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TW202237138A - Fulvestrant Pharmaceutical Composition, Preparation method and Use thereof - Google Patents

Fulvestrant Pharmaceutical Composition, Preparation method and Use thereof Download PDF

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TW202237138A
TW202237138A TW110146450A TW110146450A TW202237138A TW 202237138 A TW202237138 A TW 202237138A TW 110146450 A TW110146450 A TW 110146450A TW 110146450 A TW110146450 A TW 110146450A TW 202237138 A TW202237138 A TW 202237138A
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fulvestrant
pharmaceutical composition
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particle size
solid particles
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TWI905338B (en
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陳志祥
孫寶
王婷婷
應述歡
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大陸商上海博志研新藥物技術有限公司
大陸商上海博志研新藥物研究有限公司
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Abstract

The present disclosure provides a fulvestrant pharmaceutical composition, preparation method and use thereof. The fulvestrant pharmaceutical composition comprises fulvestrant solid particles with a particle size of Dv(10) less than or equal to 600 nm, DV(50) less than or equal to 700 nm and DV(90) less than or equal to 1000 nm. The present fulvestrant pharmaceutical composition has an appropriate release rate and can reach peak concentration and maintain a high blood concentration after administration. It also has a high drug content with no organic solvent or oil, and thus low irritability. The present fulvestrant pharmaceutical composition can be easily administrated with a reduced administration volume, thereby greatly reducing injection pain, and thus has a good market prospect.

Description

氟維司群藥物組合物、其製備方法及應用Fulvestrant pharmaceutical composition, its preparation method and application

本發明涉及氟維司群藥物組合物、其製備方法及應用，屬於藥物製劑技術領域。The invention relates to a fulvestrant pharmaceutical composition, a preparation method and application thereof, and belongs to the technical field of pharmaceutical preparations.

氟維司群(Fulvestrant)是一種選擇性雌激素受體降解劑(SERD)，用於抗雌激素療法後疾病進展的停經後婦女的激素受體陽性轉移性乳癌的治療。2002年經美國FDA批准可用於治療激素受體陽性轉移性乳腺癌。Fulvestrant is a selective estrogen receptor degrader (SERD) indicated for the treatment of hormone receptor-positive metastatic breast cancer in postmenopausal women whose disease has progressed after anti-estrogen therapy. In 2002, it was approved by the US FDA for the treatment of hormone receptor positive metastatic breast cancer.

氟維司群化學名7-(9-(4,4,5,5,5-五氟戊基亞磺醯基)壬基)雌-1 ,3 ,5(10)-三烯-3 ,17-二醇，其結構如式I所示：

Figure 02_image001
I Fulvestrant chemical name 7-(9-(4,4,5,5,5-pentafluoropentylsulfinyl)nonyl)estra-1,3,5(10)-triene-3, 17-diol, its structure is shown in formula I:
Figure 02_image001
I

氟維司群是一種親脂分子，水溶性極低。由於氟維司群溶解性差和口服生物利用度低，所以目前普遍通過肌肉內注射油基氟維司群製劑來施用。目前，氟維司群的市售製劑FASLODEX TM以500mg給予，並且需要肌肉內施用兩次50mg/mL氟維司群製劑的5mL注射液。每個5mL注射液含有10w/v％乙醇、10w/v％苯甲醇和15w/v％苯甲酸苯甲酯作為共溶劑，並用蓖麻油作為另一種共溶劑和釋放速率調節劑補充至100w/v％。由於使用黏性油基載體來溶解氟維司群，所以施用該製劑緩慢(每次注射1-2分鐘)並且疼痛。並且，FASLODEX TM標籤上增加了關於注射疼痛、坐骨神經痛、神經性疼痛和外周神經病的警告。 Fulvestrant is a lipophilic molecule with very low water solubility. Fulvestrant is commonly administered by intramuscular injection of an oil-based fulvestrant formulation due to its poor solubility and low oral bioavailability. Currently, the marketed formulation of fulvestrant, FASLODEX ™ , is administered at 500 mg and requires intramuscular administration of two 5 mL injections of the 50 mg/mL fulvestrant formulation. Each 5mL injection contains 10w/v% ethanol, 10w/v% benzyl alcohol and 15w/v% benzyl benzoate as co-solvents, supplemented to 100w/v with castor oil as another co-solvent and release rate modifier %. Administration of this formulation is slow (1-2 minutes per injection) and painful due to the use of a viscous oil-based vehicle to dissolve fulvestrant. Also, warnings about injection pain, sciatica, neuropathic pain, and peripheral neuropathy have been added to the FASLODEX ™ label.

因此，尋找不含有機溶劑或油、刺激性小、具有適宜的釋放速度，給藥後迅速達到峰濃度且維持較高血藥濃度、且施用方便、疼痛度低的氟維司群劑型，是目前急需解決的技術問題。Therefore, it is important to look for fulvestrant formulations that do not contain organic solvents or oils, are less irritating, have a suitable release rate, quickly reach the peak concentration after administration and maintain a high blood concentration, and are convenient to administer and have low pain. Technical problems that need to be solved urgently.

為改善上述技術問題，本發明提供了一種氟維司群藥物組合物，其包含氟維司群固體粒子，此氟維司群固體粒子的粒徑為Dv(10)選自小於等於600奈米，例如小於等於400奈米，Dv（50）選自小於等於700奈米且Dv（90）選自小於等於1000奈米。In order to improve the above-mentioned technical problem, the present invention provides a kind of fulvestrant pharmaceutical composition, it comprises fulvestrant solid particle, the particle diameter of this fulvestrant solid particle is Dv(10) selected from less than or equal to 600 nanometers , for example less than or equal to 400 nm, Dv(50) is selected from less than or equal to 700 nm and Dv(90) is selected from less than or equal to 1000 nm.

根據本發明的實施方案，此氟維司群固體粒子的粒徑可以為Dv(10)選自小於等於500奈米，也可以選自小於等於400奈米，如0.01奈米～400奈米，例如Dv(10)選自1奈米～550奈米，也可以選自10奈米～500奈米，如20奈米、30奈米、40奈米、50奈米、60奈米、70奈米、80奈米、90奈米、100奈米、110奈米、120奈米、130奈米、140奈米、150奈米、160奈米、170奈米、180奈米、190奈米、200奈米、210奈米、220奈米、230奈米、240奈米、250奈米、260奈米、270奈米、280奈米、290奈米、300奈米、350奈米、400奈米、450奈米、500奈米，其實例可以選自196.200奈米、132.420奈米、435.63奈米或341.71奈米。According to an embodiment of the present invention, the particle size of the fulvestrant solid particle can be Dv(10) selected from 500 nm or less, or 400 nm or less, such as 0.01 nm to 400 nm, For example, Dv(10) is selected from 1 nm to 550 nm, and can also be selected from 10 nm to 500 nm, such as 20 nm, 30 nm, 40 nm, 50 nm, 60 nm, and 70 nm. m, 80nm, 90nm, 100nm, 110nm, 120nm, 130nm, 140nm, 150nm, 160nm, 170nm, 180nm, 190nm, 200nm, 210nm, 220nm, 230nm, 240nm, 250nm, 260nm, 270nm, 280nm, 290nm, 300nm, 350nm, 400nm m, 450 nm, 500 nm, examples of which can be selected from 196.200 nm, 132.420 nm, 435.63 nm or 341.71 nm.

根據本發明的實施方案，此氟維司群固體粒子的粒徑可以為Dv（50）選自0.01奈米～700奈米，例如Dv（50）選自1奈米～600奈米，也可以選自10奈米～500奈米，如10奈米、20奈米、30奈米、40奈米、50奈米、60奈米、70奈米、80奈米、90奈米、100奈米、110奈米、120奈米、130奈米、140奈米、150奈米、160奈米、170奈米、180奈米、190奈米、200奈米、210奈米、220奈米、230奈米、240奈米、250奈米、260奈米、270奈米、280奈米、290奈米、300奈米、350奈米、400奈米、450奈米、500奈米，其實例可以選自401.800奈米、281.630奈米、448.340奈米、473.84奈米或535.27奈米。According to the embodiment of the present invention, the particle size of the fulvestrant solid particles can be Dv(50) selected from 0.01 nm to 700 nm, for example, Dv (50) selected from 1 nm to 600 nm, or Selected from 10nm to 500nm, such as 10nm, 20nm, 30nm, 40nm, 50nm, 60nm, 70nm, 80nm, 90nm, 100nm , 110nm, 120nm, 130nm, 140nm, 150nm, 160nm, 170nm, 180nm, 190nm, 200nm, 210nm, 220nm, 230nm nm, 240 nm, 250 nm, 260 nm, 270 nm, 280 nm, 290 nm, 300 nm, 350 nm, 400 nm, 450 nm, 500 nm, examples of which can be Selected from 401.800 nm, 281.630 nm, 448.340 nm, 473.84 nm or 535.27 nm.

根據本發明的實施方案，此氟維司群固體粒子的粒徑可以為Dv（90）選自1奈米～1000奈米，例如Dv（90）選自10奈米～900奈米，也可以為100奈米～800奈米，如100奈米、110奈米、120奈米、130奈米、140奈米、150奈米、160奈米、170奈米、180奈米、190奈米、200奈米、210奈米、220奈米、230奈米、240奈米、250奈米、260奈米、270奈米、280奈米、290奈米、300奈米、350奈米、400奈米、450奈米、500奈米、550奈米、600奈米、650奈米、700奈米、750奈米、800奈米，其實例可以選自716.500奈米、866.720奈米、599.350奈米、657.69奈米或657.05奈米。According to an embodiment of the present invention, the particle size of the fulvestrant solid particle can be Dv(90) selected from 1 nm to 1000 nm, for example, Dv (90) selected from 10 nm to 900 nm, or 100nm to 800nm, such as 100nm, 110nm, 120nm, 130nm, 140nm, 150nm, 160nm, 170nm, 180nm, 190nm, 200nm, 210nm, 220nm, 230nm, 240nm, 250nm, 260nm, 270nm, 280nm, 290nm, 300nm, 350nm, 400nm m, 450 nm, 500 nm, 550 nm, 600 nm, 650 nm, 700 nm, 750 nm, 800 nm, examples of which can be selected from 716.500 nm, 866.720 nm, 599.350 nm , 657.69 nm or 657.05 nm.

根據本發明的實施方案，此氟維司群固體粒子的粒徑也可以為Dv（25）選自1奈米～600奈米，例如Dv（25）選自10奈米～500奈米，也可以為Dv（25）選自100奈米～400奈米，如100奈米、110奈米、120奈米、130奈米、140奈米、150奈米、160奈米、170奈米、180奈米、190奈米、200奈米、210奈米、220奈米、230奈米、240奈米、250奈米、260奈米、270奈米、280奈米、290奈米、300奈米、350奈米、400奈米，其實例可以選自272.00奈米、189.28奈米、316.91奈米、480.27奈米或398.95奈米。According to an embodiment of the present invention, the particle size of the fulvestrant solid particle can also be Dv (25) selected from 1 nm to 600 nm, for example, Dv (25) selected from 10 nm to 500 nm, or Dv(25) can be selected from 100nm to 400nm, such as 100nm, 110nm, 120nm, 130nm, 140nm, 150nm, 160nm, 170nm, 180nm Nano, 190nm, 200nm, 210nm, 220nm, 230nm, 240nm, 250nm, 260nm, 270nm, 280nm, 290nm, 300nm , 350 nm, 400 nm, examples of which can be selected from 272.00 nm, 189.28 nm, 316.91 nm, 480.27 nm or 398.95 nm.

根據本發明的實施方案，此氟維司群固體粒子的粒徑也可以為Dv（75）選自1奈米～900奈米，例如Dv（75）選自10奈米～800奈米，也可以為Dv（75）選自100奈米～700奈米，如100奈米、110奈米、120奈米、130奈米、140奈米、150奈米、160奈米、170奈米、180奈米、190奈米、200奈米、210奈米、220奈米、230奈米、240奈米、250奈米、260奈米、270奈米、280奈米、290奈米、300奈米、350奈米、400奈米、450奈米、500奈米、550奈米、600奈米、650奈米、700奈米，其實例可以選自540.00奈米、419.10奈米、634.29奈米、596.56奈米或562.80奈米。According to an embodiment of the present invention, the particle size of the fulvestrant solid particle can also be Dv (75) selected from 1 nm to 900 nm, for example, Dv (75) selected from 10 nm to 800 nm, or Dv(75) can be selected from 100nm to 700nm, such as 100nm, 110nm, 120nm, 130nm, 140nm, 150nm, 160nm, 170nm, 180nm Nano, 190nm, 200nm, 210nm, 220nm, 230nm, 240nm, 250nm, 260nm, 270nm, 280nm, 290nm, 300nm , 350 nm, 400 nm, 450 nm, 500 nm, 550 nm, 600 nm, 650 nm, 700 nm, examples of which can be selected from 540.00 nm, 419.10 nm, 634.29 nm, 596.56 nm or 562.80 nm.

本發明中此氟維司群藥物組合物還可以包括載體。此載體可以為非油性載體。優選地，此非油性載體包括但不限於水。此水可以為常規市售注射用水，優選為滅菌注射用水。The fulvestrant pharmaceutical composition of the present invention may also include a carrier. The carrier can be a non-oily carrier. Preferably, the non-oily vehicle includes, but is not limited to, water. The water can be conventional commercially available water for injection, preferably sterile water for injection.

根據本發明的實施方案，此氟維司群藥物組合物的pH為6.5～8.0，例如6.6、6.7、6.8、6.9、7.0、7.1、7.2、7.3、7.4、7.5、7.6、7.7、7.8、7.9或8.0，如7.4。According to an embodiment of the present invention, the pH of the fulvestrant pharmaceutical composition is 6.5-8.0, such as 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9 Or 8.0, like 7.4.

根據本發明的實施方案，此氟維司群藥物組合物還可以包括選自以下的一種或多種：助懸劑、潤濕劑、滲透壓調節劑、溶劑、穩定劑、緩衝劑、pH調節劑、表面活性劑、聚合物、電解質和非電解質。其中，此聚合物可以為交聯聚合物和/或非交聯聚合物。According to an embodiment of the present invention, this fulvestrant pharmaceutical composition may also include one or more selected from the following: suspending agent, wetting agent, osmotic pressure regulator, solvent, stabilizer, buffering agent, pH regulator , surfactants, polymers, electrolytes and non-electrolytes. Wherein, the polymer may be a cross-linked polymer and/or a non-cross-linked polymer.

根據本發明的實施方案，此助懸劑包括但不限於：羧甲基纖維素鈉、聚乙二醇和聚維酮中的一種或多種。According to an embodiment of the present invention, the suspending agent includes, but is not limited to: one or more of sodium carboxymethylcellulose, polyethylene glycol and povidone.

根據本發明的實施方案，此潤濕劑包括但不限於：泊洛沙姆(Poloxamer)、聚維酮、多庫酯鈉(Docusate Sodium)、去氧膽酸鈉(Sodium Deoxycholate)和吐溫(Tween)中的一種或多種。此吐溫可以為常規市售吐溫試劑，例如吐溫20和吐溫80中的一種或多種。According to an embodiment of the present invention, such wetting agents include, but are not limited to: Poloxamer, Povidone, Docusate Sodium, Sodium Deoxycholate, and Tween ( One or more of Tween). The Tween can be one or more of conventional commercially available Tween reagents, such as Tween 20 and Tween 80.

根據本發明的實施方案，此滲透壓調節劑包括但不限於：氯化鈉、甘露醇和蔗糖中的一種或多種。According to an embodiment of the present invention, the osmotic pressure regulator includes, but is not limited to: one or more of sodium chloride, mannitol and sucrose.

根據本發明的實施方案，此溶劑包括但不限於：注射用水。According to an embodiment of the present invention, the solvent includes, but is not limited to: water for injection.

根據本發明的實施方案，此穩定劑包括但不限於：抗氧化劑、金屬離子螯合劑、聚環氧乙烷(PEO)、聚環氧乙烷衍生物、聚山梨醇酯、去氧膽酸鈉、多庫酯鈉、泊洛沙姆、聚乙氧基化植物油、聚乙氧基化蓖麻油、脫水山梨糖醇棕櫚酸酯、卵磷脂、聚乙烯醇、人血清白蛋白、聚乙烯吡咯烷酮、聚維酮、聚乙二醇、氯化鈉、氯化鈣、右旋糖、丙三醇、甘露糖醇和交聯聚合物中的一種或多種。此抗氧化劑包括但不限於檸檬酸、維生素C和維生素E中的一種或多種。此金屬離子螯合劑包括但不限於乙二胺四乙酸（EDTA）。此泊洛沙姆包括但不限於泊洛沙姆188、泊洛沙姆124和泊洛沙姆407中的一種或多種。此聚山梨醇酯包括但不限於：聚山梨醇酯80和聚山梨醇酯20中的一種或多種。此聚維酮包括但不限於：聚維酮K12、聚維酮K17、PLASDONE TMC-12聚維酮、PLASDONETM C-17聚維酮和PLASDONE TMC-30聚維酮中的一種或多種。此聚乙二醇包括但不限於聚乙二醇3350。此交聯聚合物包括但不限於羧甲基纖維素鈉。 According to an embodiment of the present invention, such stabilizers include, but are not limited to: antioxidants, metal ion chelating agents, polyethylene oxide (PEO), polyethylene oxide derivatives, polysorbate, sodium deoxycholate , docusate sodium, poloxamer, polyethoxylated vegetable oil, polyethoxylated castor oil, sorbitan palmitate, lecithin, polyvinyl alcohol, human serum albumin, polyvinylpyrrolidone, One or more of povidone, polyethylene glycol, sodium chloride, calcium chloride, dextrose, glycerol, mannitol and cross-linked polymers. Such antioxidants include, but are not limited to, one or more of citric acid, vitamin C and vitamin E. Such metal ion chelating agents include, but are not limited to, ethylenediaminetetraacetic acid (EDTA). The poloxamer includes, but is not limited to, one or more of poloxamer 188, poloxamer 124 and poloxamer 407. The polysorbate includes, but is not limited to: one or more of polysorbate 80 and polysorbate 20. The povidone includes, but is not limited to: one or more of povidone K12, povidone K17, PLASDONE ™ C-12 povidone, PLASDONE™ C-17 povidone and PLASDONE ™ C-30 povidone. Such polyethylene glycols include, but are not limited to, polyethylene glycol 3350. Such cross-linked polymers include, but are not limited to, sodium carboxymethylcellulose.

根據本發明的實施方案，此緩衝劑包括但不限於：磷酸、磷酸鹽、枸櫞酸（檸檬酸）、枸櫞酸鈉（檸檬酸鈉）、三羥甲基氨基甲烷（Tris）、氫氧化鈉、鹽酸（HCl）或其混合物的緩衝劑。According to an embodiment of the present invention, such buffering agents include, but are not limited to: phosphoric acid, phosphate salts, citric acid (citric acid), sodium citrate (sodium citrate), tris (Tris), hydroxide Buffers of sodium, hydrochloric acid (HCl), or mixtures thereof.

根據本發明的實施方案，此pH調節劑包括但不限於：磷酸、磷酸鹽、檸檬酸、檸檬酸鈉、鹽酸和氫氧化鈉。According to an embodiment of the present invention, such pH adjusting agents include, but are not limited to: phosphoric acid, phosphate salts, citric acid, sodium citrate, hydrochloric acid, and sodium hydroxide.

根據本發明的實施方案，此磷酸鹽包括但不限於磷酸氫二鈉、磷酸二氫鈉或其混合物或水合物，例如一水磷酸氫二鈉（Na 2HPO 4•H 2O）、二水磷酸氫二鈉（Na 2HPO 4•2H 2O）、無水磷酸氫二鈉（無水Na 2HPO 4）、一水磷酸二氫鈉（NaH 2PO 4•H 2O）、二水磷酸二氫鈉（NaH 2PO 4•2H 2O）和無水磷酸二氫鈉（無水NaH 2PO 4）中的一種或多種。 According to an embodiment of the present invention, the phosphate includes but not limited to disodium hydrogen phosphate, sodium dihydrogen phosphate or a mixture or hydrate thereof, such as disodium hydrogen phosphate monohydrate (Na 2 HPO 4 ·H 2 O), dihydrate Disodium hydrogen phosphate (Na 2 HPO 4 •2H 2 O), disodium hydrogen phosphate anhydrous (Na 2 HPO 4 anhydrous), sodium dihydrogen phosphate monohydrate (NaH 2 PO 4 •H 2 O), dihydrogen phosphate dihydrogen One or more of sodium (NaH 2 PO 4 •2H 2 O) and anhydrous sodium dihydrogen phosphate (anhydrous NaH 2 PO 4 ).

根據本發明的實施方案，此助溶劑包括但不限於：乙醇和丙二醇中的一種或多種。According to an embodiment of the present invention, the co-solvent includes, but is not limited to: one or more of ethanol and propylene glycol.

此氟維司群藥物組合物中，氟維司群固體粒子的重量百分比優選1.00%～50.00%，優選2.00%～30.00%，例如2.00%~25.00%，例如2.00%、3.00%、4.00%、5.00%、6.00%、7.00%、8.00%、9.00%、10.00%、11.00%、12.00%、13.00%、14.00%、15.00%、16.00%、17.00%、18.00%、19.00%、20.00%、21.00%、22.00%、23.00%、24.00%、25.00%，如5.00%或25.00%；此重量百分比是指氟維司群固體粒子的重量占氟維司群藥物組合物總重量的百分比。In this fulvestrant pharmaceutical composition, the weight percentage of fulvestrant solid particles is preferably 1.00% to 50.00%, preferably 2.00% to 30.00%, such as 2.00% to 25.00%, such as 2.00%, 3.00%, 4.00%, 5.00%, 6.00%, 7.00%, 8.00%, 9.00%, 10.00%, 11.00%, 12.00%, 13.00%, 14.00%, 15.00%, 16.00%, 17.00%, 18.00%, 19.00%, 20.00%, 21.00% , 22.00%, 23.00%, 24.00%, 25.00%, such as 5.00% or 25.00%; this weight percentage refers to the percentage of the weight of fulvestrant solid particles in the total weight of the fulvestrant pharmaceutical composition.

此氟維司群藥物組合物中，此潤濕劑的重量百分比優選0～5.00%，例如1.00%、2.00%、3.00%、4.00%、5.00%，如1.00%；此重量百分比是指表面活性劑的重量占氟維司群藥物組合物總重量的百分比。In the fulvestrant pharmaceutical composition, the weight percentage of the wetting agent is preferably 0-5.00%, such as 1.00%, 2.00%, 3.00%, 4.00%, 5.00%, such as 1.00%; this weight percentage refers to surface active The weight of agent accounts for the percentage of total weight of fulvestrant pharmaceutical composition.

此氟維司群藥物組合物中，此助懸劑的重量百分比優選0～5.00%，例如0、1.00%、2.00%、3.00%、4.00%、5.00%；此重量百分比是指助懸劑的重量占氟維司群藥物組合物總重量的百分比。In this fulvestrant pharmaceutical composition, the weight percent of this suspending agent is preferably 0～5.00%, such as 0, 1.00%, 2.00%, 3.00%, 4.00%, 5.00%; Weight accounts for the percentage of total weight of fulvestrant pharmaceutical composition.

此氟維司群藥物組合物中，此滲透壓調節劑的重量百分比優選0～5.00%，例如0、1.00%、2.00%、3.00%、4.00%、5.00%；此重量百分比是指滲透壓調節劑的重量占氟維司群藥物組合物總重量的百分比。In this fulvestrant pharmaceutical composition, the weight percentage of this osmotic pressure regulator is preferably 0-5.00%, such as 0, 1.00%, 2.00%, 3.00%, 4.00%, 5.00%; The weight of agent accounts for the percentage of total weight of fulvestrant pharmaceutical composition.

此氟維司群藥物組合物中，此緩衝劑的重量百分比優選0～1.00%，例如0、0.10%、0.20%、0.30%、0.40%、0.50%、0.60%、0.70%、0.80%、0.90%、1.00%；此重量百分比是指緩衝劑的重量占氟維司群藥物組合物總重量的百分比。In the fulvestrant pharmaceutical composition, the weight percentage of the buffering agent is preferably 0-1.00%, such as 0, 0.10%, 0.20%, 0.30%, 0.40%, 0.50%, 0.60%, 0.70%, 0.80%, 0.90% %, 1.00%; this weight percentage refers to the percentage of the weight of the buffering agent in the total weight of the fulvestrant pharmaceutical composition.

此氟維司群藥物組合物中，此穩定劑的重量百分比優選0～1.00%，例如0、0.10%、0.20%、0.30%、0.40%、0.50%、0.60%、0.70%、0.80%、0.90%、1.00%，例如0.60%或0.32%；此重量百分比是指穩定劑的重量占氟維司群藥物組合物總重量的百分比。In the fulvestrant pharmaceutical composition, the weight percentage of the stabilizer is preferably 0-1.00%, such as 0, 0.10%, 0.20%, 0.30%, 0.40%, 0.50%, 0.60%, 0.70%, 0.80%, 0.90% %, 1.00%, such as 0.60% or 0.32%; this weight percentage refers to the percentage of the weight of the stabilizer to the total weight of the fulvestrant pharmaceutical composition.

此氟維司群藥物組合物中，此pH調節劑使用量優選調節組合物溶液的pH為6.5～8.0，例如6.6、6.7、6.8、6.9、7.0、7.1、7.2、7.3、7.4、7.5、7.6、7.7、7.8、7.9或8.0，如7.4。In this fulvestrant pharmaceutical composition, the usage amount of the pH regulator is preferably to adjust the pH of the composition solution to 6.5-8.0, such as 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6 , 7.7, 7.8, 7.9 or 8.0, such as 7.4.

此氟維司群藥物組合物優選包括以下組分：1.00%～50.00%氟維司群固體粒子、0～5.00%潤濕劑、0～5.00%穩定劑、0～5.00%滲透壓調節劑、0～1.00%緩衝劑和溶劑，以及任選存在或不存在的0～5.00%的助懸劑。The fulvestrant pharmaceutical composition preferably includes the following components: 1.00% to 50.00% fulvestrant solid particles, 0 to 5.00% wetting agent, 0 to 5.00% stabilizer, 0 to 5.00% osmotic pressure regulator, 0-1.00% buffer and solvent, and optionally 0-5.00% suspending agent present or absent.

優選地，此氟維司群藥物組合物包括以下組分：1.00%～50.00%氟維司群固體粒子、0～5.00%潤濕劑、0～5.00%穩定劑、0～5.00%滲透壓調節劑和0～1.00%緩衝劑，以及任選存在或不存在的0～5.00%的助懸劑，並且餘量為溶劑。Preferably, the fulvestrant pharmaceutical composition includes the following components: 1.00% to 50.00% fulvestrant solid particles, 0 to 5.00% wetting agent, 0 to 5.00% stabilizer, 0 to 5.00% osmotic pressure regulator agent and 0-1.00% buffering agent, and 0-5.00% suspending agent optionally present or not, and the balance is solvent.

根據本發明的實施方案，此氟維司群藥物組合物可以為以下任一配方：According to an embodiment of the present invention, the fulvestrant pharmaceutical composition can be any of the following formulations:

配方一：5.00%氟維司群固體粒子、0.50%聚維酮K12、0.30%去氧膽酸鈉、2.78%甘露醇、pH調節劑和水，其中pH調節劑將稀釋劑的pH調節至pH7.4，pH調節劑為磷酸二氫鈉和磷酸氫二鈉；Formula 1: 5.00% fulvestrant solid particles, 0.50% povidone K12, 0.30% sodium deoxycholate, 2.78% mannitol, pH regulator and water, wherein the pH regulator adjusts the pH of the diluent to pH7 .4. The pH regulator is sodium dihydrogen phosphate and disodium hydrogen phosphate;

配方二：5.00%氟維司群固體粒子、0.50%聚維酮K12、0.20%泊洛沙姆188、2.78%甘露醇、pH調節劑和水，其中pH調節劑將稀釋劑的pH調節至pH7.4，pH調節劑為磷酸二氫鈉和磷酸氫二鈉；Formula 2: 5.00% fulvestrant solid particles, 0.50% povidone K12, 0.20% poloxamer 188, 2.78% mannitol, pH regulator and water, wherein the pH regulator adjusts the pH of the diluent to pH7 .4. The pH regulator is sodium dihydrogen phosphate and disodium hydrogen phosphate;

配方三：5.00%氟維司群、1.00%吐溫20、0.30%聚維酮K12、0.30%去氧膽酸鈉、2.76%甘露醇、pH調節劑和水，其中pH調節劑將稀釋劑的pH調節至pH7.4，pH調節劑為磷酸二氫鈉和磷酸氫二鈉；Formula 3: 5.00% fulvestrant, 1.00% Tween 20, 0.30% povidone K12, 0.30% sodium deoxycholate, 2.76% mannitol, pH regulator and water, wherein the pH regulator will diluent The pH is adjusted to pH7.4, and the pH regulator is sodium dihydrogen phosphate and disodium hydrogen phosphate;

配方四：5.00%氟維司群、1.00%吐溫20、0.30%聚維酮K12、0.02%多庫酯鈉、2.76%甘露醇、pH調節劑和水，其中pH調節劑將稀釋劑的pH調節至pH7.4，pH調節劑為磷酸二氫鈉和磷酸氫二鈉；Formula 4: 5.00% fulvestrant, 1.00% Tween 20, 0.30% povidone K12, 0.02% docusate sodium, 2.76% mannitol, pH regulator and water, wherein the pH regulator adjusts the pH of the diluent Regulated to pH7.4, the pH regulator is sodium dihydrogen phosphate and disodium hydrogen phosphate;

配方五：25.00%氟維司群、1.00%吐溫20、0.20%CMC-Na、0.42%磷酸氫二鈉、0.09%磷酸二氫鈉、2.29%甘露醇、0.30%去氧膽酸鈉、0.30%PVP K12和水。Formula 5: 25.00% fulvestrant, 1.00% Tween 20, 0.20% CMC-Na, 0.42% disodium hydrogen phosphate, 0.09% sodium dihydrogen phosphate, 2.29% mannitol, 0.30% sodium deoxycholate, 0.30 %PVP K12 and water.

配方六：25.00%氟維司群、1.60%吐溫20、0.20%CMC-Na、0.42%磷酸氫二鈉、0.09%磷酸二氫鈉、2.27%甘露醇、0.30%去氧膽酸鈉、0.30%PVP K12和水。Formula 6: 25.00% fulvestrant, 1.60% Tween 20, 0.20% CMC-Na, 0.42% disodium hydrogen phosphate, 0.09% sodium dihydrogen phosphate, 2.27% mannitol, 0.30% sodium deoxycholate, 0.30 %PVP K12 and water.

本發明還提供了氟維司群藥物組合物的製備方法，其包括以下步驟：The present invention also provides a preparation method of the fulvestrant pharmaceutical composition, which comprises the following steps:

步驟1：將氟維司群固體粒子與配方中的其他組分混合，得到預混物；Step 1: mixing fulvestrant solid particles with other components in the formulation to obtain a premix;

步驟2：將步驟1得到的預混物與鋯珠共同研磨，得到氟維司群藥物組合物即可。Step 2: Grinding the premix obtained in Step 1 with zirconium beads to obtain the fulvestrant pharmaceutical composition.

步驟1中，此混合優選攪拌混合。In step 1, the mixing is preferably stirring and mixing.

步驟2中，此鋯珠的粒徑可以為0.01mm～2mm，例如0.1mm 、0.3mm、0.6mm或1mm。In step 2, the particle size of the zirconium beads may be 0.01mm-2mm, such as 0.1mm, 0.3mm, 0.6mm or 1mm.

步驟2中，此鋯珠與此預混物的體積比值優選1～5，例如1、1.5、2或3。In step 2, the volume ratio of the zirconium beads to the premix is preferably 1-5, such as 1, 1.5, 2 or 3.

步驟2中，此研磨的時間可以為1分鐘～24小時，也可以為5分鐘～20小時，例如4小時或12小時。In step 2, the grinding time can be 1 minute to 24 hours, or 5 minutes to 20 hours, for example, 4 hours or 12 hours.

根據本發明的實施方案，鋯珠是指常規市售氧化鋯珠。According to an embodiment of the present invention, zirconia beads refer to conventional commercially available zirconia beads.

本發明還提供了氟維司群藥物組合物在製備氟維司群藥物製劑中的應用。The present invention also provides the application of the fulvestrant pharmaceutical composition in the preparation of fulvestrant pharmaceutical preparations.

此氟維司群藥物製劑包括但不限於片劑、顆粒劑、膠囊、微丸、口服液和注射劑等中的一種或多種。優選地，所述片劑包括但不限於緩釋片、滲透泵片和口崩片中的一種或多種。優選地，所述注射劑可以為液體注射劑、注射用粉劑或注射用片劑；例如，所述液體注射劑可以為混懸劑，比如為水混懸劑或混懸用粉末；例如，所述混懸用粉末可以為凍乾粉針。The pharmaceutical preparation of fulvestrant includes, but is not limited to, one or more of tablets, granules, capsules, pellets, oral liquids, and injections. Preferably, the tablet includes, but is not limited to, one or more of sustained release tablets, osmotic pump tablets and orally disintegrating tablets. Preferably, the injection can be a liquid injection, powder for injection or tablet for injection; for example, the liquid injection can be a suspension, such as an aqueous suspension or a powder for suspension; for example, the suspension The powder can be freeze-dried powder for injection.

根據本發明的實施方案，此注射劑可以為長效注射劑；此長效注射劑可以是水混懸劑，也可以是混懸用粉末，臨用時採用特定的稀釋劑分散成混懸劑。According to the embodiment of the present invention, the injection can be a long-acting injection; the long-acting injection can be an aqueous suspension, or a powder for suspension, which is dispersed into a suspension with a specific diluent just before use.

根據本發明的實施方案，此氟維司群在長效注射劑中的濃度不低於50mg/ml。 According to an embodiment of the present invention, the concentration of the fulvestrant in the long-acting injection is not lower than 50 mg/ml.

本發明還提供一種氟維司群藥物製劑，其含有上述氟維司群藥物組合物。The present invention also provides a fulvestrant pharmaceutical preparation, which contains the above-mentioned fulvestrant pharmaceutical composition.

根據本發明的實施方案，此氟維司群藥物製劑具有如上文所述的劑型選擇和/或氟維司群濃度。 According to an embodiment of the present invention, the pharmaceutical formulation of fulvestrant has the dosage form selection and/or fulvestrant concentration as described above.

本發明還提供上述氟維司群藥物組合物和/或氟維司群藥物製劑在預防和/或治療激素受體陽性轉移性乳腺癌中的應用。The present invention also provides the application of the above fulvestrant pharmaceutical composition and/or fulvestrant pharmaceutical preparation in the prevention and/or treatment of hormone receptor positive metastatic breast cancer.

本發明還提供一種預防和/或治療激素受體陽性轉移性乳腺癌的方法，包括將上述氟維司群藥物組合物和/或氟維司群藥物製劑給予需要的患者，例如人。 The present invention also provides a method for preventing and/or treating hormone receptor positive metastatic breast cancer, comprising administering the above-mentioned fulvestrant pharmaceutical composition and/or fulvestrant pharmaceutical preparation to a patient in need, such as a human.

根據本發明的實施方案，“Dv(10)”、 “Dv(25)”、“Dv(50)”、 “Dv(75)”和“Dv(90)”是指體積加權的粒子直徑，其中在測量時分別有累積10v/v％、25v/v％、50v/v％、75v/v％或90v/v％的粒子具有相等或較小的直徑。例如，如果粒子群的Dv(50)為約25微米，則50％體積的粒子具有小於或等於約25微米的直徑。According to an embodiment of the invention, "Dv(10)", "Dv(25)", "Dv(50)", "Dv(75)" and "Dv(90)" refer to volume-weighted particle diameters, where Cumulatively 10 v/v %, 25 v/v %, 50 v/v %, 75 v/v % or 90 v/v % of the particles respectively have an equal or smaller diameter when measured. For example, if the Dv(50) of a population of particles is about 25 microns, then 50% of the volume of particles have diameters less than or equal to about 25 microns.

除非另有說明，本申請上下文中的粒子直徑參數，例如“D(10)”、 “D(25)”、“D(50)”、 “D(75)”和“D(90)”均指體積加權的粒子直徑，其分別具有與“Dv(10)”、 “Dv(25)”、“Dv(50)”、 “Dv(75)”和“Dv(90)”相同的含義。Unless otherwise stated, particle diameter parameters in the context of this application, such as "D(10)", "D(25)", "D(50)", "D(75)" and "D(90)" are all Refers to volume-weighted particle diameters, which have the same meanings as "Dv(10)", "Dv(25)", "Dv(50)", "Dv(75)" and "Dv(90)", respectively.

在不違背本領域常識的基礎上，上述各優選條件，可任意組合，即得本發明各較佳實例。On the basis of not violating common knowledge in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain preferred examples of the present invention.

本發明所用試劑和原料均市售可得。 The reagents and raw materials used in the present invention are all commercially available.

根據本發明的實施方案，室溫是指環境溫度為10℃～35℃。According to an embodiment of the present invention, room temperature refers to an ambient temperature of 10°C to 35°C.

本發明的有益效果在於：本發明的氟維司群藥物組合物具有有利的釋放速度，給藥後迅速達到峰濃度且維持較高血藥濃度，生物利用度高；本發明的氟維司群藥物組合物的活性藥物成分含量高、不含有機溶劑或油，刺激性小，且施用方便，給藥體積減小，注射疼痛度大大降低，市場化前景良好。The beneficial effect of the present invention is that: the fulvestrant pharmaceutical composition of the present invention has a favorable release rate, reaches the peak concentration rapidly after administration and maintains a high blood drug concentration, and has high bioavailability; the fulvestrant of the present invention The pharmaceutical composition has high content of active pharmaceutical ingredients, does not contain organic solvent or oil, has little irritation, is convenient to administer, reduces administration volume, greatly reduces pain of injection, and has good market prospects.

本申請要求享有2020年12月10日向中國國家知識產權局提交的申請號為202011433060.4，名稱為“氟維司群藥物組合物、其製備方法及應用”的在先專利申請的優先權權益。該在先申請的全文以引用的方式結合至本文中。This application claims to enjoy the priority rights of the previous patent application with the application number 202011433060.4 and the name "fulvestrant pharmaceutical composition, its preparation method and application" submitted to the State Intellectual Property Office of China on December 10, 2020. The entirety of this prior application is incorporated herein by reference.

下文將結合具體實施例對本發明的技術方案做更進一步的詳細說明。應當理解，下列實施例僅為示例性地說明和解釋本發明，而不應被解釋為對本發明保護範圍的限制。凡基於本發明上述內容所實現的技術均涵蓋在本發明旨在保護的範圍內。The technical solutions of the present invention will be further described in detail below in conjunction with specific embodiments. It should be understood that the following examples are only for illustrating and explaining the present invention, and should not be construed as limiting the protection scope of the present invention. All technologies realized based on the above contents of the present invention are covered within the scope of protection intended by the present invention.

除非另有說明，以下實施例中使用的原料和試劑均為市售商品，或者可以通過已知方法製備。下列實施例中未注明具體條件的實驗方法，按照常規方法和條件，或按照商品說明書選擇。Unless otherwise stated, the raw materials and reagents used in the following examples are commercially available or can be prepared by known methods. For the experimental methods that do not specify specific conditions in the following examples, select according to conventional methods and conditions, or according to the product instructions.

實施例Example 11

表1 混懸注射液處方表 處方 1 組成（ w/v% ） 氟維司群 25.00 吐溫20 1.62 甘露醇 2.29 無水磷酸二氫鈉 0.09 無水磷酸氫二鈉 0.42 滅菌注射用水 70.58（q.s. 100） Table 1 Prescription Form for Suspension Injection Prescription 1 Composition ( w/v% ) Fulvestrant 25.00 Tween 20 1.62 Mannitol 2.29 Anhydrous Sodium Dihydrogen Phosphate 0.09 Anhydrous Disodium Hydrogen Phosphate 0.42 Sterile water for injection 70.58 (qs 100)

按表1處方1的用量配製稱原輔料，混合均勻後加入1倍體積的0.3mm鋯珠放置於研磨罐中進行研磨，研磨3小時，停止研磨，濾出得到氟維司群初始混懸液。將初混懸液加入1倍體積的0.1mm鋯珠放置於研磨罐中進行研磨，於不同時間取樣採用雷射細微性儀測定（雷射細微性儀參數設置：分散介質：水； 散介質折射率：1.333； 樣品材質吸收率：0.01；樣品材質折射率：1.521）測定粒徑，研磨20.5小時，停止研磨，得到氟維司群藥物組合物。研磨採用球磨儀進行，行星式球磨儀參數設置：固定參數：公轉盤直徑約191mm，自轉杯直徑約71mm，自轉杯高度約70mm，自轉杯容量100ml，公轉盤轉速10r/min自轉速度：720r/min。Prepare the raw and auxiliary materials according to the dosage of prescription 1 in Table 1. After mixing evenly, add 0.3mm zirconium beads of 1 times the volume and place them in a grinding jar for grinding. After grinding for 3 hours, stop grinding, and filter out to obtain the initial fulvestrant suspension. . Add 1 times the volume of the primary suspension to 0.1mm zirconium beads and place them in a grinding tank for grinding. Samples are taken at different times and measured by a laser micrometer (parameter settings of the laser micrometer: dispersion medium: water; dispersion medium refraction Ratio: 1.333; Absorption rate of sample material: 0.01; Refractive index of sample material: 1.521) Measure the particle size, grind for 20.5 hours, stop grinding, and obtain the fulvestrant pharmaceutical composition. Grinding is carried out with a ball mill, planetary ball mill parameter settings: fixed parameters: diameter of the revolution disk is about 191mm, diameter of the rotation cup is about 71mm, height of the rotation cup is about 70mm, capacity of the rotation cup is 100ml, rotation speed of the revolution disk is 10r/min Rotation speed: 720r/ min.

採用偏振光顯微鏡觀察研磨後混懸液中粒子的粒徑形態。所述不同時間研磨後混懸液中氟維司群固體粒子的粒徑分佈資料如表2和所示。此研磨後混懸液中氟維司群固體粒子的粒徑分佈和形態分別見圖1、圖2。The particle size and shape of the particles in the suspension after grinding were observed with a polarized light microscope. The particle size distribution data of fulvestrant solid particles in the suspension after grinding at different times are shown in Table 2. The particle size distribution and morphology of fulvestrant solid particles in the suspension after grinding are shown in Figure 1 and Figure 2, respectively.

結果顯示，偏振光顯微鏡觀察到的粒子形態大小與雷射細微性儀粒徑測定一致。研磨20.5h後混懸液中氟維司群固體為8μm左右球狀物。採用處方2以及最小的研磨珠研磨後3小時後粒徑達最小，再延長時間研磨，粒徑不僅不減小反而增加。The results showed that the particle shape and size observed by the polarizing microscope were consistent with the particle size measured by the laser micrometer. After milling for 20.5 hours, the fulvestrant solid in the suspension was spherical with a diameter of about 8 μm. Using prescription 2 and the smallest grinding beads, the particle size reaches the minimum after 3 hours of grinding, and then prolonging the grinding time, the particle size not only does not decrease but increases.

表2 實施例1混懸液中不同時間研磨得到組合物中氟維司群的粒徑分佈(體積加權) 研磨時間 D10 (μm) D25 (μm) D50 (μm) D75 (μm) D90 (μm) 0 1.156 1.543 2.066 2.610 3.161 0.5 0.709 0.942 1.349 1.924 2.510 1.5 0.808 0.946 1.154 1.388 1.612 3 0.744 0.878 1.050 1.268 1.537 17.5 0.988 1.352 5.318 6.731 8.113 20.5 1.032 3.658 5.649 7.392 9.015 Table 2 The particle size distribution (volume weighted) of fulvestrant in the composition obtained by grinding the suspension in Example 1 for different times grinding time D10 (μm) D25 (μm) D50 (μm) D75 (μm) D90 (μm) 0 1.156 1.543 2.066 2.610 3.161 0.5 0.709 0.942 1.349 1.924 2.510 1.5 0.808 0.946 1.154 1.388 1.612 3 0.744 0.878 1.050 1.268 1.537 17.5 0.988 1.352 5.318 6.731 8.113 20.5 1.032 3.658 5.649 7.392 9.015

實施例Example 22

表3 實施例2和3混懸注射液處方表 組成 比例（ % ， W/W ） 處方 2 處方 3 氟維司群 5.00 5.00 PVP K12（聚維酮K12） 0.50 0.50 去氧膽酸鈉 0.30 0 泊洛沙姆188 0 0.20 稀釋劑 94.20 94.30 Table 3 Example 2 and 3 Suspension Injection Prescription Form composition Ratio ( % , W/W ) Prescription 2 Prescription 3 Fulvestrant 5.00 5.00 PVP K12 (Povidone K12) 0.50 0.50 sodium deoxycholate 0.30 0 Poloxamer 188 0 0.20 Thinner 94.20 94.30

按表3處方2的用量配製稱原輔料。稀釋劑組成（以稀釋劑的總重量計，w/w%）：甘露醇2.95%，0.122%磷酸二氫鈉、0.58%磷酸氫二鈉，余量為水，pH7.4。將初混懸液加入1.5倍體積的0.3mm鋯珠放置於研磨罐中進行研磨，研磨12小時，得到氟維司群藥物組合物。研磨採用球磨儀進行，行星式球磨儀參數設置：固定參數：公轉盤直徑約191mm，自轉杯直徑約71mm，自轉杯高度約70mm，自轉杯容量100ml，公轉盤轉速10r/min自轉速度：720r/min。According to the dosage preparation of prescription 2 in table 3, the raw and auxiliary materials are called. Diluent composition (based on the total weight of the diluent, w/w%): 2.95% mannitol, 0.122% sodium dihydrogen phosphate, 0.58% disodium hydrogen phosphate, the balance is water, pH 7.4. Add 1.5 times the volume of the primary suspension to 0.3 mm zirconium beads and place in a grinding jar for grinding for 12 hours to obtain the fulvestrant pharmaceutical composition. Grinding is carried out with a ball mill, planetary ball mill parameter settings: fixed parameters: diameter of the revolution disk is about 191mm, diameter of the rotation cup is about 71mm, height of the rotation cup is about 70mm, capacity of the rotation cup is 100ml, rotation speed of the revolution disk is 10r/min Rotation speed: 720r/ min.

採用奈米細微性儀測定（NICOMP Particle Sizing Systems, 參數設置：分散介質：水； 分散介質折射率：1.333； 黏度：0.933 cp；溫度：23℃，光強設定值：300kHz）測定粒徑。採用偏振光顯微鏡觀察研磨4h和研磨終點12h的粒徑形態。The particle size was measured by a nanometer (NICOMP Particle Sizing Systems, parameter settings: dispersion medium: water; dispersion medium refractive index: 1.333; viscosity: 0.933 cp; temperature: 23°C, light intensity setting: 300kHz). The particle size and morphology of grinding 4h and grinding end point 12h were observed by polarizing microscope.

所述研磨12h後混懸液中氟維司群固體粒子的粒徑分佈資料如表4和圖3所示。此研磨4h、12h後混懸液中氟維司群固體粒子的粒徑形態分別見圖4和圖5。研磨4h、12h後混懸液中氟維司群固體粒子分別為小於2微米和小於1微米的粒子。The particle size distribution data of fulvestrant solid particles in the suspension after grinding for 12 hours are shown in Table 4 and FIG. 3 . The particle size and morphology of fulvestrant solid particles in the suspension after grinding for 4 hours and 12 hours are shown in Figure 4 and Figure 5 respectively. After grinding for 4 hours and 12 hours, the solid particles of fulvestrant in the suspension were particles less than 2 microns and less than 1 microns, respectively.

表4混懸液中氟維司群的粒徑分佈(體積加權) 處方編號 D10 (nm) D25 (nm) D50 (nm) D75 (nm) D90 (nm) 2 196.20 272.00 401.80 540.00 716.50 4 132.42 189.28 281.63 419.10 599.35 5 / 316.91 448.34 634.29 866.72 6 435.63 480.27 535.27 596.56 657.69 7 341.71 398.95 473.84 562.80 657.05 Particle size distribution (volume weighted) of fulvestrant in the suspension of table 4 prescription number D10 (nm) D25 (nm) D50 (nm) D75 (nm) D90 (nm) 2 196.20 272.00 401.80 540.00 716.50 4 132.42 189.28 281.63 419.10 599.35 5 / 316.91 448.34 634.29 866.72 6 435.63 480.27 535.27 596.56 657.69 7 341.71 398.95 473.84 562.80 657.05

實施例Example 33

按表3處方3的用量配製稱原輔料。稀釋劑組成（以稀釋劑的總重量計，w/w%）：甘露醇2.95%，0.122%磷酸二氫鈉、0.58%磷酸氫二鈉，余量為水，pH7.4。將初混懸液加入1.5倍體積的0.3mm鋯珠放置於研磨罐中進行研磨，研磨4小時，得到氟維司群藥物組合物。研磨採用球磨儀進行，行星式球磨儀參數設置：固定參數：公轉盤直徑約191mm，自轉杯直徑約71mm，自轉杯高度約70mm，自轉杯容量100ml，公轉盤轉速10r/min自轉速度：720r/min。According to the dosage preparation of prescription 3 in table 3, the raw and auxiliary materials are called. Diluent composition (based on the total weight of the diluent, w/w%): 2.95% mannitol, 0.122% sodium dihydrogen phosphate, 0.58% disodium hydrogen phosphate, the balance is water, pH 7.4. Add 1.5 times the volume of the primary suspension to 0.3 mm zirconium beads and place in a grinding jar for grinding for 4 hours to obtain the fulvestrant pharmaceutical composition. Grinding is carried out with a ball mill, planetary ball mill parameter settings: fixed parameters: diameter of the revolution disk is about 191mm, diameter of the rotation cup is about 71mm, height of the rotation cup is about 70mm, capacity of the rotation cup is 100ml, rotation speed of the revolution disk is 10r/min Rotation speed: 720r/ min.

此研磨後混懸液中氟維司群固體粒子的粒徑形態見圖6。The particle size and shape of fulvestrant solid particles in the suspension after grinding are shown in FIG. 6 .

結果顯示，與處方2截然不同的是，研磨4h後混懸液中氟維司群固體粒子為5~15um塊狀聚集物。The results showed that, quite different from prescription 2, the solid particles of fulvestrant in the suspension were 5-15um massive aggregates after grinding for 4 hours.

實施例Example 44

表5 實施例4和混懸注射液處方表 組成 比例（ % ， W/W ） 處方 4 處方 5 氟維司群 5.00 5.00 吐溫20 1.00 1.00 PVPk12（聚維酮K12） 0.30 0.30 去氧膽酸鈉 0.30 0 多庫酯鈉 0 0.02 Table 5 Embodiment 4 and suspension injection prescription form composition Ratio ( % , W/W ) Prescription 4 Prescription 5 Fulvestrant 5.00 5.00 Tween 20 1.00 1.00 PVPk12 (Povidone K12) 0.30 0.30 sodium deoxycholate 0.30 0 Docusate Sodium 0 0.02

按表5處方4和5的用量配製稱原輔料。稀釋劑組成（以稀釋劑的總重量計，w/w%）：甘露醇2.95%，0.122g磷酸二氫鈉、0.58g磷酸氫二鈉，余量為水，pH7.4。將初混懸液加入1.5倍體積的0.3mm鋯珠放置於研磨罐中進行研磨，研磨17小時，得到氟維司群藥物組合物。研磨採用球磨儀進行，行星式球磨儀參數設置：固定參數：公轉盤直徑約191mm，自轉杯直徑約71mm，自轉杯高度約70mm，自轉杯容量100ml，公轉盤轉速10r/min自轉速度：720r/min。Prepare raw and auxiliary materials according to the dosage of prescription 4 and 5 in table 5. Diluent composition (based on the total weight of the diluent, w/w%): mannitol 2.95%, 0.122g sodium dihydrogen phosphate, 0.58g disodium hydrogen phosphate, the balance is water, pH7.4. Add 1.5 times the volume of the primary suspension to 0.3 mm zirconium beads and place it in a grinding tank for grinding for 17 hours to obtain the fulvestrant pharmaceutical composition. Grinding is carried out with a ball mill, planetary ball mill parameter settings: fixed parameters: diameter of the revolution disk is about 191mm, diameter of the rotation cup is about 71mm, height of the rotation cup is about 70mm, capacity of the rotation cup is 100ml, rotation speed of the revolution disk is 10r/min Rotation speed: 720r/ min.

採用奈米細微性儀測定（NICOMP Particle Sizing Systems, 參數設置：分散介質：水； 分散介質折射率：1.333； 黏度：0.933 cp；溫度：23℃，光強設定值：300kHz）測定粒徑。The particle size was measured by a nanometer (NICOMP Particle Sizing Systems, parameter settings: dispersion medium: water; dispersion medium refractive index: 1.333; viscosity: 0.933 cp; temperature: 23°C, light intensity setting: 300kHz).

所述處方4和5研磨17h後混懸液中氟維司群固體粒子的粒徑分佈資料如表4，表6、圖7和圖8所示。The particle size distribution data of the fulvestrant solid particles in the suspension after the prescriptions 4 and 5 were ground for 17 hours are shown in Table 4, Table 6, Figure 7 and Figure 8 .

表6 處方4和處方5的高斯分佈平均粒徑 光強（奈米）（ Intensity Mean Diameter ） 標準差（ St.Dev. 奈米） 體積（奈米）（ Intensity Mean Diameter ） 標準差（ St.Dev. 奈米） 數量權重平均粒徑（奈米）（ Intensity Mean Diameter ） 標準差（ St.Dev. 奈米） 處方4 342.68 202.05 335.20 197.63 335.20 197.63 處方5 427.78 220.06 512.07 263.42 512.07 263.42 Table 6 Gaussian distribution mean particle size of prescription 4 and prescription 5 Light intensity (nm) ( Intensity Mean Diameter ) Standard Deviation ( St.Dev.nm ) Volume (nanometer) ( Intensity Mean Diameter ) Standard Deviation ( St.Dev.nm ) Quantity Weighted Average Particle Size (nm) ( Intensity Mean Diameter ) Standard Deviation ( St.Dev.nm ) Prescription 4 342.68 202.05 335.20 197.63 335.20 197.63 Prescription 5 427.78 220.06 512.07 263.42 512.07 263.42

實施例Example 55

表7 實施例5處方6和處方7混懸注射液處方表 組成 比例（%，W/W） 處方6 處方7 氟維司群 25 25 吐溫20 1 1.6 CMC-Na 0.2 0.2 磷酸氫二鈉 0.42 0.42 磷酸二氫鈉 0.09 0.09 甘露醇 2.29 2.27 去氧膽酸鈉 0.3 0.3 PVP K12 0.3 0.3 滅菌注射用水 Qs. 100 Qs. 100 Table 7 Example 5 Prescription 6 and Prescription 7 Suspension Injection Prescription Form composition Ratio (%, W/W) Prescription 6 Prescription 7 Fulvestrant 25 25 Tween 20 1 1.6 CMC-Na 0.2 0.2 Disodium phosphate 0.42 0.42 Sodium dihydrogen phosphate 0.09 0.09 Mannitol 2.29 2.27 sodium deoxycholate 0.3 0.3 PVP K12 0.3 0.3 Sterile water for injection Qs. 100 Qs. 100

按表7處方用量配製稱原輔料，加入1.5倍體積的鋯珠放置於研磨罐中進行研磨,其中處方6和7分別採用0.3mm和0.6mm鋯珠，研磨時間分別為21小時和25小時，得到氟維司群藥物組合物。研磨採用球磨儀進行，行星式球磨儀參數設置：固定參數：公轉盤直徑約191mm，自轉杯直徑約71mm，自轉杯高度約70mm，自轉杯容量100ml，公轉盤轉速10r/min自轉速度：720r/min。According to the prescription dosage in Table 7, prepare and weigh the raw and auxiliary materials, add 1.5 times the volume of zirconium beads and place them in the grinding tank for grinding, wherein prescriptions 6 and 7 use 0.3mm and 0.6mm zirconium beads respectively, and the grinding time is 21 hours and 25 hours respectively. The fulvestrant pharmaceutical composition is obtained. Grinding is carried out with a ball mill, planetary ball mill parameter settings: fixed parameters: diameter of the revolution disk is about 191mm, diameter of the rotation cup is about 71mm, height of the rotation cup is about 70mm, capacity of the rotation cup is 100ml, rotation speed of the revolution disk is 10r/min Rotation speed: 720r/ min.

採用奈米細微性儀測定（NICOMP Particle Sizing Systems, 參數設置：分散介質：水； 分散介質折射率：1.333； 黏度：0.933 cp；溫度：23℃，光強設定值：300kHz）測定粒徑。上述處方6和7研磨後混懸液中氟維司群固體粒子的粒徑分佈資料如表4、圖9和圖10所示。The particle size was measured by a nanometer (NICOMP Particle Sizing Systems, parameter settings: dispersion medium: water; dispersion medium refractive index: 1.333; viscosity: 0.933 cp; temperature: 23°C, light intensity setting: 300kHz). The particle size distribution data of fulvestrant solid particles in the suspension after grinding of the above prescriptions 6 and 7 are shown in Table 4, Figure 9 and Figure 10.

採用掃描電鏡（FEI，型號F50）觀察形態大小。掃描電鏡電壓10kv，束流2.0測試。上述處方6和7研磨後混懸液中氟維司群固體粒子的電鏡照片見圖11和圖12所示。均觀察到小於1µm的不規則塊狀粒子。The morphology and size were observed with a scanning electron microscope (FEI, model F50). Scanning electron microscope voltage 10kv, beam current 2.0 test. The electron micrographs of fulvestrant solid particles in the suspension after grinding prescriptions 6 and 7 are shown in Fig. 11 and Fig. 12 . Irregular lumpy particles smaller than 1 µm were observed.

按照EP10.0方法檢測氟維司群有關物質。有關物質結果見表8。結果顯示，自製混懸液有關物質單雜和總雜均低於上市對比製劑，表明品質較優。According to the EP10.0 method, the related substances of fulvestrant were detected. The results of related substances are shown in Table 8. The results showed that the single and total impurities of related substances in the self-made suspension were lower than those of the comparative preparations on the market, indicating better quality.

表8 實施例5（處方6和7）製劑與對比製劑的有關物質結果 樣品 單雜（%） 總雜 （%） 6-Keto fulvestrant* 6,7-fulvestrant Fulvestrant β-Isomer Fulvestrant Sulphone* Fulvestrant Bromo Analogue Fulvestrant Extended Fulvestrant Sterol Dimer 其他最大 實施例5處方6    0.00 ND ND ND ND ND ND 00.06 0.11 實施例5處方7    ND ND ND 0.02 ND ND ND 00.06 0.11 FASLODEX(LOT: RD693) 0.02 ND ND 0.16 ND ND ND 00.07 0.37 FASLODEX(LOT: RH832) 0.02 ND ND 0.15 ND ND ND 00.07 0.23 注：ND表示未檢出； *為氟維司群的降解產物； 6-Keto fulvestrant（6-酮氟維司群）、6,7-fulvestrant（6,7-氟維司群）、Fulvestrant β-Isomer（氟維司群β異構體）、Fulvestrant Sulphone（氟維司群碸）、Fulvestrant Bromo Analogue（氟維司群溴類似物）、Fulvestrant Extended（氟維司群擴展）、Fulvestrant Sterol Dimer（氟維司群甾醇二聚體）。 Table 8 Results of related substances in the formulations of Example 5 (prescriptions 6 and 7) and comparative formulations sample Simple miscellaneous (%) Total miscellaneous (%) 6-Keto fulvestrant* 6,7-fulvestrant Fulvestrant β-Isomer Fulvestrant Sulphone* Fulvestrant Bromo Analogue Fulvestrant Extended Fulvestrant Sterol Dimer other largest Embodiment 5 Prescription 6 0.00 ND ND ND ND ND ND 00.06 0.11 Embodiment 5 Prescription 7 ND ND ND 0.02 ND ND ND 00.06 0.11 FASLODEX (LOT: RD693) 0.02 ND ND 0.16 ND ND ND 00.07 0.37 FASLODEX (LOT: RH832) 0.02 ND ND 0.15 ND ND ND 00.07 0.23 Note: ND means not detected; * is the degradation product of fulvestrant; 6-Keto fulvestrant (6-keto fulvestrant), 6,7-fulvestrant (6,7-fulvestrant), Fulvestrant β -Isomer (Fulvestrant Beta Isomer), Fulvestrant Sulphone (Fulvestrant), Fulvestrant Bromo Analogue (Fulvestrant Bromo Analogue), Fulvestrant Extended (Fulvestrant Extended), Fulvestrant Sterol Dimer ( fulvestrant sterol dimer).

實施例Example 66

將實施例5所得的處方6和處方7製劑用稀釋劑稀釋至50mg/ml。稀釋劑組成為：1.62%吐溫20、0.2%羧甲基纖維素鈉、2.29%甘露醇、0.09%無水磷酸二氫鈉、0.42%無水磷酸氫二鈉。Prescription 6 and prescription 7 preparations obtained in Example 5 were diluted to 50 mg/ml with a diluent. The diluent consists of: 1.62% Tween 20, 0.2% sodium carboxymethylcellulose, 2.29% mannitol, 0.09% anhydrous sodium dihydrogen phosphate, and 0.42% anhydrous disodium hydrogen phosphate.

將稀釋後的處方6（G2）和處方7（G3）氟維司群混懸液、上市對比製劑氟維司群注射劑FASLODEX（G1，50 mg/ml，德國VETTER Pharma-fertigung GmbH & Co KG，批號：RH832，有效期2024年2月）按氟維司群15mg/kg（給藥體積0.3 mL/kg）以及未稀釋的處方7氟維司群混懸液按氟維司群30mg/kg（G4，給藥體積0.11 mL/kg）大腿外側肌肉注射給予雄性Wistar大鼠，SPF級動物，189~200 g，6~8周齡（北京維通利華實驗動物技術有限公司，品質合格證號110011200110944286，使用許可證號SYXK（蘇）2018-0034），每組3只。Diluted prescription 6 (G2) and prescription 7 (G3) fulvestrant suspension, marketed comparison preparation fulvestrant injection FASLODEX (G1, 50 mg/ml, VETTER Pharma-fertigung GmbH & Co KG, Germany, Batch number: RH832, valid until February 2024) Fulvestrant 15mg/kg (administration volume 0.3 mL/kg) and undiluted prescription 7 fulvestrant suspension Fulvestrant 30mg/kg (G4 , administration volume 0.11 mL/kg) intramuscular injection into the outer thigh of male Wistar rats, SPF grade animals, 189-200 g, 6-8 weeks old (Beijing Weitong Lihua Experimental Animal Technology Co., Ltd., quality certificate number 110011200110944286, Use license number SYXK (SU) 2018-0034), 3 mice per group.

給藥後進行臨床觀察，給藥第一天（D1）觀察2次：給藥前和給藥後當天下午，此後每天觀察1次，總45天。臨床觀察包括皮膚、被毛、眼、耳、鼻、口腔、胸部、腹部、泌尿生殖部、四肢等部位，以及呼吸、運動、泌尿、排便和行為改變和給藥部位肌肉刺激反應等。並且，在給藥前（0 h，D-1）、D1給藥後1、3、7、24 h，D4(72h)、D7(144h)、D11(240h)、D15(336h)、D20(456h)、D25(576h)、D30(696h)、D35(816h)、D40(936h)和D45(1056h)採集血樣，進行生物分析和採用WinNonlin 8.1版本的非房室模型計算各組的藥代動力學參數Tmax，Cmax，AUC（0-t），AUC（0-∞），T1/2，MRT，CL、Vz等。Clinical observations were carried out after the administration, and the observations were made twice on the first day of administration (D1): before the administration and in the afternoon after the administration, and once a day thereafter, for a total of 45 days. Clinical observations include skin, coat, eyes, ears, nose, mouth, chest, abdomen, genitourinary, limbs and other parts, as well as changes in breathing, exercise, urination, defecation and behavior, and muscle irritation at the administration site. And, before administration (0 h, D-1), 1, 3, 7, 24 h after D1 administration, D4 (72h), D7 (144h), D11 (240h), D15 (336h), D20 ( 456h), D25(576h), D30(696h), D35(816h), D40(936h) and D45(1056h) blood samples were collected for bioanalysis and non-compartmental model of WinNonlin version 8.1 to calculate the pharmacokinetics of each group Scientific parameters Tmax, Cmax, AUC (0-t), AUC (0-∞), T1/2, MRT, CL, Vz, etc.

給藥D45後，解剖動物並對給藥部位進行組織病理學檢查，觀察炎症反應和藥物殘留。各劑量組所有受試動物臨床觀察、體重、給藥部位刺激觀察、給藥部位大體解剖均未見異常，給藥部位未見炎症和藥物殘留，組織病理學檢查未見與給予供試品相關的異常。After administration of D45, the animals were dissected and histopathological examination was performed on the administration site to observe the inflammatory response and drug residue. No abnormality was found in the clinical observation, body weight, stimulation observation of the administration site, and gross anatomy of the administration site of all the animals tested in each dose group, and no inflammation and drug residues were found at the administration site, and no histopathological examination was found to be related to the administration of the test product. exception.

大鼠給予15 mg/kg和30 mg/kg劑量氟維司群混懸液下藥代動力學參數見表9，以及圖13、圖14、圖15、圖16和圖17。結果顯示：Wistar大鼠單次肌肉注射給予15 mg/kg給藥製劑後，Cmax從大到小依次為：G1＞G3＞G2；藥物濃度-時間曲線下面積AUCINF_obs從大到小依次為：G1＞G3＞G2；AUClast從大到小依次為：G1＞G3＞G2；藥物末端消除半衰期T1/2_Z從大到小依次為：G1＞G3＞G2；清除率Cl_ obs從大到小依次為：G2＞G3＞G1；平均駐留時間MRTINF_obs從大到小依次為：G3＞G2＞G1；分佈容積Vz_obs從大到小依次為：G2＞G3＞G1。以上結果表明自製混懸液緩釋效果優於上市對比製劑。上市對比製劑達峰時間Tmax大於自製混懸液，表明混懸液能更加迅速起效。The pharmacokinetic parameters of fulvestrant suspension administered to rats at doses of 15 mg/kg and 30 mg/kg are shown in Table 9, and Figure 13, Figure 14, Figure 15, Figure 16 and Figure 17. The results showed that after a single intramuscular injection of 15 mg/kg of the drug preparation in Wistar rats, the order of Cmax from large to small was: G1>G3>G2; the area under the drug concentration-time curve AUCINF_obs from large to small was: G1 >G3>G2; AUClast from large to small: G1>G3>G2; drug terminal elimination half-life T1/2_Z from large to small: G1>G3>G2; clearance rate Cl_obs from large to small: G2>G3>G1; the order of average residence time MRTINF_obs from large to small is: G3>G2>G1; the order of distribution volume Vz_obs from large to small is: G2>G3>G1. The above results show that the sustained-release effect of the self-made suspension is better than that of the listed comparison preparation. The peak time Tmax of the listed comparative preparation is greater than that of the self-made suspension, indicating that the suspension can take effect more quickly.

Wistar大鼠單次肌肉注射給予批號為20201221-1的給藥製劑後，15 mg/kg和30 mg/kg劑量下藥代參數比較，氟維司群的血漿暴露量（AUClast）增加低於劑量的增加，MRT無差異，說明高濃度高劑量混懸劑給藥後的藥物持續穩定緩釋，不會引起藥物突釋。After a single intramuscular injection of Wistar rats with the drug formulation of batch number 20201221-1, comparing pharmacokinetic parameters at doses of 15 mg/kg and 30 mg/kg, the increase in plasma exposure (AUClast) of fulvestrant was lower than that of the dose Increased, MRT no difference, indicating that the high-concentration and high-dose suspension drug sustained and stable drug release, will not cause sudden drug release.

表9 大鼠給予15 mg/kg和30 mg/kg劑量氟維司群製劑下藥代動力學參數 變數 Variable 單位 Units G1( 15 mg/kg) G2( 15 mg/kg) N Mean SD CV% N Mean SD CV% AUCINF_obs h*ng/mL 3 5420 1210 22.3 3 2620 407 15.6 AUClast h*ng/mL 3 4690 822 17.5 3 2220 349 15.7 Cl_F_obs mL/h/kg 3 2860 649 22.7 3 5830 996 17.1 Cmax ng/mL 3 19.1 4.15 21.8 3 11.4 3.53 30.9 MRTINF_obs h 3 463 120 25.9 3 530 69.4 13.1 MRTlast h 3 270 23.4 8.66 3 339 16.8 4.95 T1/2_Z h 3 440 225 51.1 3 364 42.2 11.6 Tmax h 3 24.0 96.0 96.0 3 3.00 3.00 3.00 Vz_F_obs mL/kg 3 1680000 512000 30.5 3 3090000 840000 27.2 表9（續） 變數 Variable 單位 Units G3( 15 mg/kg) G4( 30 mg/kg) N Mean SD CV% N Mean SD CV% AUCINF_obs h*ng/mL 3 3840 514 13.4 3 5670 4140 73.1 AUClast h*ng/mL 3 2970 175 5.90 3 3350 1760 52.4 Cl_F_obs mL/h/kg 3 3950 491 12.4 3 8310 6820 82.1 Cmax ng/mL 3 14.4 3.67 25.5 3 10.6 7.06 66.5 MRTINF_obs h 3 652 313 48.0 3 1010 535 53.1 MRTlast h 3 348 66.6 19.1 3 409 46.8 11.4 T1/2_Z h 3 414 194 46.9 3 648 396 61.1 Tmax h 3 3.00 3.00 3.00 3 1.00 3.00 168 Vz_F_obs mL/kg 3 2270000 743000 32.8 3 6010000 3250000 54.1 Table 9 Pharmacokinetic parameters of fulvestrant preparations given to rats at doses of 15 mg/kg and 30 mg/kg Variable Variable Units _ G1( 15mg/kg) G2( 15mg/kg) N mean SD CV% N mean SD CV% AUCINF_obs h*ng/mL 3 5420 1210 22.3 3 2620 407 15.6 AUClast h*ng/mL 3 4690 822 17.5 3 2220 349 15.7 Cl_F_obs mL/h/kg 3 2860 649 22.7 3 5830 996 17.1 Cmax ng/mL 3 19.1 4.15 21.8 3 11.4 3.53 30.9 MRTINF_obs h 3 463 120 25.9 3 530 69.4 13.1 MRTlast h 3 270 23.4 8.66 3 339 16.8 4.95 T1/2_Z h 3 440 225 51.1 3 364 42.2 11.6 Tmax h 3 24.0 96.0 96.0 3 3.00 3.00 3.00 Vz_F_obs mL/kg 3 1680000 512000 30.5 3 3090000 840000 27.2 Table 9 (continued) Variable Variable Units _ G3( 15mg/kg) G4( 30mg/kg) N mean SD CV% N mean SD CV% AUCINF_obs h*ng/mL 3 3840 514 13.4 3 5670 4140 73.1 AUClast h*ng/mL 3 2970 175 5.90 3 3350 1760 52.4 Cl_F_obs mL/h/kg 3 3950 491 12.4 3 8310 6820 82.1 Cmax ng/mL 3 14.4 3.67 25.5 3 10.6 7.06 66.5 MRTINF_obs h 3 652 313 48.0 3 1010 535 53.1 MRTlast h 3 348 66.6 19.1 3 409 46.8 11.4 T1/2_Z h 3 414 194 46.9 3 648 396 61.1 Tmax h 3 3.00 3.00 3.00 3 1.00 3.00 168 Vz_F_obs mL/kg 3 2270000 743000 32.8 3 6010000 3250000 54.1

無none

[圖1] 係實施例1中研磨後混懸液中氟維司群固體粒子的粒徑分佈圖。 [圖2] 係實施例1中研磨後混懸液中氟維司群固體偏振光顯微鏡觀察圖，尺規為20微米。 [圖3] 係實施例2中研磨12h後混懸液中氟維司群固體粒子的粒徑分佈圖。 [圖4] 係實施例2中研磨4h後混懸液中氟維司群固體偏振光顯微鏡觀察圖，尺規為10微米。 [圖5] 係實施例2中研磨12h後混懸液中氟維司群固體偏振光顯微鏡觀察圖，尺規為10微米。 [圖6] 係實施例3中研磨4h後混懸液中氟維司群固體偏振光顯微鏡觀察圖，尺規為10微米。 [圖7] 係實施例4中處方4研磨17h後混懸液中氟維司群固體粒子的粒徑分佈圖。 [圖8] 係實施例4中處方5研磨17h後混懸液中氟維司群固體粒子的粒徑分佈圖。 [圖9] 係實施例5中處方6研磨後混懸液中氟維司群固體粒子的粒徑分佈圖。 [圖10] 係實施例5中處方7研磨後混懸液中氟維司群固體粒子的粒徑分佈圖。 [圖11] 係實施例5中處方6研磨後混懸液中氟維司群固體粒子的掃描電鏡圖。 [圖12] 係實施例5中處方7研磨後混懸液中氟維司群固體粒子的掃描電鏡圖。 [圖13] 係大鼠給予15 mg/kg和30 mg/kg劑量氟維司群混懸液的總藥時曲線圖。 [圖14] 係大鼠給予15 mg/kg劑量氟維司群混懸液（G1）的藥時曲線。 [圖15] 係大鼠給予15 mg/kg劑量氟維司群混懸液（G2）的藥時曲線。 [圖16] 係大鼠給予15 mg/kg劑量氟維司群混懸液（G3）的藥時曲線。 [圖17] 係大鼠給予30 mg/kg劑量氟維司群混懸液（G4）的藥時曲線。 [ Fig. 1 ] is the particle size distribution diagram of fulvestrant solid particles in the suspension after grinding in Example 1. [Fig. 2] It is the polarized light microscope observation picture of the fulvestrant solid in the suspension after grinding in Example 1, and the ruler is 20 microns. [Fig. 3] is the particle size distribution diagram of fulvestrant solid particles in the suspension after grinding for 12 hours in Example 2. [Fig. 4] It is the polarized light microscope observation picture of the fulvestrant solid in the suspension after grinding for 4 hours in Example 2, and the scale is 10 microns. [Fig. 5] It is a polarized light microscope observation picture of the fulvestrant solid in the suspension after grinding for 12 hours in Example 2, and the scale is 10 microns. [Fig. 6] It is the polarized light microscope observation picture of the fulvestrant solid in the suspension after grinding for 4 hours in Example 3, and the scale is 10 microns. [ Fig. 7 ] is the particle size distribution diagram of fulvestrant solid particles in the suspension after prescription 4 in Example 4 was ground for 17 hours. [ Fig. 8 ] is the particle size distribution diagram of fulvestrant solid particles in the suspension after prescription 5 in Example 4 was ground for 17 hours. [ Fig. 9 ] is the particle size distribution diagram of fulvestrant solid particles in the suspension after grinding prescription 6 in Example 5. [ Fig. 10 ] is the particle size distribution diagram of fulvestrant solid particles in the suspension after grinding prescription 7 in Example 5. [ Fig. 11 ] is the scanning electron micrograph of fulvestrant solid particles in the suspension after grinding prescription 6 in Example 5. [Fig. 12] It is the scanning electron micrograph of fulvestrant solid particles in the suspension after prescription 7 in Example 5 is grinded. [Fig. 13] The total drug-time curves of fulvestrant suspension administered to rats at doses of 15 mg/kg and 30 mg/kg. [Fig. 14] The drug-time curve of fulvestrant suspension (G1) administered to rats at a dose of 15 mg/kg. [Fig. 15] The drug-time curve of fulvestrant suspension (G2) administered to rats at a dose of 15 mg/kg. [Fig. 16] The drug-time curve of fulvestrant suspension (G3) administered to rats at a dose of 15 mg/kg. [Fig. 17] The drug-time curve of fulvestrant suspension (G4) administered to rats at a dose of 30 mg/kg.

Claims (10)

一種氟維司群藥物組合物，包含：氟維司群固體粒子，該氟維司群固體粒子的粒徑為Dv(10)選自小於等於600奈米，例如小於等於400奈米，Dv（50）選自小於等於700奈米且Dv（90）選自小於等於1000奈米； 優選地，該氟維司群固體粒子的粒徑為該Dv(10)選自0.01奈米～400奈米； 優選地，該氟維司群固體粒子的粒徑為該Dv(10)選自1奈米～350奈米；以及 優選地，該氟維司群固體粒子的粒徑為該Dv(10)選自10奈米～450奈米； 例如，該氟維司群固體粒子的粒徑為Dv(10)選自小於等於400奈米。 A fulvestrant pharmaceutical composition, comprising: fulvestrant solid particles, the particle diameter of the fulvestrant solid particles is Dv(10) selected from less than or equal to 600 nanometers, such as less than or equal to 400 nanometers, Dv( 50) selected from less than or equal to 700 nm and Dv(90) selected from less than or equal to 1000 nm; Preferably, the particle size of the fulvestrant solid particle is such that the Dv(10) is selected from 0.01 nm to 400 nm; Preferably, the particle size of the fulvestrant solid particles is such that the Dv(10) is selected from 1 nm to 350 nm; and Preferably, the particle size of the fulvestrant solid particle is such that the Dv(10) is selected from 10 nm to 450 nm; For example, the particle diameter of the fulvestrant solid particle is selected from Dv(10) less than or equal to 400 nm. 如請求項1所述的氟維司群藥物組合物，其中該氟維司群固體粒子的粒徑為該Dv（50）選自0.01奈米至700奈米； 優選地，該氟維司群固體粒子的粒徑為該Dv（50）選自1奈米～600奈米； 優選地，該氟維司群固體粒子的粒徑為該Dv（50）選自10奈米～500奈米； 優選地，該氟維司群固體粒子的粒徑為該Dv（90）選自1奈米～1000奈米； 優選地，該氟維司群固體粒子的粒徑為該Dv（90）選自10奈米～900奈米；以及 優選地，該氟維司群固體粒子的粒徑為該Dv（90）選自100奈米～800奈米。 The fulvestrant pharmaceutical composition according to claim 1, wherein the particle size of the fulvestrant solid particle is such that the Dv(50) is selected from 0.01 nm to 700 nm; Preferably, the particle size of the fulvestrant solid particles is such that the Dv(50) is selected from 1 nm to 600 nm; Preferably, the particle size of the fulvestrant solid particles is such that the Dv(50) is selected from 10 nm to 500 nm; Preferably, the particle size of the fulvestrant solid particle is such that the Dv(90) is selected from 1 nm to 1000 nm; Preferably, the particle size of the fulvestrant solid particles is such that the Dv(90) is selected from 10 nm to 900 nm; and Preferably, the particle size of the fulvestrant solid particles is such that the Dv(90) is selected from 100 nm to 800 nm. 如請求項1或2所述的氟維司群藥物組合物，其中該氟維司群固體粒子的粒徑為Dv（25）選自1奈米～600奈米，例如該Dv（25）選自10奈米～500奈米，也可以為該Dv（25）選自100奈米～400奈米； 優選地，該氟維司群固體粒子的粒徑Dv（75）選自1奈米～900奈米，例如該Dv（75）選自10奈米～800奈米，也可以為該Dv（75）選自100奈米～700奈米。 The fulvestrant pharmaceutical composition according to claim 1 or 2, wherein the particle size of the fulvestrant solid particle is Dv (25) selected from 1 nm to 600 nm, for example, the Dv (25) selected From 10 nm to 500 nm, or the Dv(25) can be selected from 100 nm to 400 nm; Preferably, the particle size Dv (75) of the fulvestrant solid particle is selected from 1 nm to 900 nm, for example, the Dv (75) is selected from 10 nm to 800 nm, and it can also be the Dv (75 ) selected from 100 nm to 700 nm. 如請求項1至3其中任一項所述的氟維司群藥物組合物，更包括：載體； 優選地，該載體為非油性載體； 優選地，該非油性載體包括但不限於水； 優選地，該氟維司群藥物組合物中，該氟維司群固體粒子的重量百分比優選1.00%～50.00%，優選2.00%～30.00%，例如2.00%~25.00%；以及 優選地，該氟維司群藥物組合物的pH為6.5～8.0。 The fulvestrant pharmaceutical composition as described in any one of claims 1 to 3, further comprising: a carrier; Preferably, the carrier is a non-oily carrier; Preferably, the non-oily carrier includes but not limited to water; Preferably, in the fulvestrant pharmaceutical composition, the weight percentage of the fulvestrant solid particles is preferably 1.00% to 50.00%, preferably 2.00% to 30.00%, such as 2.00% to 25.00%; and Preferably, the pH of the fulvestrant pharmaceutical composition is 6.5-8.0. 如請求項1至4其中任一項所述的氟維司群藥物組合物，更包括選自以下的一種或多種輔料：助懸劑、潤濕劑、滲透壓調節劑、溶劑、穩定劑、緩衝劑、pH調節劑、表面活性劑、聚合物、電解質和非電解質； 例如，該潤濕劑的重量百分比優選0～5.00%；和/或 該助懸劑的重量百分比優選0～5.00%；和/或 該滲透壓調節劑的重量百分比優選0～5.00%；和/或 該緩衝劑的重量百分比優選0～1.00%；和/或 該穩定劑的重量百分比優選0～1.00%；和/或 該pH調節劑使用量優選調節組合物溶液的pH為6.5～8.0。 The fulvestrant pharmaceutical composition as described in any one of claims 1 to 4, further comprising one or more adjuvants selected from the following: suspending agent, wetting agent, osmotic pressure regulator, solvent, stabilizer, Buffers, pH regulators, surfactants, polymers, electrolytes and non-electrolytes; For example, the weight percentage of the wetting agent is preferably 0-5.00%; and/or The weight percentage of the suspending agent is preferably 0-5.00%; and/or The weight percentage of the osmotic pressure regulator is preferably 0-5.00%; and/or The weight percentage of the buffering agent is preferably 0-1.00%; and/or The weight percentage of the stabilizer is preferably 0-1.00%; and/or The usage amount of the pH adjuster is preferably used to adjust the pH of the composition solution to 6.5-8.0. 如請求項5所述的氟維司群藥物組合物，其中該助懸劑包括但不限於羧甲基纖維素鈉、聚乙二醇和聚維酮中的一種或多種；和/或 該潤濕劑包括但不限於泊洛沙姆、聚維酮、多庫酯鈉、去氧膽酸鈉和吐溫中的一種或多種；和/或 該滲透壓調節劑包括但不限於氯化鈉、甘露醇和蔗糖中的一種或多種；和/或 該溶劑包括但不限於注射用水；和/或 該穩定劑包括但不限於抗氧化劑、金屬離子螯合劑、聚環氧乙烷、聚環氧乙烷衍生物、聚山梨醇酯、去氧膽酸鈉、多庫酯鈉、泊洛沙姆、聚乙氧基化植物油、聚乙氧基化蓖麻油、脫水山梨糖醇棕櫚酸酯、卵磷脂、聚乙烯醇、人血清白蛋白、聚乙烯吡咯烷酮、聚維酮、聚乙二醇、氯化鈉、氯化鈣、右旋糖、丙三醇、甘露糖醇和交聯聚合物中的一種或多種；和/或 該緩衝劑包括但不限於磷酸、磷酸鹽、檸檬酸、檸檬酸鈉、鹽酸、氫氧化鈉、三羥甲基氨基甲烷、氫氧化鈉、鹽酸或其混合物的緩衝劑；和/或 該pH調節劑包括但不限於磷酸、磷酸鹽、檸檬酸、檸檬酸鈉、鹽酸和氫氧化鈉。 The fulvestrant pharmaceutical composition as claimed in item 5, wherein the suspending agent includes but not limited to one or more of sodium carboxymethylcellulose, polyethylene glycol and povidone; and/or The wetting agent includes, but is not limited to, one or more of poloxamer, povidone, docusate sodium, sodium deoxycholate, and Tween; and/or The osmotic pressure regulator includes, but is not limited to, one or more of sodium chloride, mannitol, and sucrose; and/or The solvent includes but is not limited to water for injection; and/or The stabilizer includes but not limited to antioxidant, metal ion chelating agent, polyethylene oxide, polyethylene oxide derivative, polysorbate, sodium deoxycholate, docusate sodium, poloxamer, Polyethoxylated Vegetable Oil, Polyethoxylated Castor Oil, Sorbitan Palmitate, Lecithin, Polyvinyl Alcohol, Human Serum Albumin, Polyvinylpyrrolidone, Povidone, Macrogol, Chlorinated One or more of sodium, calcium chloride, dextrose, glycerol, mannitol, and cross-linked polymers; and/or Such buffers include, but are not limited to, buffers of phosphoric acid, phosphate salts, citric acid, sodium citrate, hydrochloric acid, sodium hydroxide, tris, sodium hydroxide, hydrochloric acid, or mixtures thereof; and/or The pH adjusters include, but are not limited to, phosphoric acid, phosphate salts, citric acid, sodium citrate, hydrochloric acid, and sodium hydroxide. 如請求項6所述的氟維司群藥物組合物，其中該抗氧化劑包括但不限於檸檬酸、維生素C和維生素E中的一種或多種；和/或 該金屬離子螯合劑包括但不限於乙二胺四乙酸；和/或 該泊洛沙姆包括但不限於泊洛沙姆188、泊洛沙姆124和泊洛沙姆407中的一種或多種；和/或 該聚山梨醇酯包括但不限於聚山梨醇酯80和聚山梨醇酯20中的一種或多種；和/或 該聚維酮包括但不限於聚維酮K12、聚維酮K17、PLASDONETM C-12聚維酮、PLASDONETM C-17聚維酮和PLASDONETM C-30聚維酮中的一種或多種；和/或 該聚乙二醇包括但不限於聚乙二醇3350；和/或 該交聯聚合物包括但不限於羧甲基纖維素鈉；和/或 該磷酸鹽包括但不限於一水磷酸二氫鈉、二水磷酸二氫鈉、無水磷酸二氫鈉、一水磷酸二氫鈉、二水磷酸二氫鈉和無水磷酸二氫鈉中的一種或多種。 The fulvestrant pharmaceutical composition as claimed in item 6, wherein the antioxidant includes but not limited to one or more of citric acid, vitamin C and vitamin E; and/or The metal ion chelating agent includes, but is not limited to, ethylenediaminetetraacetic acid; and/or The poloxamer includes but is not limited to one or more of poloxamer 188, poloxamer 124 and poloxamer 407; and/or The polysorbate includes, but is not limited to, one or more of polysorbate 80 and polysorbate 20; and/or The povidone includes but is not limited to one or more of povidone K12, povidone K17, PLASDONETM C-12 povidone, PLASDONETM C-17 povidone and PLASDONETM C-30 povidone; and/or The polyethylene glycol includes but is not limited to polyethylene glycol 3350; and/or The cross-linked polymer includes, but is not limited to, sodium carboxymethylcellulose; and/or The phosphate includes but is not limited to one or Various. 如請求項1至7其中任一項所述的氟維司群藥物組合物，其中該氟維司群藥物組合物包括以下組分：1.00%～50.00%氟維司群固體粒子、0～5.00%潤濕劑、0～5.00%穩定劑、0～5.00%滲透壓調節劑、0～1.00%緩衝劑和溶劑，以及任選存在或不存在的0～5.00%的助懸劑。The fulvestrant pharmaceutical composition according to any one of claims 1 to 7, wherein the fulvestrant pharmaceutical composition comprises the following components: 1.00% to 50.00% fulvestrant solid particles, 0 to 5.00 % wetting agent, 0-5.00% stabilizer, 0-5.00% osmotic pressure regulator, 0-1.00% buffer and solvent, and 0-5.00% suspending agent optionally present or absent. 如請求項8所述的氟維司群藥物組合物，其中該氟維司群藥物組合物包括以下組分：5.00%～25.00%氟維司群固體粒子、0～5.00%潤濕劑、0～5.00%穩定劑、0～5.00%滲透壓調節劑、0～1.00%緩衝劑、0～5.00%的助懸劑，並且餘量為溶劑。The fulvestrant pharmaceutical composition according to claim 8, wherein the fulvestrant pharmaceutical composition comprises the following components: 5.00% to 25.00% fulvestrant solid particles, 0 to 5.00% wetting agent, 0 ～5.00% stabilizer, 0～5.00% osmotic pressure regulator, 0～1.00% buffer, 0～5.00% suspending agent, and the balance is solvent. 一種如請求項1至9其中任一項所述的氟維司群藥物組合物在製備氟維司群藥物製劑中的應用，其中： 優選地，該氟維司群藥物製劑包括但不限於片劑、顆粒劑、膠囊、微丸、口服液和注射劑； 優選地，該注射劑選自長效注射劑；及 優選地，該長效注射劑選自水混懸劑或混懸用粉。 An application of the fulvestrant pharmaceutical composition as described in any one of claims 1 to 9 in the preparation of fulvestrant pharmaceutical preparations, wherein: Preferably, the fulvestrant pharmaceutical preparations include but not limited to tablets, granules, capsules, pellets, oral liquids and injections; Preferably, the injection is selected from long-acting injections; and Preferably, the long-acting injection is selected from aqueous suspension or powder for suspension.
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