Fulvestrant pharmaceutical composition as well as preparation method and application thereof

Abstract

The invention provides a fulvestrant pharmaceutical composition as well as a preparation method and application thereof. The fulvestrant pharmaceutical composition comprises fulvestrant solid particles, and the particle sizes of the fulvestrant solid particles are as follows: Dv (10) is less than or equal to 600 nanometers, Dv (50) is less than or equal to 700 nanometers, and Dv (90) is less than or equal to 1000 nanometers. The fulvestrant pharmaceutical composition disclosed by the invention has a proper release speed, and after administration, the fulvestrant pharmaceutical composition rapidly reaches a peak concentration and maintains a relatively high blood concentration; the injection is high in drug content, free of organic solvent or oil, small in irritation, convenient to apply, small in administration volume, greatly reduced in injection pain degree and good in market prospect.

Description

[0001] This application is a divisional application of a Chinese invention patent application with an application date of December 8, 2021, an application number of 202111493817.3, and a title of "Fulvestrant Pharmaceutical Composition, Its Preparation Method and Application".

[0002] This application claims the priority benefit of a prior patent application with an application number of 202011433060.4 and a title of "Fulvestrant Pharmaceutical Composition, Its Preparation Method and Application", which was filed with the State Intellectual Property Office of China on December 10, 2020. The full text of the prior application is incorporated herein by reference. Technical Field

[0003] The present invention relates to a fulvestrant pharmaceutical composition, its preparation method and application, and belongs to the technical field of pharmaceutical preparations. Background Art

[0004] Fulvestrant is a selective estrogen receptor degrader (SERD) used for the treatment of hormone receptor-positive metastatic breast cancer in postmenopausal women with disease progression after anti-estrogen therapy. It was approved by the US FDA in 2002 for the treatment of hormone receptor-positive metastatic breast cancer.

[0005] The chemical name of fulvestrant is 7-(9-(4,4,5,5,5-pentafluoropentylsulfinyl)nonyl)estra-1,3,5(10)-triene-3,17-diol, and its structure is shown in Formula I:

[0006]

[0007] Fulvestrant is a lipophilic molecule with extremely low water solubility. Due to the poor solubility and low oral bioavailability of fulvestrant, it is currently commonly administered by intramuscular injection of an oil-based fulvestrant preparation. Currently, the commercially available preparation of fulvestrant, FASLODEXTM, is administered at 500 mg and requires two intramuscular injections of 5 mL of a 50 mg / mL fulvestrant preparation. Each 5 mL injection contains 10 w / v% ethanol, 10 w / v% benzyl alcohol, and 15 w / v% benzyl benzoate as co-solvents, and is supplemented with castor oil as another co-solvent and release rate regulator to 100 w / v%. Due to the use of a viscous oil-based carrier to dissolve fulvestrant, the administration of this preparation is slow (1 - 2 minutes per injection) and painful. Moreover, warnings regarding injection pain, sciatica, neuropathic pain, and peripheral neuropathy have been added to the FASLODEXTM label.

[0008] Therefore, finding a fulvestrant dosage form that does not contain organic solvents or oils, has low irritation, has an appropriate release rate, rapidly reaches the peak concentration and maintains a high blood drug concentration after administration, and is convenient to administer and has a low pain level is an urgent technical problem to be solved currently. SUMMARY OF THE INVENTION

[0009] To address the above technical problems, the present invention provides a fulvestrant pharmaceutical composition comprising fulvestrant solid particles, wherein the particle size of the fulvestrant solid particles has a Dv(10) selected from being less than or equal to 600 nm, such as less than or equal to 400 nm, a Dv(50) selected from being less than or equal to 700 nm and a Dv(90) selected from being less than or equal to 1000 nm.

[0010] According to an embodiment of the present invention, the particle size of the fulvestrant solid particles may have a Dv(10) selected from being less than or equal to 500 nm, selected from being less than or equal to 400 nm, such as from 0.01 nm to 400 nm, for example, a Dv(10) selected from 1 nm to 550 nm, and may also be selected from 10 nm to 500 nm, such as 20 nm, 30 nm, 40 nm, 50 nm, 60 nm, 70 nm, 80 nm, 90 nm, 100 nm, 110 nm, 120 nm, 130 nm, 140 nm, 150 nm, 160 nm, 170 nm, 180 nm, 190 nm, 200 nm, 210 nm, 220 nm, 230 nm, 240 nm, 250 nm, 260 nm, 270 nm, 280 nm, 290 nm, 300 nm, 350 nm, 400 nm, 450 nm, 500 nm, and its examples may be selected from 196.200 nm, 132.420 nm, 435.63 nm or 341.71 nm.

[0011] According to an embodiment of the present invention, the particle size of the fulvestrant solid particles may have a Dv(50) selected from 0.01 nm to 700 nm, for example, a Dv(50) selected from 1 nm to 600 nm, and may also be selected from 10 nm to 500 nm, such as 10 nm, 20 nm, 30 nm, 40 nm, 50 nm, 60 nm, 70 nm, 80 nm, 90 nm, 100 nm, 110 nm, 120 nm, 130 nm, 140 nm, 150 nm, 160 nm, 170 nm, 180 nm, 190 nm, 200 nm, 210 nm, 220 nm, 230 nm, 240 nm, 250 nm, 260 nm, 270 nm, 280 nm, 290 nm, 300 nm, 350 nm, 400 nm, 450 nm, 500 nm, and its examples may be selected from 401.800 nm, 281.630 nm, 448.340 nm, 473.84 nm or 535.27 nm.

[0012] According to an embodiment of the present invention, the particle size of the solid particles of fulvestrant may be such that Dv(90) is selected from 1 nanometer to 1000 nanometers, for example, Dv(90) is selected from 10 nanometers to 900 nanometers, and may also be 100 nanometers to 800 nanometers, such as 100 nanometers, 110 nanometers, 120 nanometers, 130 nanometers, 140 nanometers, 150 nanometers, 160 nanometers, 170 nanometers, 180 nanometers, 190 nanometers, 200 nanometers, 210 nanometers, 220 nanometers, 230 nanometers, 240 nanometers, 250 nanometers, 260 nanometers, 270 nanometers, 280 nanometers, 290 nanometers, 300 nanometers, 350 nanometers, 400 nanometers, 450 nanometers, 500 nanometers, 550 nanometers, 600 nanometers, 650 nanometers, 700 nanometers, 750 nanometers, 800 nanometers, and its examples may be selected from 716.500 nanometers, 866.720 nanometers, 599.350 nanometers, 657.69 nanometers or 657.05 nanometers.

[0013] According to an embodiment of the present invention, the particle size of the solid particles of fulvestrant may also be such that Dv(25) is selected from 1 nanometer to 600 nanometers, for example, Dv(25) is selected from 10 nanometers to 500 nanometers, and may also be Dv(25) is selected from 100 nanometers to 400 nanometers, such as 100 nanometers, 110 nanometers, 120 nanometers, 130 nanometers, 140 nanometers, 150 nanometers, 160 nanometers, 170 nanometers, 180 nanometers, 190 nanometers, 200 nanometers, 210 nanometers, 220 nanometers, 230 nanometers, 240 nanometers, 250 nanometers, 260 nanometers, 270 nanometers, 280 nanometers, 290 nanometers, 300 nanometers, 350 nanometers, 400 nanometers, and its examples may be selected from 272.00 nanometers, 189.28 nanometers, 316.91 nanometers, 480.27 nanometers or 398.95 nanometers.

[0014] According to an embodiment of the present invention, the particle size of the solid particles of fulvestrant may also be such that Dv(75) is selected from 1 nanometer to 900 nanometers, for example, Dv(75) is selected from 10 nanometers to 800 nanometers, and may also be Dv(75) is selected from 100 nanometers to 700 nanometers, such as 100 nanometers, 110 nanometers, 120 nanometers, 130 nanometers, 140 nanometers, 150 nanometers, 160 nanometers, 170 nanometers, 180 nanometers, 190 nanometers, 200 nanometers, 210 nanometers, 220 nanometers, 230 nanometers, 240 nanometers, 250 nanometers, 260 nanometers, 270 nanometers, 280 nanometers, 290 nanometers, 300 nanometers, 350 nanometers, 400 nanometers, 450 nanometers, 500 nanometers, 550 nanometers, 600 nanometers, 650 nanometers, 700 nanometers, and its examples may be selected from 540.00 nanometers, 419.10 nanometers, 634.29 nanometers, 596.56 nanometers or 562.80 nanometers.

[0015] The fulvestrant pharmaceutical composition described in the present invention may further comprise a carrier. The carrier may be a non-oily carrier. Preferably, the non-oily carrier includes but is not limited to water. The water may be commercially available injection water for injection, preferably sterilized water for injection.

[0016] According to an embodiment of the present invention, the pH of the fulvestrant pharmaceutical composition is 6.5 to 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.

[0017] According to an embodiment of the present invention, the fulvestrant pharmaceutical composition may further comprise one or more selected from the following: suspending agents, wetting agents, osmotic pressure regulators, solvents, stabilizers, buffers, pH regulators, surfactants, polymers, electrolytes and non-electrolytes. Among them, the polymer may be a cross-linked polymer and / or a non-cross-linked polymer.

[0018] 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.

[0019] According to an embodiment of the present invention, the wetting agent includes but is not limited to one or more of poloxamer, povidone, sodium docusate, sodium deoxycholate and Tween. The Tween may be a commercially available Tween reagent, such as one or more of Tween 20 and Tween 80.

[0020] 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.

[0021] According to an embodiment of the present invention, the solvent includes but is not limited to water for injection.

[0022] According to an embodiment of the present invention, the stabilizers include, but are not limited to: one or more of antioxidants, metal ion chelators, polyethylene oxide (PEO), polyethylene oxide derivatives, polysorbates, sodium deoxycholate, sodium docusate, poloxamers, polyethoxylated vegetable oils, polyethoxylated castor oils, sorbitan palmitates, lecithins, polyvinyl alcohols, human serum albumin, polyvinylpyrrolidones, povidones, polyethylene glycols, sodium chloride, calcium chloride, dextrose, glycerol, mannitol, and crosslinked polymers. The antioxidants include, but are not limited to, one or more of citric acid, vitamin C, and vitamin E. The metal ion chelators include, but are not limited to, ethylenediaminetetraacetic acid (EDTA). The poloxamers include, but are not limited to, one or more of poloxamer 188, poloxamer 124, and poloxamer 407. The polysorbates include, but are not limited to, one or more of polysorbate 80 and polysorbate 20. The povidones include, but are not limited to, one or more of povidone K12, povidone K17, PLASDONETM C-12 povidone, PLASDONETM C-17 povidone, and PLASDONETM C-30 povidone. The polyethylene glycols include, but are not limited to, polyethylene glycol 3350. The crosslinked polymers include, but are not limited to, sodium carboxymethyl cellulose.

[0023] According to an embodiment of the present invention, the buffers include, but are not limited to: buffers of phosphoric acid, phosphates, citric acid (citrate), sodium citrate, tris(hydroxymethyl)aminomethane (Tris), sodium hydroxide, hydrochloric acid (HCl), or mixtures thereof.

[0024] According to an embodiment of the present invention, the pH adjusters include, but are not limited to: phosphoric acid, phosphates, citric acid, sodium citrate, hydrochloric acid, and sodium hydroxide.

[0025] According to an embodiment of the present invention, the phosphates include, but are not limited to, disodium hydrogen phosphate, sodium dihydrogen phosphate, or mixtures or hydrates thereof, such as disodium hydrogen phosphate monohydrate (Na2HPO4·H2O), disodium hydrogen phosphate dihydrate (Na2HPO4·2H2O), anhydrous disodium hydrogen phosphate (anhydrous Na2HPO4), sodium dihydrogen phosphate monohydrate (NaH2PO4·H2O), sodium dihydrogen phosphate dihydrate (NaH2PO4·2H2O), and anhydrous sodium dihydrogen phosphate (anhydrous NaH2PO4).

[0026] According to an embodiment of the present invention, the co-solvents include, but are not limited to: one or more of ethanol and propylene glycol.

[0027] In the described fulvestrant pharmaceutical composition, the weight fraction of fulvestrant solid particles is preferably 1.00% to 50.00%, more preferably 2.00% to 30.00%, for example 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%; the said weight fraction refers to the percentage of the weight of fulvestrant solid particles in the total weight of the fulvestrant pharmaceutical composition.

[0028] In the described fulvestrant pharmaceutical composition, the weight fraction of the wetting agent is preferably 0 to 5.00%, for example 1.00%, 2.00%, 3.00%, 4.00%, 5.00%, such as 1.00%; the said weight fraction refers to the percentage of the weight of the surfactant in the total weight of the fulvestrant pharmaceutical composition.

[0029] In the described fulvestrant pharmaceutical composition, the weight fraction of the suspending agent is preferably 0 to 5.00%, for example 0, 1.00%, 2.00%, 3.00%, 4.00%, 5.00%; the said weight fraction refers to the percentage of the weight of the suspending agent in the total weight of the fulvestrant pharmaceutical composition.

[0030] In the described fulvestrant pharmaceutical composition, the weight fraction of the osmotic pressure regulator is preferably 0 to 5.00%, for example 0, 1.00%, 2.00%, 3.00%, 4.00%, 5.00%; the said weight fraction refers to the percentage of the weight of the osmotic pressure regulator in the total weight of the fulvestrant pharmaceutical composition.

[0031] In the described fulvestrant pharmaceutical composition, the weight fraction of the buffer is preferably 0 to 1.00%, for example 0, 0.10%, 0.20%, 0.30%, 0.40%, 0.50%, 0.60%, 0.70%, 0.80%, 0.90%, 1.00%; the said weight fraction refers to the percentage of the weight of the buffer in the total weight of the fulvestrant pharmaceutical composition.

[0032] In the described fulvestrant pharmaceutical composition, the weight fraction of the stabilizer is preferably 0 to 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%; the weight fraction refers to the percentage of the weight of the stabilizer in the total weight of the fulvestrant pharmaceutical composition.

[0033] In the described fulvestrant pharmaceutical composition, the usage amount of the pH regulator preferably adjusts the pH of the composition solution to 6.5 to 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.

[0034] The described fulvestrant pharmaceutical composition preferably comprises 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 to 1.00% buffer and solvent, and 0 to 5.00% suspending agent optionally present or absent.

[0035] Preferably, the described fulvestrant pharmaceutical composition preferably comprises 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 and 0 to 1.00% buffer, and 0 to 5.00% suspending agent optionally present or absent, and the balance is solvent.

[0036] According to the embodiments of the present invention, the described fulvestrant pharmaceutical composition can be any of the following formulations:

[0037] Formulation 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 pH 7.4, and the pH regulator is sodium dihydrogen phosphate and disodium hydrogen phosphate;

[0038] Formulation 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 pH 7.4, and the pH regulator is sodium dihydrogen phosphate and disodium hydrogen phosphate;

[0039] Formulation Three: 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 adjusts the pH of the diluent to pH 7.4, and the pH regulator is sodium dihydrogen phosphate and disodium hydrogen phosphate;

[0040] Formulation Four: 5.00% fulvestrant, 1.00% Tween 20, 0.30% povidone K12, 0.02% sodium docusate, 2.76% mannitol, pH regulator and water, wherein the pH regulator adjusts the pH of the diluent to pH 7.4, and the pH regulator is sodium dihydrogen phosphate and disodium hydrogen phosphate;

[0041] Formulation Five: 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.

[0042] Formulation Six: 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.

[0043] The present invention also provides a preparation method of the fulvestrant pharmaceutical composition as described above, which comprises the following steps:

[0044] Step 1: Mix the fulvestrant solid particles with other components in the formulation to obtain a premix;

[0045] Step 2: Grind the premix obtained in Step 1 together with zirconium beads to obtain the fulvestrant pharmaceutical composition.

[0046] In Step 1, the mixing is preferably stirring mixing.

[0047] In Step 2, the particle size of the zirconium beads can be 0.01 mm to 2 mm, such as 0.1 mm, 0.3 mm, 0.6 mm or 1 mm.

[0048] In Step 2, the volume ratio of the zirconium beads to the premix is preferably 1 to 5, such as 1, 1.5, 2 or 3.

[0049] In Step 2, the grinding time can be 1 minute to 24 hours, or 5 minutes to 20 hours, such as 4 hours or 12 hours.

[0050] According to the embodiments of the present invention, the zirconium beads refer to conventional commercially available zirconia beads.

[0051] The present invention also provides the use of the above-mentioned fulvestrant pharmaceutical composition in the preparation of a fulvestrant pharmaceutical preparation.

[0052] The fulvestrant pharmaceutical preparation includes but is not limited to one or more of tablets, granules, capsules, pellets, oral liquids, injections, etc. Preferably, the tablets include but are 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, a powder for injection, or a 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 powder for suspension can be a freeze-dried powder injection.

[0053] According to an 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, and is dispersed into a suspension with a specific diluent when used.

[0054] According to an embodiment of the present invention, the concentration of fulvestrant in the long-acting injection is not less than 50 mg / ml.

[0055] The present invention also provides a fulvestrant pharmaceutical preparation which contains the above-mentioned fulvestrant pharmaceutical composition.

[0056] According to an embodiment of the present invention, the fulvestrant pharmaceutical preparation has the dosage form selection and / or fulvestrant concentration as described above.

[0057] The present invention also provides the use of the above-mentioned fulvestrant pharmaceutical composition and / or fulvestrant pharmaceutical preparation in the prevention and / or treatment of hormone receptor-positive metastatic breast cancer.

[0058] The present invention also provides a method for preventing and / or treating hormone receptor-positive metastatic breast cancer, which includes administering the above-mentioned fulvestrant pharmaceutical composition and / or fulvestrant pharmaceutical preparation to a patient in need, such as a human.

[0059] According to an embodiment of the present invention, the "Dv(10)", "Dv(25)", "Dv(50)", "Dv(75)", and "Dv(90)" refer to volume-weighted particle diameters, where 10 v / v%, 25 v / v%, 50 v / v%, 75 v / v%, or 90 v / v% of the particles have equal or smaller diameters during measurement. For example, if the Dv(50) of a particle population is about 25 microns, then 50% of the volume of the particles has a diameter less than or equal to about 25 microns.

[0060] Unless otherwise specified, the particle diameter parameters in the context of this application, such as "D(10)", "D(25)", "D(50)", "D(75)" and "D(90)", all refer to volume-weighted particle diameters, which respectively have the same meaning as "Dv(10)", "Dv(25)", "Dv(50)", "Dv(75)" and "Dv(90)".

[0061] On the basis of not violating the common knowledge in the art, the above preferred conditions can be combined arbitrarily to obtain various preferred examples of the present invention.

[0062] The reagents and raw materials used in the present invention are all commercially available.

[0063] According to the embodiments of the present invention, the room temperature refers to an environmental temperature of 10°C to 35°C.

[0064] The beneficial effects of the present invention are as follows: The fulvestrant pharmaceutical composition of the present invention has a favorable release rate, rapidly reaches the peak concentration after administration and maintains a high blood drug concentration, and has high bioavailability; the active pharmaceutical ingredient content of the fulvestrant pharmaceutical composition of the present invention is high, does not contain organic solvents or oils, has low irritation, is convenient to administer, reduces the administration volume, greatly reduces the injection pain, and has good market prospects. Description of the Drawings

[0065] Figure 1 It is the particle size distribution diagram of fulvestrant solid particles in the suspension after grinding in Example 1;

[0066] Figure 2 It is the observation diagram of fulvestrant solid under polarized light microscope in the suspension after grinding in Example 1, and the scale bar is 20 microns;

[0067] Figure 3 It is the particle size distribution diagram of fulvestrant solid particles in the suspension after grinding for 12 h in Example 2;

[0068] Figure 4 It is the observation diagram of fulvestrant solid under polarized light microscope in the suspension after grinding for 4 h in Example 2, and the scale bar is 10 microns;

[0069] Figure 5 It is the observation diagram of fulvestrant solid under polarized light microscope in the suspension after grinding for 12 h in Example 2, and the scale bar is 10 microns;

[0070] Figure 6 It is the observation diagram of fulvestrant solid under polarized light microscope in the suspension after grinding for 4 h in Example 3, and the scale bar is 10 microns;

[0071] Figure 7 It is the particle size distribution diagram of fulvestrant solid particles in the suspension after grinding for 17 h of Prescription 4 in Example 4;

[0072] Figure 8 Particle size distribution diagram of fulvestrant solid particles in the suspension after grinding for 17 h in Prescription 5 of Example 4;

[0073] Figure 9 Particle size distribution diagram of fulvestrant solid particles in the suspension after grinding in Prescription 6 of Example 5;

[0074] Figure 10 Particle size distribution diagram of fulvestrant solid particles in the suspension after grinding in Prescription 7 of Example 5;

[0075] Figure 11 Scanning electron micrograph of fulvestrant solid particles in the suspension after grinding in Prescription 6 of Example 5;

[0076] Figure 12 Scanning electron micrograph of fulvestrant solid particles in the suspension after grinding in Prescription 7 of Example 5;

[0077] Figure 13 Total plasma concentration-time curve of rats administered fulvestrant suspension at doses of 15 mg / kg and 30 mg / kg;

[0078] Figure 14 Plasma concentration-time curve of rats administered fulvestrant suspension at a dose of 15 mg / kg (G1);

[0079] Figure 15 Plasma concentration-time curve of rats administered fulvestrant suspension at a dose of 15 mg / kg (G2);

[0080] Figure 16 Plasma concentration-time curve of rats administered fulvestrant suspension at a dose of 15 mg / kg (G3);

[0081] Figure 17 Plasma concentration-time curve of rats administered fulvestrant suspension at a dose of 30 mg / kg (G4). Detailed implementation manners

[0082] The technical solutions of the present invention will be further described in detail below with reference to specific embodiments. It should be understood that the following embodiments are only illustrative of and explanatory of the present invention, and should not be construed as limiting the protection scope of the present invention. All technologies implemented based on the above content of the present invention are covered within the scope of protection intended by the present invention.

[0083] Unless otherwise specified, the raw materials and reagents used in the following embodiments are all commercially available products, or can be prepared by known methods. The experimental methods without specific conditions noted in the following embodiments are carried out according to conventional methods and conditions, or selected according to the product specifications.

[0084] Example 1

[0085] Table 1 Prescription Table of Suspension Injection

[0086] Prescription 1 Composition (w / v%) Fulvestrant 25.00 Tween 20 1.62 Mannitol 2.29 Sodium dihydrogen phosphate anhydrous 0.09 Disodium hydrogen phosphate anhydrous 0.42 Sterile water for injection 70.58 (q.s. 100)

[0087] Weigh the raw and auxiliary materials according to the dosage of Prescription 1 in Table 1. After mixing evenly, add zirconium beads with a volume of 1 times and a diameter of 0.3 mm and place them in a grinding tank for grinding for 3 hours. Stop grinding and filter to obtain the initial suspension of fulvestrant. Add zirconium beads with a volume of 1 times and a diameter of 0.1 mm to the initial suspension, place them in a grinding tank for grinding, and sample at different times for particle size measurement using a laser particle size analyzer (parameters of the laser particle size analyzer: dispersion medium: water; refractive index of the dispersion medium: 1.333; absorption rate of the sample material: 0.01; refractive index of the sample material: 1.521). Measure the particle size. Grind for 20.5 hours and stop grinding to obtain the fulvestrant pharmaceutical composition. The grinding is carried out using a ball mill. The parameters of the planetary ball mill are set as follows: fixed parameters: the diameter of the public turntable is about 191 mm, the diameter of the self-rotating cup is about 71 mm, the height of the self-rotating cup is about 70 mm, the capacity of the self-rotating cup is 100 ml, the rotation speed of the public turntable is 10 r / min, and the self-rotation speed is 720 r / min.

[0088] Use a polarized light microscope to observe the particle size and morphology of the particles in the suspension after grinding. The particle size distribution data of the fulvestrant solid particles in the suspension after grinding at different times are shown in Table 2. The particle size distribution and morphology of the fulvestrant solid particles in the suspension after grinding are shown in Figure 1 and Figure 2 .

[0089] The results show that the particle morphology and size observed by the polarized light microscope are consistent with the particle size measurement by the laser particle size analyzer. The fulvestrant solid in the suspension after grinding for 20.5 h is spherical with a diameter of about 8 μm. After grinding with Prescription 2 and the smallest grinding beads for 3 hours, the particle size reaches the minimum. If the grinding time is extended, the particle size not only does not decrease but increases.

[0090] Table 2 Particle Size Distribution (Volume Weighted) of Fulvestrant in the Composition Obtained by Grinding the Suspension at Different Times in Example 1

[0091] 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

[0092] Example 2

[0093] Table 3 Prescription Table of Suspension Injections for Examples 2 and 3

[0094]

[0095] Weigh the raw and auxiliary materials according to the dosage of Prescription 2 in Table 3. Composition of the diluent (by total weight of the diluent, w / w%): mannitol 2.95%, sodium dihydrogen phosphate 0.122%, disodium hydrogen phosphate 0.58%, the balance being water, pH 7.4. Add the initial suspension to 1.5 times the volume of 0.3 mm zirconium beads and place them in a grinding jar for grinding for 12 hours to obtain a fulvestrant pharmaceutical composition. The grinding is carried out using a ball mill, and the parameter settings of the planetary ball mill are as follows: Fixed parameters: the diameter of the public turntable is about 191 mm, the diameter of the self-rotating cup is about 71 mm, the height of the self-rotating cup is about 70 mm, the capacity of the self-rotating cup is 100 ml, the rotation speed of the public turntable is 10 r / min, and the self-rotation speed is 720 r / min.

[0096] Use a nano particle size analyzer (NICOMP Particle Sizing Systems, parameter settings: dispersion medium: water; refractive index of the dispersion medium: 1.333; viscosity: 0.933 cp; temperature: 23 °C, light intensity setting value: 300 kHz) to measure the particle size. Observe the particle size morphology at 4 h and 12 h (the end point of grinding) of grinding using a polarized light microscope.

[0097] The particle size distribution data of the fulvestrant solid particles in the suspension after grinding for 12 h are shown in Table 4 and Figure 3 as follows. The particle size morphologies of the fulvestrant solid particles in the suspension after grinding for 4 h and 12 h are shown in Figure 4 and Figure 5 respectively. The fulvestrant solid particles in the suspension after grinding for 4 h and 12 h are particles smaller than 2 microns and smaller than 1 micron respectively.

[0098] Table 4 Particle size distribution of fulvestrant in the suspension (volume weighted)

[0099] 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

[0100] Example 3

[0101] Weigh the raw and auxiliary materials according to the dosage of Prescription 3 in Table 3. Composition of the diluent (by total weight of the diluent, w / w%): mannitol 2.95%, sodium dihydrogen phosphate 0.122%, disodium hydrogen phosphate 0.58%, the balance being water, pH 7.4. Add the initial suspension to 1.5 times the volume of 0.3 mm zirconium beads and place them in a grinding jar for grinding for 4 hours to obtain a fulvestrant pharmaceutical composition. The grinding is carried out using a ball mill, and the parameter settings of the planetary ball mill are as follows: Fixed parameters: the diameter of the public turntable is about 191 mm, the diameter of the self-rotating cup is about 71 mm, the height of the self-rotating cup is about 70 mm, the capacity of the self-rotating cup is 100 ml, the rotation speed of the public turntable is 10 r / min, and the self-rotation speed is 720 r / min.

[0102] The particle size morphology of the fulvestrant solid particles in the suspension after grinding is shown in Figure 6 .

[0103] The results showed that, quite different from Formulation 2, the solid particles of fulvestrant in the suspension were 5 - 15 μm massive aggregates after grinding for 4 h.

[0104] Example 4

[0105] Table 5 Prescription tables of Example 4 and suspension injection

[0106]

[0107] Weigh the raw and auxiliary materials according to the dosages of Prescription 4 and 5 in Table 5. Composition of the diluent (w / w% based on the total weight of the diluent): mannitol 2.95%, 0.122 g of sodium dihydrogen phosphate, 0.58 g of disodium hydrogen phosphate, and the balance being water, with a pH of 7.4. Add the initial suspension to 1.5 times the volume of 0.3 mm zirconium beads and place them in a grinding jar for grinding for 17 hours to obtain the fulvestrant pharmaceutical composition. The grinding is carried out using a ball mill, and the parameters of the planetary ball mill are set as follows: Fixed parameters: the diameter of the public turntable is about 191 mm, the diameter of the self-rotating cup is about 71 mm, the height of the self-rotating cup is about 70 mm, the capacity of the self-rotating cup is 100 ml, the rotation speed of the public turntable is 10 r / min, and the self-rotation speed is 720 r / min.

[0108] The particle size is measured using a nanoparticle size analyzer (NICOMP Particle Sizing Systems, parameters set as follows: dispersion medium: water; refractive index of the dispersion medium: 1.333; viscosity: 0.933 cp; temperature: 23 °C, light intensity setting value: 300 kHz).

[0109] The particle size distribution data of the solid particles of fulvestrant in the suspension after grinding Prescription 4 and 5 for 17 h are shown in Table 4, Table 6 Figure 7 and Figure 8 as shown.

[0110] Table 6 Gaussian distribution average particle sizes of Prescription 4 and Prescription 5

[0111]

[0112] Example 5

[0113] Table 7 Prescription tables of Prescription 6 and Prescription 7 of Example 5 for suspension injection

[0114]

[0115] Weigh the raw and auxiliary materials according to the prescription dosage in Table 7, add zirconium beads with a volume 1.5 times that of the materials, place them in a grinding jar for grinding. For Prescription 6 and 7, 0.3 mm and 0.6 mm zirconium beads are used respectively, and the grinding times are 21 hours and 25 hours respectively to obtain the fulvestrant pharmaceutical composition. The grinding is carried out using a ball mill. The parameter settings of the planetary ball mill are as follows: Fixed parameters: The diameter of the public turntable is about 191 mm, the diameter of the self-rotating cup is about 71 mm, the height of the self-rotating cup is about 70 mm, the capacity of the self-rotating cup is 100 ml, the rotation speed of the public turntable is 10 r / min, and the self-rotation speed is 720 r / min.

[0116] Use a nano particle size analyzer (NICOMP Particle Sizing Systems, parameter settings: Dispersing medium: water; Refractive index of the dispersing medium: 1.333; Viscosity: 0.933 cp; Temperature: 23 °C, Light intensity setting value: 300 kHz) to measure the particle size. The particle size distribution data of the fulvestrant solid particles in the suspensions after grinding of Prescription 6 and 7 are shown in Table 4 Figure 9 and Figure 10 as shown.

[0117] Use a scanning electron microscope (FEI, model F50) to observe the morphology and size. The voltage of the scanning electron microscope is 10 kv and the beam current is 2.0 for testing. The electron microscope photos of the fulvestrant solid particles in the suspensions after grinding of Prescription 6 and 7 are shown in Figure 11 and Figure 12 as shown. Irregular block particles smaller than 1 μm are observed in both cases.

[0118] Detect the related substances of fulvestrant according to the EP10.0 method. The results of the related substances are shown in Table 8. The results show that the single impurity and total impurity of the self-made suspension are lower than those of the marketed reference preparation, indicating better quality.

[0119] Table 8 Results of related substances of the preparations in Example 5 (Prescription 6 and 7) and the reference preparation

[0120]

[0121] Note: ND indicates not detected;

[0122] * is the degradation product of fulvestrant;

[0123] 6-Keto fulvestrant, 6,7-fulvestrant, Fulvestrant β-Isomer, Fulvestrant Sulphone, Fulvestrant Bromo Analogue, Fulvestrant Extended, Fulvestrant Sterol Dimer.

[0124] Example 6

[0125] The formulations of Prescription 6 and Prescription 7 obtained in Example 5 were diluted to 50 mg / ml with a diluent. The composition of the diluent was: 1.62% Tween 20, 0.2% sodium carboxymethylcellulose, 2.29% mannitol, 0.09% sodium dihydrogen phosphate anhydrous, 0.42% disodium hydrogen phosphate anhydrous.

[0126] The diluted fulvestrant suspensions of Prescription 6 (G2) and Prescription 7 (G3), the marketed comparator fulvestrant injection FASLODEX (G1, 50 mg / ml, VETTER Pharma-fertigung GmbH & Co KG, Germany, batch number: RH832, expiration date February 2024), were intramuscularly injected into the lateral thigh muscles of male Wistar rats at a dose of fulvestrant 15 mg / kg (administration volume 0.3 mL / kg), and the undiluted fulvestrant suspension of Prescription 7 was injected at a dose of fulvestrant 30 mg / kg (G4, administration volume 0.11 mL / kg). The animals were SPF grade, weighing 189 - 200 g, 6 - 8 weeks old (Beijing Vital River Laboratory Animal Technology Co., Ltd., quality certificate number 110011200110944286, use license number SYXK (Su) 2018 - 0034), with 3 rats in each group.

[0127] Clinical observations were carried out after administration. On the first day of administration (D1), observations were made 2 times: before administration and on the afternoon of the same day after administration. Thereafter, observations were made once a day for a total of 45 days. Clinical observations included skin, hair, eyes, ears, nose, mouth, chest, abdomen, urogenital region, limbs and other parts, as well as respiration, movement, urination, defecation, behavior changes and muscle irritation responses at the administration site. Also, blood samples were collected before administration (0 h, D-1), 1, 3, 7, 24 h after administration on D1, D4 (72 h), D7 (144 h), D11 (240 h), D15 (336 h), D20 (456 h), D25 (576 h), D30 (696 h), D35 (816 h), D40 (936 h) and D45 (1056 h) for bioanalysis and non-compartmental model calculation of pharmacokinetic parameters such as Tmax, Cmax, AUC(0-t), AUC(0-∞), T1 / 2, MRT, CL, Vz, etc. for each group using WinNonlin version 8.1.

[0128] After administration on D45, the animals were dissected and histopathological examination was performed on the administration site to observe inflammatory reactions and drug residues. No abnormalities were found in the clinical observations, body weights, irritation observations at the administration site, gross anatomy of the administration site in all the test animals in each dose group. No inflammation or drug residues were found at the administration site, and no abnormalities related to the test article were found in the histopathological examination.

[0129] The pharmacokinetic parameters of rats administered with 15 mg / kg and 30 mg / kg doses of fulvestrant suspension are shown in Table 9, and Figure 13 , 14 , 15, 16 and 17. The results showed that after single intramuscular injection of 15 mg / kg of the administration preparation in Wistar rats, the Cmax values from large to small were: G1 > G3 > G2; the area under the drug concentration-time curve AUCINF_obs from large to small were: G1 > G3 > G2; the AUClast from large to small were: G1 > G3 > G2; the terminal elimination half-life of the drug T1 / 2_Z from large to small were: G1 > G3 > G2; the clearance Cl_obs from large to small were: G2 > G3 > G1; the mean residence time MRTINF_obs from large to small were: G3 > G2 > G1; the volume of distribution Vz_obs from large to small were: G2 > G3 > G1. The above results indicate that the sustained-release effect of the self-prepared suspension is better than that of the marketed comparative preparation. The peak time Tmax of the marketed comparative preparation is greater than that of the self-prepared suspension, indicating that the suspension can take effect more rapidly.

[0130] After a single intramuscular injection of the administration preparation with batch number 20201221-1 to Wistar rats, when comparing the pharmacokinetic parameters at the doses of 15 mg / kg and 30 mg / kg, the increase in the plasma exposure (AUClast) of fulvestrant was lower than the increase in the dose, and there was no difference in MRT, indicating that the drug was continuously and stably released after administration of the high-concentration and high-dose suspension, without causing sudden drug release.

[0131] Table 9 Pharmacokinetic parameters of rats administered fulvestrant preparations at doses of 15 mg / kg and 30 mg / kg

[0132]

[0133] Table 9 (continued)

[0134]

Claims

1. A fulvestrant pharmaceutical composition, characterized in that: It contains solid particles of fulvestrant, and the particle size Dv(10) of the solid particles of fulvestrant is selected from 80 to 600 nanometers, Dv(50) is selected from less than or equal to 700 nanometers, and Dv(90) is selected from less than or equal to 1000 nanometers.

2. The fulvestrant pharmaceutical composition according to claim 1, wherein: The particle size Dv(10) of the solid particles of fulvestrant is selected from 90 to 500 nanometers, for example, selected from 100 to 450 nanometers, for example, selected from 300 to 450 nanometers.

3. The fulvestrant pharmaceutical composition according to claim 1 or 2, characterized in that: The particle size Dv(50) of the solid particles of fulvestrant is selected from 100 to 700 nanometers, for example, selected from 200 to 600 nanometers, for example, selected from 400 to 600 nanometers.

4. The fulvestrant pharmaceutical composition according to any one of claims 1-3, characterized in that: The particle size Dv(90) of the solid particles of fulvestrant is selected from 400 to 900 nanometers, for example, selected from 500 to 900 nanometers, for example, selected from 600 nanometers to 700 nanometers.

5. The fulvestrant pharmaceutical composition according to any one of claims 1-4, characterized in that: The particle size Dv(25) of the solid particles of fulvestrant is selected from 100 to 600 nanometers, for example, selected from 300 to 500 nanometers. and / or The particle size Dv(75) of the solid particles of fulvestrant is selected from 300 to 900 nanometers, for example, selected from 400 nanometers to 800 nanometers, for example, selected from 400 nanometers to 700 nanometers.

6. The fulvestrant pharmaceutical composition according to any one of claims 1-5, characterized in that: The fulvestrant pharmaceutical composition further comprises a non-oily carrier; In the fulvestrant pharmaceutical composition, the weight fraction of the solid particles of fulvestrant is selected from 1.00% to 50.00%; The pH of the fulvestrant pharmaceutical composition is 6.5 to 8.0; Preferably, the non-oily carrier is selected from water; Preferably, in the fulvestrant pharmaceutical composition, the weight fraction of the solid particles of fulvestrant is selected from 2.00% to 30.00%, for example, 2.00% to 25.00%.

7. The fulvestrant pharmaceutical composition according to any one of claims 1-6, characterized in that: The fulvestrant pharmaceutical composition further comprises one or more excipients selected from the following: suspending agents, wetting agents, osmotic pressure regulators, solvents, stabilizers, buffers, pH regulators, surfactants, polymers, electrolytes and non-electrolytes; Preferably: The weight fraction of the wetting agent is selected from 0 to 5.00%; and / or, The weight fraction of the suspending agent is selected from 0 to 5.00%; and / or, The weight fraction of the osmotic pressure regulator is selected from 0 to 5.00%; and / or, The weight fraction of the buffer is selected from 0 to 1.00%; and / or, The weight fraction of the stabilizer is selected from 0 to 1.00%; and / or, The amount of the pH regulator used is the amount to adjust the pH of the composition solution to 6.5 to 8.

0. Preferably: The suspending agent is selected from one or more of sodium carboxymethylcellulose, polyethylene glycol and polyvinylpyrrolidone; and / or, The wetting agent is selected from one or more of poloxamer, polyvinylpyrrolidone, sodium docusate, sodium deoxycholate and tween; and / or, The osmotic pressure regulator is selected from one or more of sodium chloride, mannitol and sucrose; and / or, The solvent is selected from water for injection; and / or, The stabilizer(s) selected from antioxidants, metal ion chelators, polyethylene oxide, polyethylene oxide derivatives, polysorbates, sodium deoxycholate, sodium docusate, poloxamers, polyethoxylated vegetable oils, polyethoxylated castor oils, sorbitan palmitates, lecithins, polyvinyl alcohols, human serum albumins, polyvinylpyrrolidones, povidones, polyethylene glycols, sodium chloride, calcium chloride, dextrose, glycerol, mannitol, and cross-linked polymers; and / or, The buffer(s) selected from phosphoric acid, phosphates, citric acid, sodium citrate, hydrochloric acid, sodium hydroxide, tris(hydroxymethyl)aminomethane, sodium hydroxide, hydrochloric acid, or mixtures thereof; and / or, The pH regulator(s) selected from phosphoric acid, phosphates, citric acid, sodium citrate, hydrochloric acid, and sodium hydroxide. Preferably, the fulvestrant pharmaceutical composition according to claim 20, characterized in that: The antioxidant(s) selected from citric acid, vitamin C, and vitamin E; The metal ion chelator selected from ethylenediaminetetraacetic acid; The poloxamer(s) selected from poloxamer 188, poloxamer 124, and poloxamer 407; The polysorbate(s) selected from polysorbate 80 and polysorbate 20; The povidone(s) selected from povidone K12, povidone K17, PLASDONETM C-12 povidone, PLASDONETM C-17 povidone, and PLASDONETM C-30 povidone; The polyethylene glycol selected from polyethylene glycol 3350; The cross-linked polymer selected from sodium carboxymethyl cellulose; The phosphate(s) selected from sodium dihydrogen phosphate monohydrate, sodium dihydrogen phosphate dihydrate, anhydrous sodium dihydrogen phosphate, sodium dihydrogen phosphate monohydrate, sodium dihydrogen phosphate dihydrate, and anhydrous sodium dihydrogen phosphate; 8. The fulvestrant pharmaceutical composition according to any one of claims 1-7, wherein the fulvestrant pharmaceutical composition comprises the following components by weight fraction: 1.00% - 50.00% fulvestrant solid particles, 0 - 5.00% wetting agent, 0 - 5.00% stabilizer, 0 - 5.00% osmotic pressure regulator, 0 - 1.00% buffer, and solvent, and optionally 0 - 5.00% suspending agent, present or absent. Preferably, the fulvestrant pharmaceutical composition comprises the following components by weight fraction: 5.00% - 25.00% fulvestrant solid particles, 0 - 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.

9. Use of the fulvestrant pharmaceutical composition according to any one of claims 1 - 8 in the preparation of a fulvestrant pharmaceutical preparation; Preferably, the fulvestrant pharmaceutical preparation is selected from tablets, granules, capsules, pellets, oral liquids, and injections; Preferably, the injection is selected from long-acting injections; for example, the long-acting injection is selected from aqueous suspensions or powders for suspension.

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