
  • Chromatographic conditions and system suitability test using octadecylsilane bonded silica as a filler; pH 3.0 aqueous phosphoric acid-methanol-acetonitrile as mobile phase, determined by liquid chromatography.
  • Stability test condition 1 (accelerated test): The package was a commercially available package, and the inspection conditions were 40 ° C ⁇ 2 ° C, and RH was 75% ⁇ 5%. The results of the accelerated test are shown in Table 5.
  • Stability test condition 2 (intermediate condition test): The package is a commercially available package, and the inspection conditions are 30 ° C ⁇ 2 ° C, RH 65% ⁇ 5%. The intermediate condition test results are shown in Table 6.
  • Stability test condition 3 Long-term test: The package is a commercially available package, and the inspection conditions are 25 ° C ⁇ 2 ° C, RH 60% ⁇ 5%. Long-term test results are shown in Table 7.
  • the HC-1119 soft capsule prepared in Example 2 was taken.
  • Subjects were given a single empty stomach on the first day of the test, 0 to 0.5 h before taking the drug and 0.5 h, 0.75 h, 1 h, 2 h ( ⁇ 5 min), 4 h, 8 h, 12 h ( ⁇ 15 min), 24 h ( ⁇ 30 min) after taking the drug.
  • On the 2nd day before administration each blood sample was collected, and 3 mL of venous blood was collected at each time point, and placed in an anticoagulation tube (the type of anticoagulant was determined according to the established analytical test method).
  • the sample should be centrifuged as soon as possible (approximately 3000 rpm, 10 minutes) to separate the plasma. Separated plasma samples are stored in duplicate in a plasma cryotube, labeling the subject's enrollment number, the subject's initials, and the date and time of collection. Plasma samples should be stored in the -60 ° C ⁇ -80 ° C refrigerator as soon as possible. One blood sample will be kept in the research center, and one blood sample will be transported to a professional testing company for plasma drug concentration determination.
  • Table 8 is the clinical pharmacokinetic data of the 80 mg dose of the HC-1119 soft capsule of the present invention.
  • Table 9 shows the clinical pharmacokinetic data of the FDA-released enzalutamide 160 mg dose.
  • HC-1119 is a deuterated enzalutamide, and the in vitro biological activity of both is the same.
  • HC-1119 soft capsules showed that in the case of halving the dose, the dose of HC-1119 80 mg could reach the parent drug exposure and blood concentration of not less than 160 mg of enzalutamide.
  • steady state Ctrough 18.9 [mu]g/mL on day 84
  • steady state Cmin 12 [mu]g/mL over enzalutamide (160 mg dose).
  • HC-1119 soft capsules reduce the fluctuation of the pharmacokinetics of the drug between subjects.
  • the degree of fluctuation of the data is expressed by a coefficient of variation (CV).
  • CV coefficient of variation
  • the low CV means that the pharmacokinetics of HC-1119 soft capsules is less fluctuating between different patients, which can reduce the risk and safety risks caused by individual differences in patients.
  • HC-1119 soft capsules further enhance drug safety.
  • the HC-1119 preparation of the present invention by dissolving the raw material of HC-1119 in a soft capsule preparation made of polyglycolic acid decanoic acid glyceride, significantly improves the solubility of HC-1119 and greatly improves the bioavailability. Degree, the difference between the blood drug concentration and exposure in the individual is reduced, and the safety of medication is improved.
  • the HC-1119 soft capsule of the present invention has good stability.

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Abstract

一种雄激素受体抑制剂HC-1119制剂，它由下述重量配比的原辅料制备而成：雄激素受体抑制剂HC-1119 1～100份、溶剂100～1000份、抗氧剂0.11～11份。还提供了一种HC-1119软胶囊以及HC-1119制剂，通过将HC-1119原料溶于辛酸癸酸聚乙二醇甘油酯，明显改善了HC-1119的溶解性，大大提高了生物利用度，减小了血药谷浓度和暴露量在个体间的差异，提高了用药安全性，HC-1119软胶囊稳定性好。

Description

一种HC-1119制剂及其制备方法和用途 技术领域
本发明具体涉及雄激素受体抑制剂HC-1119制剂及其制备方法和用途。
背景技术
HC-1119为雄激素受体(Androgen Receptor，AR)抑制剂，它可竞争性抑制雄激素与AR的结合，阻断AR信号通路的传递，适应症为雄激素信号通路依赖性的疾病，包括但不局限于前列腺癌，乳腺癌。其化学名为：4-{3-[4-氰基-3-(三氟甲基)苯基]-5,5-二甲基-4-氧代-2-硫代-1-咪唑烷基}-2-氟-N-三氘代甲基苯酰胺，结构如式Ⅰ所示：
Figure PCTCN2019086694-appb-000001
申请号：201280052853.9，发明名称：咪唑二酮类化合物及其用途，该专利申请即公开了化合物HC-1119。
HC-1119理化性质研究结果表明，HC-1119难溶于水，体外实验结果显示，采用Caco-2细胞模型评价HC-1119的渗透性，结果提示HC-1119具有高渗透性的特征(10μM HC-1119表观渗透系数为11.4～13.6×10 -6cm/s)，因此HC-1119为难溶性，高渗透性药物，属于BSC分类第2类，提高药物的生物利用度是药物开发的关键。
发明内容
为解决上述问题，本发明提供了一种HC-1119制剂及含有该制剂的HC-1119软胶囊。
本发明的HC-1119制剂，由下述重量配比的原辅料制备而成：
雄激素受体抑制剂HC-1119 1～100份、溶剂100～1000份、抗氧剂0.11～11份。
其中，所述溶剂为辛酸癸酸聚乙二醇甘油酯、大豆油、甘油、聚乙二醇、聚乙二醇甘油酯和辛酸癸酸甘油酯中的一种或几种的组合物；
优选地，所述聚乙二醇甘油酯选自聚乙二醇甘油单酯、聚乙二醇甘油三酯中一种或两种；所述辛酸癸酸甘油酯选自辛酸癸酸甘油三酯；
优选地，所述溶剂为辛酸癸酸聚乙二醇甘油酯。
其中，所述抗氧剂为丁羟基茴香醚、丁羟基甲苯、芳香胺抗氧剂中的一种或几种的组合物；
优选地，所述抗氧剂为丁羟基茴香醚和丁羟基甲苯的组合物；其中，丁羟基茴香醚0.1～10份，丁羟基甲苯0.01～1份。
进一步地，上述HC-1119制剂由下述重量配比的原辅料制备而成：
雄激素受体抑制剂HC-1119 5～55份、辛酸癸酸聚乙二醇甘油酯460～980份、丁羟基茴香醚0.25～1.5份、丁羟基甲苯0.025～0.15份。
进一步地，上述HC-1119制剂由下述重量配比的原辅料制备而成：
雄激素受体抑制剂HC-1119 25～55份、辛酸癸酸聚乙二醇甘油酯920～980份、丁羟基茴香醚0.5～1.5份、丁羟基甲苯0.05～0.15份；
或者，雄激素受体抑制剂HC-1119 15～25份、辛酸癸酸聚乙二醇甘油酯460～500份、丁羟基茴香醚0.25～0.75份、丁羟基甲苯0.025～0.075份；
或者，雄激素受体抑制剂HC-1119 5～15份、辛酸癸酸聚乙二醇甘油酯460～500份、丁羟基茴香醚0.25～0.75份、丁羟基甲苯0.025～0.075份。
进一步地，上述HC-1119制剂由下述重量配比的原辅料制备而成：
雄激素受体抑制剂HC-1119 40份、辛酸癸酸聚乙二醇甘油酯958.9份、丁羟基茴香醚1份、丁羟基甲苯0.1份；
或者，雄激素受体抑制剂HC-1119 20份、辛酸癸酸聚乙二醇甘油酯479.5份、丁羟基茴香醚0.5份、丁羟基甲苯0.05份；
或者，雄激素受体抑制剂HC-1119 10份、辛酸癸酸聚乙二醇甘油酯479.5份、丁羟基茴香醚0.5份、丁羟基甲苯0.05份；
或者，雄激素受体抑制剂HC-1119 12份、辛酸癸酸聚乙二醇甘油酯271.5份、丁羟基茴香醚0.03份、丁羟基甲苯0.03份。
进一步地，一粒制剂是由下述重量的原料加辅料制备而成：
雄激素受体抑制剂HC-1119 1～100mg，优选80mg；
或者，雄激素受体抑制剂HC-1119 25～55mg，优选为40mg；
或者，雄激素受体抑制剂HC-1119 15～25mg，优选为20mg；
或者，雄激素受体抑制剂HC-1119 5～15mg，优选为10mg。
其中，所述制剂为片剂，液体制剂、软胶囊；优选地，所述制剂为软胶囊。
本发明还提供了一种雄激素受体抑制剂HC-1119软胶囊，它由前述的制剂和胶囊壳组成；
所述胶囊壳由下述重量配比的辅料组成：明胶100份，甘油20～60份，山梨醇溶液20～60份或山梨醇10～50份，二氧化钛0.5～2份，纯化水50～100份。
本发明还提供了前述的制剂的制备方法，它包括如下步骤：
(1)HC-1119原料药粉碎至粒径1-150μm，备用；
(2)氮气保护下，将上述重量配比的HC-1119原料药、辛酸癸酸聚乙二醇甘油酯、丁羟基茴香醚和丁羟基甲苯混合，40～60℃，搅拌至HC-1119原料药完全溶解，再抽真空用氮气置换，即得。
其中，步骤(2)所述溶解温度为45℃±3℃。
本发明还提供了前述HC-1119软胶囊的制备方法，它包括如下步骤：
1)胶囊壳制备：
a化胶罐升温至70℃，加入上述重量配比的的水、甘油、山梨醇溶液，搅拌20分钟；
b取部分上述溶液，加入上述重量配比的的二氧化钛，用高速剪切机进行分散；将分散均匀的溶液加入化胶罐；
c加入上述重量配比的明胶，分散至粘稠状；
d密闭化胶罐，真空脱气，维持真空度-0.06～-0.1Mpa下搅拌1小时，温度50～60℃、非真空状态下保温过夜；
2)软胶囊制备：
A氮气保护下，控制胶皮厚度0.8mm-1.10mm、胶囊内容物填充量为理论装量的±5％，压制胶囊；
B胶囊压制完成后，由冷风吹送至滚筒，定型，加入吸油棉进行擦丸，于温度25.0～30.0℃，湿度≦25.0％下干燥至内容物水分低于5.0％，即得。
本发明还提供了前述的HC-1119制剂在制备治疗雄激素信号通路依赖性的疾病的药物中的用途；优选地，所述雄激素信号通路依赖性的疾病为前列腺癌、乳腺癌；优选地，所述前列腺癌为去势抵抗性前列腺癌。
本发明还提供了前述的软胶囊在制备治疗雄激素信号通路依赖性的疾病的药物中的用途；优选地，所述雄激素信号通路依赖性的疾病为前列腺癌、乳腺癌；优选地，所述前列腺癌为去势抵抗性前列腺癌。
本发明还提供了一种雄激素受体抑制剂HC-1119的口服制剂，它是由有效剂量的HC-1119为活性成分，加上药学上可接受的辅料制备而成的口服制剂，每制剂单位含有雄激素受体抑制剂HC-11191～100mg。
所述的制剂单位是指片剂的每片、胶囊剂的每粒胶囊、颗粒剂的每袋等药学常规制剂的剂型单位。
优选地，每制剂单位含有雄激素受体抑制剂HC-1119 80mg。
优选地，每制剂单位含有雄激素受体抑制剂HC-1119 25～55mg，优选为40mg；
或者，每制剂单位含有雄激素受体抑制剂HC-1119 15～25mg，优选为20mg；
或者，每制剂单位含有雄激素受体抑制剂HC-1119 5～15mg，优选为10mg。
本发明还提供了前述的口服制剂在制备治疗雄激素信号通路依赖性的疾病的药物中的用途；优选地，所述雄激素信号通路依赖性的疾病为前列腺癌、乳腺癌；优选地，所述前列腺癌为去势抵抗性前列腺癌。
本发明还提供了一种治疗雄激素信号通路依赖性的疾病的方法，它是给予患者前述的HC-1119制剂、前述的软胶囊或者前述的口服制剂；
优选地，所述雄激素信号通路依赖性的疾病为前列腺癌、乳腺癌；优选地，所述前列腺癌为去势抵抗性前列腺癌。
本发明还提供了一种雄激素受体抑制剂HC-1119的给药方法，它是每次给予患者1～100mg的雄激素受体抑制剂HC-1119，1天1次，或者1天2次，或者2天1次，或者3天1次，或者4天1 次，或者5天1次，或者6天1次，或者1周1次。
优选地，它是每次给予患者80mg的雄激素受体抑制剂HC-1119，1天1次。
优选地，它是每次给予患者25～55mg的雄激素受体抑制剂HC-1119，优选为40mg；
或者，它是每次给予患者15～25mg的雄激素受体抑制剂HC-1119，优选为20mg；
或者，它是每次给予患者5～15mg的雄激素受体抑制剂HC-1119，优选为10mg。
优选地，所述雄激素受体抑制剂HC-1119是通过给予前述的HC-1119制剂、前述的软胶囊的方式给予。
本发明还提供了一种治疗雄激素信号通路依赖性的疾病的方法，它是每次给予患者1～100mg的雄激素受体抑制剂HC-1119，1天1次。
优选地，它是每次给予患者80mg的雄激素受体抑制剂HC-1119，1天1次。
优选地，它是每次给予患者25～55mg的雄激素受体抑制剂HC-1119，优选为40mg；
或者，它是每次给予患者15～25mg的雄激素受体抑制剂HC-1119，优选为20mg；
或者，它是每次给予患者5～15mg的雄激素受体抑制剂HC-1119，优选为10mg。
优选地，所述雄激素受体抑制剂HC-1119是通过给予前述的HC-1119制剂、前述的软胶囊的方式给予。
其中，所述雄激素信号通路依赖性的疾病为前列腺癌、乳腺癌；优选地，所述前列腺癌为趋势抵抗性前列腺癌。
本发明中，山梨醇溶液购买于SPI Pharma New Castle，型号为Sorbitol Special TM。
本发明的HC-1119制剂，通过将HC-1119原料溶于辛酸癸酸聚乙二醇甘油酯，明显改善了HC-1119的溶解性，大大提高了生物利用度，减小了血药谷浓度和暴露量在个体间的差异，提高了用药安全性。本发明的HC-1119软胶囊，稳定性好。
在临床药代动力学实验中，软胶囊制剂显示在减半剂量的情况下能够达到原研药恩杂鲁胺的暴露量，减小了血药谷浓度(Ctrough)和暴露量(AUC)在个体间的差异，提高了安全性。
显然，根据本发明的上述内容，按照本领域的普通技术知识和惯用手段，在不脱离本发明上述基本技术思想前提下，还可以做出其它多种形式的修改、替换或变更。
以下通过实施例形式的具体实施方式，对本发明的上述内容再作进一步的详细说明。但不应将此理解为本发明上述主题的范围仅限于以下的实例。凡基于本发明上述内容所实现的技术均属于本发明的范围。
具体实施方式
本发明具体实施方式中使用的原料、设备均为已知产品，通过购买市售产品获得。
其中，山梨醇溶液购买于SPI Pharma New Castle，型号为Sorbitol Special TM。
本发明中出现的缩写：CCMG(辛酸癸酸聚乙二醇甘油酯)、BHA(丁羟基茴香醚)、BHT(丁羟基甲苯)。
实施例1、本发明HC-1119软胶囊制备
1、原辅料处方
本发明原辅料处方如表1所示。
表1本发明原辅料处方
Figure PCTCN2019086694-appb-000002
2、制备方法
1)胶囊壳制备
①按处方量称取山梨醇、甘油、明胶、二氧化钛；
②开启化胶罐，65～70℃保温；
③取约70％处方量的纯化水，加入处方量的山梨醇，搅拌至溶解完全；
④将上述山梨醇溶液转移至化胶罐，开启搅拌，并加热至70℃；
⑤停止搅拌，将处方量的甘油转移至化胶罐，并取剩余30％处方量的纯化水逐步将残留的甘油溶解并转移至化胶罐后，续搅拌至溶解完全，加热至70℃后，保温10min；
⑥停止搅拌，取部分上述溶液，加入处方量二氧化钛，用高剪切机进行分散，将分散均匀的溶液加入化胶罐；
⑦缓慢将处方量明胶加入化胶罐，开启搅拌，待溶解至均匀粘稠状；
⑧密闭化胶罐，开启真空脱气，维持真空度-0.06～-0.1Mpa下搅拌1小时后停止搅拌，停止真空并于60℃保温过夜，备用。
2)内容物制备
①预处理：BHT和HC-1119粉碎过100目筛；
②按处方量称取HC-1119、CCMG、HBA和BHT；
③开启配液罐，45℃±3℃保温，依次将处方量的BHT、BHA、HC-1119投入到配液罐中，缓慢加入处方量CCMG，密闭配液罐，通入氮气保护，启动搅拌，至溶液澄清透明，停止搅拌及加热，冷却至室温，备用。
3)软胶囊制备
①压丸：将内容物转移至加料斗内，持续充氮气保护，开始压丸。充填过程中，应随时挑选出外观不合格的胶囊，同时应控制胶皮厚度0.8mm-1.10mm、胶囊内容物填充量为理论装量的±5％。
②胶囊压制完成后，由冷风吹送至滚筒，定型。加入吸油棉进行擦丸；
③取样测定：内容物水分和胶皮水分至约8.0％时停止一次干燥工序；
④晾丸：胶囊转入干燥间(温度20～25℃，湿度RH28～35％)进行二次干燥，每3h取样测定一次，直至胶囊囊皮水分低于5.0％，内容物水分低于5.0％，停止晾丸。
实施例2、本发明HC-1119软胶囊制备
1、原辅料处方
本发明原辅料处方如表2所示。
表2本发明原辅料处方
Figure PCTCN2019086694-appb-000003
2制备方法
1)胶囊壳制备
①按处方量称取山梨醇溶液、甘油、明胶、二氧化钛；
②开启化胶罐，设定加热温度70℃，将处方量的纯化水、山梨醇溶液、甘油加入化胶罐中，搅拌20分钟，使混合均匀；
③取部分上述溶液，加入处方量二氧化钛，用高剪切机进行分散，将分散均匀的溶液加入化胶罐；
④缓慢将处方量明胶加入化胶罐，开启搅拌，待溶解至均匀粘稠状；
⑤密闭化胶罐，开启真空脱气，维持真空度-0.06～-0.1MPa下搅拌1小时后停止搅拌，停止真空并于60℃保温过夜，备用。
2)内容物制备
①预处理：HC-1119微粉化处理，D90<20μm；
②按处方量称取HC-1119、CCMG、BHA、BHT；
③以下操作全程充氮保护，开启配液罐，加入处方量的CCMG(抽真空，氮气置换)升温至45℃±3℃保温，加入处方量的BHA和BHT搅拌溶解；
④将HC-1119投入到配液罐中，启动搅拌至溶液澄清透明，停止搅拌及加热，冷却至室温，200目筛网过滤，备用。
3)软胶囊制备
①胶皮厚度调节：出胶，调节胶皮厚度(1.00～1.10mm)及调试工艺参数；
②清洗管路：用CCMG进行调试，同时进行工艺参数及装量初步调节；
③试压丸：待工艺参数稳定后，加入内容物至进料斗清洗管路，调节装量；
④压丸：将内容物转移至加料斗内，持续充氮气保护，开始压丸。充填过程中，应随时挑选出外观不合格的胶囊，同时监控装量差异和胶皮厚度，均应控制在±5％，发现异常及时调整。
⑤胶囊压制完成后，由冷风吹送至滚筒，定型。加入吸油棉进行擦丸，擦净后，继续干燥，干燥条件：温度25.0～30.0℃，湿度≦25.0％，取样测定，直至胶囊囊皮水分低于5.0％，内容物水分低于5.0％，停止干燥。
实施例3、本发明HC-1119软胶囊制备
本发明原辅料处方如表3所示。
表3本发明原辅料处方
Figure PCTCN2019086694-appb-000004
Figure PCTCN2019086694-appb-000005
2制备方法
1)胶囊壳制备
①按处方量称取山梨醇溶液、甘油、明胶、二氧化钛；
②开启化胶桶，设定加热温度70℃，将处方量的纯化水、山梨醇溶液、甘油加入化胶罐中，搅拌20分钟，使混合均匀；
③取部分上述溶液，加入处方量二氧化钛，用高剪切机进行分散，将分散均匀的溶液加入化胶罐；；
④缓慢将处方量明胶加入化胶罐，开启搅拌，待溶解至均匀粘稠状；
⑤密闭化胶罐，开启真空脱气，维持真空度-0.06～-0.1MPa下搅拌1小时后停止搅拌，停止真空并于60℃保温过夜。
2)内容物制备
①预处理：HC-1119微粉化处理，D90<20μm；
②按处方量称取HC-1119、CCMG、BHA、BHT；
③以下操作全程充氮保护，开启配液罐，加入处方量的CCMG(抽真空，氮气置换)升温至45℃±3℃保温，加入处方量的BHA和BHT搅拌溶解；
④将HC-1119投入到配液罐中，启动搅拌至溶液澄清透明，停止搅拌及加热，冷却至室温，200目筛网过滤，备用。
3)软胶囊制备
①胶皮厚度调节：出胶，调节胶皮厚度(1.00～1.10mm)及调试工艺参数；
②清洗管路：用CCMG进行调试，同时进行工艺参数及装量初步调节；
③试压丸：待工艺参数稳定后，加入内容物至进料斗清洗管路，调节装量；
④压丸：将内容物转移至加料斗内，持续充氮气保护，开始压丸。充填过程中，应随时挑选出外观不合格的胶囊，同时监控装量差异和胶皮厚度，均应控制在±5％，发现异常及时调整。
⑤胶囊压制完成后，由冷风吹送至滚筒，定型。加入吸油棉进行擦丸，擦净后，继续干燥，干燥条件：温度25.0～30.0℃，湿度≦25.0％，取样测定，直至胶囊囊皮水分低于5.0％，内容物水分低于5.0％，停止干燥。
实施例4、本发明HC-1119软胶囊制备
本发明原辅料处方如表4所示。
表4本发明原辅料处方
Figure PCTCN2019086694-appb-000006
Figure PCTCN2019086694-appb-000007
2制备方法
1)胶囊壳制备
①按处方量称取山梨醇溶液、甘油、明胶、二氧化钛；
②开启化胶桶，设定加热温度70℃，将处方量的纯化水、山梨醇溶液、甘油加入化胶罐中，搅拌20分钟，使混合均匀；
③取部分上述溶液，加入处方量二氧化钛，用高剪切机进行分散，将分散均匀的溶液加入化胶罐；；
④缓慢将处方量明胶加入化胶罐，开启搅拌，待溶解至均匀粘稠状；
⑤密闭化胶罐，开启真空脱气，维持真空度-0.06～-0.1MPa下搅拌1小时后停止搅拌，停止真空并于60℃保温过夜。
2)内容物制备
①预处理：HC-1119微粉化处理，D90<20μm；
②按处方量称取HC-1119、CCMG、BHA、BHT；
③以下操作全程充氮保护，开启配液罐，加入处方量的CCMG(抽真空，氮气置换)升温至45℃±3℃保温，加入处方量的BHA和BHT搅拌溶解；
④将HC-1119投入到配液罐中，启动搅拌至溶液澄清透明，停止搅拌及加热，冷却至室温，200目筛网过滤，备用。
3)软胶囊制备
①胶皮厚度调节：出胶，调节胶皮厚度(1.00～1.10mm)及调试工艺参数；
②清洗管路：用CCMG进行调试，同时进行工艺参数及装量初步调节；
③试压丸：待工艺参数稳定后，加入内容物至进料斗清洗管路，调节装量；
④压丸：将内容物转移至加料斗内，持续充氮气保护，开始压丸。充填过程中，应随时挑选出外观不合格的胶囊，同时监控装量差异和胶皮厚度，均应控制在±5％，发现异常及时调整。
⑤胶囊压制完成后，由冷风吹送至滚筒，定型。加入吸油棉进行擦丸，擦净后，继续干燥，干燥条件：温度25.0～30.0℃，湿度≦25.0％，取样测定，直至胶囊囊皮水分低于5.0％，内容物水分低于5.0％，停止干燥。
以下通过实验例来说明本发明的有益效果：
实验例1、本发明HC-1119软胶囊稳定性试验
1、实验方法
稳定性试验方案：对实施例2生产的软胶囊进行稳定性试验，分别进行加速6月和长期12月的稳定性考察。考察了3个条件，分别为加速试验(40℃±2℃，相对湿度(RH)75％±5％)；中间条件试验(30℃±2℃，RH 65％±5％)和长期试验(25℃±2℃，RH 60％±5％)。包装为铝塑泡罩包装，外置中封袋。在各个时间点分别对软胶囊的性状、酸值、过氧化值、有关物质、溶出度、抗氧化剂量、水分、微生物限度和含量进行了考察。
性状：检测方法为目视，标准为本品为类白色椭圆形胶囊，内容物为淡黄色油状液体，无沉淀。
有关物质：取本品内容物，照高效液相色谱法(中国药典2015版通则0512)试验检测。
抗氧化剂量：取本品内容物，照高效液相色谱法(中国药典2015版通则0512)试验检测。
溶出度：取本品，照溶出度测定法(通则0931第二法)，以含0.2％十二烷基硫酸钠的盐酸溶液900ml为溶出介质，转速为每分钟50转，依法操作，经30分钟时，取溶液适量，试验测定。
过氧化值：取本品内容物，照脂肪与脂肪油测定法(通则0713)项下过氧化值测定方法测定。
酸值：取本品内容物，照脂肪与脂肪油测定法(通则0713)项下酸值测定方法测定。
水分：取本品内容物，照水分测定法(中国药典2015版通则0832第一法1)测定。
微生物限度：取本品，照非无菌产品微生物限度检查(通则1105、1106和1107)进行测试。
含量测定：照高效液相色谱法(中国药典2015版通则0512)测定。
色谱条件与系统适用性试验：用十八烷基硅烷键合硅胶为填充剂；以pH 3.0磷酸水溶液-甲醇-乙腈为流动相，用液相色谱法测定。
2、实验结果：
(1)稳定性试验条件一(加速试验)：包装为市售包装，考察条件为40℃±2℃，RH 75％±5％。加速试验结果如表5所示。
表5本发明HC-1119软胶囊加速试验结果
Figure PCTCN2019086694-appb-000008
Figure PCTCN2019086694-appb-000009
(2)稳定性试验条件二(中间条件试验)：包装为市售包装，考察条件为30℃±2℃，RH 65％±5％。中间条件试验结果表6所示。
表6本发明HC-1119软胶囊中间条件试验结果
Figure PCTCN2019086694-appb-000010
(3)稳定性试验条件三(长期试验)：包装为市售包装，考察条件为25℃±2℃，RH 60％±5％。长期试验结果表7所示。
表7本发明HC-1119软胶囊长期试验结果
Figure PCTCN2019086694-appb-000011
Figure PCTCN2019086694-appb-000012
经加速6个月、中间条件12个月和长期12个月考察，HC-1119软胶囊在现有包装条件下，重点考察的各项质量指标目前均在质量标准制定的限度范围内，有关物质、含量、溶出度、性状与0月比较均未出现较大差异，产品稳定。
实验例2、本发明HC-1119软胶囊临床药代动力学试验
1、给药方式
取实施例2制备的HC-1119软胶囊。
(1)给药剂量：每天80mg(40mg软胶囊2枚)
(2)给药方法：连续给药，1日1次，首次给药空腹服用，其后不限制饮食。
2、实验方法
药代动力学研究中，共9例受试者参与此研究。
1)单次给药生物样本采集：
受试者于试验第1天单次空腹服药，服药前0～0.5h及服药后0.5h、0.75h、1h、2h(±5min)、4h、8h、12h(±15min)、24h(±30min，第2天给药前)，各进行一次血样采集，各时间点采集静脉血3mL，置抗凝管中(抗凝剂种类依据建立的分析测试方法确定)。
2)连续给药生物样本采集：
连续给药的第7、21、35、42、56、70、84天给药前0～0.5h，第84天给药后0.5h、0.75h、1h、2h(±5min)、4h、8h、12h(±15min)、24h(±30min，第85天给药前)。各时间点采集静脉血3mL，置抗凝管中(抗凝剂种类依据建立的分析测试方法确定)。
3)样本处理：
样本应尽快离心(约3000转/分，10分钟)，分离血浆。分离的血浆样品需一式两份保存于血浆冻存管中，标签标记受试者的入组号、受试者的姓名缩写、收集的时间日期。血浆样品应尽快保存于 -60℃～-80℃冰箱中。1份血样将被保留在研究中心，1份血样将被运输至专业的检测公司进行血浆药物浓度测定。
3、实验结果
表8为本发明HC-1119软胶囊80mg剂量的临床药代动力学数据。
表8本发明HC-1119软胶囊临床药代动力学参数(2x40mg规格软胶囊，QD 84天)
Figure PCTCN2019086694-appb-000013
表9为美国FDA公开的恩杂鲁胺160mg剂量的临床药代动力学数据
表9恩杂鲁胺临床药代动力学数据(160mg QD 49天)
Figure PCTCN2019086694-appb-000014
HC-1119是氘代的恩杂鲁胺，两者的体外生物活性是一样的。但是在临床药代动力学实验中HC-1119软胶囊显示在剂量减半的情况下，HC-1119 80mg剂量即可以达到不低于恩杂鲁胺160mg剂量的母药暴露量及血药浓度。对于HC-1119(80mg剂量)，第84天稳态Ctrough＝18.9μg/mL,高于恩杂鲁胺(160mg剂量)的稳态Cmin＝12μg/mL。对于HC-1119(80mg剂量)，第84天稳态AUC＝479.7h*μg/mL,高于恩杂鲁胺(160mg剂量)的稳态AUC＝321.5h*μg/mL.HC-1119软胶囊能够降低使用剂量，提高药物安全性和病人的服药依从性。
同时，HC-1119软胶囊减小了药物的药代动力学在实验对象间的波动。数据的波动程度用标准偏差系数CV(coefficient of variation)来表示的。对于HC-1119(80mg剂量)，第84天稳态Ctrough相应的CV＝14.5％,低于恩杂鲁胺(160mg剂量)的稳态Cmin相应的CV＝29.3％。对于HC-1119 (80mg剂量)，第84天稳态AUC相应的CV＝14％,低于恩杂鲁胺(160mg剂量)的稳态AUC相应的CV＝26.6％。低的CV意味着HC-1119软胶囊的药代动力学在不同病人间的波动小，能减小病人个体差异带来的疗效及安全性方面的风险。HC-1119软胶囊从而进一步地提高了药物安全性。
综上，本发明的HC-1119制剂，通过将HC-1119原料溶于辛酸癸酸聚乙二醇甘油酯制成的软胶囊制剂，明显改善了HC-1119的溶解性，大大提高了生物利用度，减小了血药谷浓度和暴露量在个体间的差异，提高了用药安全性。本发明的HC-1119软胶囊具有良好的稳定性。

Claims (28)

  1. 一种雄激素受体抑制剂HC-1119制剂，其特征在于：它由下述重量配比的原辅料制备而成：
    雄激素受体抑制剂HC-1119 1～100份、溶剂100～1000份、抗氧剂0.11～11份。
  2. 根据权利要求1所述的制剂，其特征在于：所述溶剂为辛酸癸酸聚乙二醇甘油酯、大豆油、甘油、聚乙二醇、聚乙二醇甘油酯和辛酸癸酸甘油酯中的一种或几种的组合物；
    优选地，所述聚乙二醇甘油酯选自聚乙二醇甘油单酯、聚乙二醇甘油三酯中一种或两种；所述辛酸癸酸甘油酯选自辛酸癸酸甘油三酯；
    优选地，所述溶剂为辛酸癸酸聚乙二醇甘油酯。
  3. 根据权利要求1所述的制剂，其特征在于：所述抗氧剂为丁羟基茴香醚、丁羟基甲苯、芳香胺抗氧剂中的一种或几种的组合物；
    优选地，所述抗氧剂为丁羟基茴香醚和丁羟基甲苯的组合物；其中，丁羟基茴香醚0.1～10份，丁羟基甲苯0.01～1份。
  4. 根据权利要求1所述的制剂，其特征在于：它由下述重量配比的原辅料制备而成：
    雄激素受体抑制剂HC-1119 5～55份、辛酸癸酸聚乙二醇甘油酯460～980份、丁羟基茴香醚0.25～1.5份、丁羟基甲苯0.025～0.15份。
  5. 根据权利要求4所述的制剂，其特征在于：它由下述重量配比的原辅料制备而成：
    雄激素受体抑制剂HC-1119 25～55份、辛酸癸酸聚乙二醇甘油酯920～980份、丁羟基茴香醚0.5～1.5份、丁羟基甲苯0.05～0.15份；
    或者，雄激素受体抑制剂HC-1119 15～25份、辛酸癸酸聚乙二醇甘油酯460～500份、丁羟基茴香醚0.25～0.75份、丁羟基甲苯0.025～0.075份；
    或者，雄激素受体抑制剂HC-1119 5～15份、辛酸癸酸聚乙二醇甘油酯460～500份、丁羟基茴香醚0.25～0.75份、丁羟基甲苯0.025～0.075份。
  6. 根据权利要求4或5所述的制剂，其特征在于：它是由下述重量配比的原辅料制备而成：
    雄激素受体抑制剂HC-1119 40份、辛酸癸酸聚乙二醇甘油酯958.9份、丁羟基茴香醚1份、丁羟基甲苯0.1份；
    或者，雄激素受体抑制剂HC-1119 20份、辛酸癸酸聚乙二醇甘油酯479.5份、丁羟基茴香醚0.5份、丁羟基甲苯0.05份；
    或者，雄激素受体抑制剂HC-1119 10份、辛酸癸酸聚乙二醇甘油酯479.5份、丁羟基茴香醚0.5份、丁羟基甲苯0.05份；
    或者，雄激素受体抑制剂HC-1119 12份、辛酸癸酸聚乙二醇甘油酯271.5份、丁羟基茴香醚0.03份、丁羟基甲苯0.03份。
  7. 根据权利要求6所述的制剂，其特征在于：一粒制剂是由下述重量的原料加辅料制备而成：
    雄激素受体抑制剂HC-1119 1～100mg，优选80mg；
    或者，雄激素受体抑制剂HC-1119 25～55mg，优选为40mg；
    或者，雄激素受体抑制剂HC-1119 15～25mg，优选为20mg；
    或者，雄激素受体抑制剂HC-1119 5～15mg，优选为10mg。
  8. 根据权利要求1～5或7任一项所述的制剂，其特征在于：所述制剂为片剂，液体制剂、软胶囊；优选地，所述制剂为软胶囊。
  9. 一种雄激素受体抑制剂HC-1119软胶囊，其特征在于：它由权利要求1～8任一项所述的制剂和胶囊壳组成；
    所述胶囊壳由下述重量配比的辅料组成：明胶100份，甘油20～60份，山梨醇溶液20～60份或山梨醇10～50份，二氧化钛0.5～2份，纯化水50～100份。
  10. 权利要求1～8任一项所述的制剂的制备方法，其特征在于：它包括如下步骤：
    (1)HC-1119原料药粉碎至粒径1-150μm，备用；
    (2)氮气保护下，将上述重量配比的HC-1119原料药、辛酸癸酸聚乙二醇甘油酯、丁羟基茴香醚和丁羟基甲苯混合，40～60℃，搅拌至HC-1119原料药完全溶解，再抽真空用氮气置换，即得。
  11. 根据权利要求10所述的制备方法，其特征在于：步骤(2)所述溶解温度为45℃±3℃。
  12. 权利要求9所述的软胶囊的制备方法，其特征在于：它包括如下步骤：
    1)胶囊壳制备：
    a化胶罐升温至70℃，加入上述重量配比的的水、甘油、山梨醇溶液，搅拌20分钟；
    b取部分上述溶液，加入上述重量配比的的二氧化钛，用高速剪切机进行分散；将分散均匀的溶液加入化胶罐；
    c加入上述重量配比的明胶，分散至粘稠状；
    d密闭化胶罐，真空脱气，维持真空度-0.06～-0.1Mpa下搅拌1小时，温度50～60℃、非真空状态下保温过夜；
    2)软胶囊制备：
    A氮气保护下，控制胶皮厚度0.8mm-1.10mm、胶囊内容物填充量为理论装量的±5％，压制胶囊；
    B胶囊压制完成后，由冷风吹送至滚筒，定型，加入吸油棉进行擦丸，于温度25.0～30.0℃，湿度≦25.0％下干燥至内容物水分低于5.0％，即得。
  13. 权利要求1～8任一项所述的制剂在制备治疗雄激素信号通路依赖性的疾病的药物中的用途；优选地，所述雄激素信号通路依赖性的疾病为前列腺癌、乳腺癌；优选地，所述前列腺癌为去势抵抗性前列腺癌。
  14. 权利要求9所述的软胶囊在制备治疗雄激素信号通路依赖性的疾病的药物中的用途；优选地，所述雄激素信号通路依赖性的疾病为前列腺癌、乳腺癌；优选地，所述前列腺癌为去势抵抗性前列腺癌。
  15. 一种雄激素受体抑制剂HC-1119的口服制剂，其特征在于：它是由有效剂量的HC-1119为活性成分，加上药学上可接受的辅料制备而成的口服制剂，每制剂单位含有雄激素受体抑制剂HC-1119 1～100mg。
  16. 根据权利要求15所述的口服制剂，其特征在于：每制剂单位含有雄激素受体抑制剂HC-1119 80mg。
  17. 根据权利要求15所述的口服制剂，其特征在于：每制剂单位含有雄激素受体抑制剂HC-1119 25～55mg，优选为40mg；
    或者，每制剂单位含有雄激素受体抑制剂HC-1119 15～25mg，优选为20mg；
    或者，每制剂单位含有雄激素受体抑制剂HC-1119 5～15mg，优选为10mg。
  18. 权利要求15～17任一项所述的口服制剂在制备治疗雄激素信号通路依赖性的疾病的药物中的用途；优选地，所述雄激素信号通路依赖性的疾病为前列腺癌、乳腺癌；优选地，所述前列腺癌为去势抵抗性前列腺癌。
  19. 一种治疗雄激素信号通路依赖性的疾病的方法，其特征在于：它是给予患者权利要求1～8任一项所述的制剂、权利要求9所述的软胶囊或者权利要求15～17任一项所述的口服制剂；
    优选地，所述雄激素信号通路依赖性的疾病为前列腺癌、乳腺癌；优选地，所述前列腺癌为去势抵抗性前列腺癌。
  20. 一种雄激素受体抑制剂HC-1119的给药方法，其特征在于：它是每次给予患者1～100mg的雄激素受体抑制剂HC-1119，1天1次，或者1天2次，或者2天1次，或者3天1次，或者4天1次，或者5天1次，或者6天1次，或者1周1次。
  21. 根据权利要求20所述的给药方法，其特征在于：它是每次给予患者80mg的雄激素受体抑制剂HC-1119，1天1次。
  22. 根据权利要求20所述的给药方法，其特征在于：它是每次给予患者25～55mg的雄激素受体抑制剂HC-1119，优选为40mg；
    或者，它是每次给予患者15～25mg的雄激素受体抑制剂HC-1119，优选为20mg；
    或者，它是每次给予患者5～15mg的雄激素受体抑制剂HC-1119，优选为10mg。
  23. 根据权利要求20～22所述的给药方法，其特征在于：所述雄激素受体抑制剂HC-1119是通过给予权利要求1～8任一项所述的制剂、权利要求9所述的软胶囊的方式给予。
  24. 一种治疗雄激素信号通路依赖性的疾病的方法，其特征在于：它是每次给予患者1～100mg的雄激素受体抑制剂HC-1119，1天1次。
  25. 根据权利要求24所述的方法，其特征在于：它是每次给予患者80mg的雄激素受体抑制剂HC-1119，1天1次。
  26. 根据权利要求24所述的方法，其特征在于：它是每次给予患者25～55mg的雄激素受体抑制剂HC-1119，优选为40mg；
    或者，它是每次给予患者15～25mg的雄激素受体抑制剂HC-1119，优选为20mg；
    或者，它是每次给予患者5～15mg的雄激素受体抑制剂HC-1119，优选为10mg。
  27. 根据权利要求24～26所述的方法，其特征在于：所述雄激素受体抑制剂HC-1119是通过给予权利要求1～8任一项所述的制剂、权利要求9所述的软胶囊的方式给予。
  28. 根据权利要求24～27所述的方法，其特征在于：所述雄激素信号通路依赖性的疾病为前列腺 癌、乳腺癌；优选地，所述前列腺癌为趋势抵抗性前列腺癌。
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