WO2024131944A1

WO2024131944A1 - Pharmaceutical composition, and preparation method therefor and use thereof

Info

Publication number: WO2024131944A1
Application number: PCT/CN2023/141051
Authority: WO
Inventors: 王曼曼; 范思祥; 李明; 黄保华; 王贵涛
Original assignee: 同宜医药（苏州）有限公司
Priority date: 2022-12-23
Filing date: 2023-12-22
Publication date: 2024-06-27

Abstract

The present invention belongs to the field of biomedicine, and relates to a pharmaceutical composition of formula (X-1), and a preparation method therefor and the use thereof. Specifically, the pharmaceutical composition contains a ligand-drug conjugate as shown below, a pH regulator and a freeze-drying excipient. The present invention also relates to a liquid preparation, lyophilized preparation and reconstituted liquid preparation containing the pharmaceutical composition.

Description

Pharmaceutical composition and its preparation method and use

CROSS-REFERENCE TO RELATED APPLICATIONS

The present invention claims priority to the invention patent application entitled “Pharmaceutical composition, preparation method and use thereof” and application number 202211666696.2 filed in China on December 23, 2022 and the invention patent application entitled “Pharmaceutical composition, preparation method and use thereof” and application number 202311733674.8 filed in China on December 15, 2023, the entire contents of which are incorporated herein by reference.

Technical Field

The present invention relates to the field of biomedicine, and in particular to a conjugate drug composition, in particular a drug composition comprising a ligand-drug conjugate, and a preparation method and use thereof.

Background technique

There are many specific or overexpressed receptors on the surface of tumor cells and diseased cells. The ligands of these receptors bind to the receptors with good specificity, moderate affinity and obvious biological effects. Ligand-drug conjugates (LDCs) can couple the ligands that bind to the receptors with therapeutic drugs to target biologically active molecules into target cells, where the ligands can be peptides or small molecules.

The dual ligand-drug conjugate uses dual targeting ligands to enhance the affinity and targeting of the drug conjugate to diseased cells, so that it can carry highly effective toxin drugs such as camptothecin drugs. The linker prevents the conjugate from releasing drug molecules outside the cell (intercellular matrix, blood circulation system, etc.), ensuring the stability of the drug when circulating in the body, and reducing drug toxicity, without toxic effects on normal cells. After entering the targeted cell, the linker cleaves to release drug molecules with therapeutic effects, which can avoid the generation of multidrug resistance (MDR).

LDC preparations need to ensure good stability during the preparation process, long-term storage, and subsequent use. LDC drugs have a relatively complex structure and are easily degraded under acidic or alkaline conditions. If LDC is not properly formulated in liquid, the LDC in the liquid solution tends to decompose, aggregate, or undergo undesirable chemical modifications, etc. Therefore, LDC preparations for therapeutic purposes are more challenging.

Summary of the invention

Problem that the invention aims to solve

The present invention provides a stable conjugate pharmaceutical composition suitable for administration to a subject, specifically comprising a ligand- The present invention also provides a stable liquid preparation, a lyophilized preparation and a reconstituted liquid preparation containing the above-mentioned pharmaceutical composition, which are suitable for administration to a subject, as well as an industrially producible preparation method and use of the above-mentioned composition and preparation.

Solutions for solving problems

[1]. A pharmaceutical composition comprising a ligand-drug conjugate or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient;

The ligand-drug conjugate is a compound X-1 that targets folate receptors and TRPV6 receptors, and has the following structure:

Preferably, the ligand-drug conjugate is an enantiomeric compound X having the following structure:

[2] The pharmaceutical composition according to [1], characterized in that the pharmaceutically acceptable excipients include one or more of a pH adjuster and a lyophilization excipient.

[3] The pharmaceutical composition according to [2], characterized in that the pH regulator is an alkaline pH regulator; preferably, the alkaline pH regulator is one or more of histidine, histidine hydrochloride, tromethamine, tromethamine hydrochloride or alkaline salts.

[4] The pharmaceutical composition according to [3], characterized in that the alkaline salt is a hydroxide, a citrate, a phosphate, a borate, an acetate, a bicarbonate or a carbonate; preferably, the alkaline salt is an alkaline sodium salt or an alkaline potassium salt; more preferably, the hydroxide is sodium hydroxide or potassium hydroxide; more preferably, the citrate is sodium citrate; the phosphate is sodium phosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, or sodium hydrogen phosphate, more preferably disodium hydrogen phosphate; the borate is sodium borate; the acetate is sodium acetate or acetate The bicarbonate is potassium bicarbonate; the carbonate is sodium carbonate.

[5] The pharmaceutical composition according to any one of [2] to [4], characterized in that the pH adjuster is tromethamine, histidine, sodium citrate or disodium hydrogen phosphate; preferably histidine.

[6] The pharmaceutical composition according to any one of [2] to 5], characterized in that the lyophilization excipient is one or more of a polyol or a sugar.

[7]. The pharmaceutical composition according to [6], characterized in that the polyol is one or more of mannitol, sorbitol or xylitol, preferably mannitol.

[8] The pharmaceutical composition according to [6], characterized in that the carbohydrate is one or more of a monosaccharide, a disaccharide or a polysaccharide, preferably a disaccharide.

[9]. The pharmaceutical composition according to [8], characterized in that the monosaccharide is glucose or fructose; the disaccharide is sucrose, trehalose, lactose or maltose, preferably sucrose or trehalose; and the polysaccharide is dextran, cyclodextrin, hydroxypropyl methylcellulose, hydroxypropyl cellulose, sodium carboxymethyl cellulose or dextran.

[10]. The pharmaceutical composition according to any one of [2] to [9], characterized in that the mass ratio of the pH regulator to the lyophilization excipient is 1:3 to 1:50, for example, 1:3.125, 1:4.2, 1:5, 1:5125, 1:6.125, 1:6.25, 1:7, 1:7125, 1:8.3, 1:9, 1:95, 1:10, 1:125. :10.25, 1:11, 1:12.5, 1:13, 1:14, 1:15, 1:16.7, 1:17, 1:18.75, 1:19, 1:20, 1:21 ,1:21.5,1:22,1:23,1:24,1:25,1:25.175,1:26,1:27,1:28,1:29,1:30,1:31,1 :32, 1:33, 1:34, 1:35, 1:36, 1:37.5, 1:38, 1:39, 1:40, 1:41, 1:42, 1:43, 1:44, 1:45, 1:46, 1:47, 1:48, 1:49 or 1:50; preferably, the mass ratio of the pH regulator to the lyophilization excipient is 1:6 to 1:40, for example 1:6.2 5, 1:8.3, 1:12.5, 1:15, 1:16.7, 1:17, 1:18.75, 1:19, 1:20, 1:25 or 1:37.5; further preferably, the mass ratio of the pH regulator to the lyophilization excipient is 1:15 to 1:20, for example, 1:15, 1:16.7, 1:17, 1:18.75, 1:19 or 1:20.

[11]. The pharmaceutical composition according to any one of [2] to [10], characterized in that the molar mass ratio of the ligand-drug conjugate or its pharmaceutically acceptable salt to the pH regulator is 1:3 to 1:7, for example, 1:3, 1:3.1, 1:3.2, 1:3.3, 1:3.4, 1:3.5, 1:3.6, 1:3.7, 1:3.8, 1:3.9, 1:4, 1:4.1, 1:4.2, 1:4.3, 1:4.4, 1:4.5, 1:4.6, 1:4.7, 1:4.8, .8, 1:4.9, 1:5, 1:5.1, 1:5.2, 1:5.3, 1:5.4, 1:5.5, 1:5.6, 1:5.7, 1:5.8, 1:5.9, 1:6, 1:6.1, 1:6.2, 1:6.3, 1:6.4, 1:6.5, 1:6.6, 1:6.7, 1:6.8, 1:6.9, 1:7; preferably, the molar mass ratio of the ligand-drug conjugate or its pharmaceutically acceptable salt to the pH regulator is 1:3.1, 1:4.8, or 1:6.2.

[12] The pharmaceutical composition according to [11], characterized in that when the pH adjuster is histidine, the mass ratio of the ligand-drug conjugate or its pharmaceutically acceptable salt to the pH adjuster is 2.5:1 to 7.5:1, for example, 2.5:1, 2.6:1, 2.7:1, 2.8:1, 2.9:1, 3.0:1, 3.1:1, 3.125:1, 3.2:1, 3.3:1, 3.4:1, 3.5:1, 3.6:1, 3.75:1, 3.8:1, 3.9:1, 4.0:1, 4.1:1, 4.2:1, 4.3:1, 4.4:1, 4.5:1, 4.6:1, 4.7:1, 4.8:1, 4.9:1, 5.0:1, 5.1:1, 5.2:1, 5 .3:1, 5.4:1, 5.5:1, 5.6:1, 5.7:1, 5.8:1, 5.9:1, 6:1, 6.1:1, 6.2:1, 6.25:1, 6.3:1, 6.4:1, 6.5:1, 6.6:1, 6.7 :1, 6.8:1, 6.9:1, 7.0:1, 7.1:1, 7.2:1, 7.3:1, 7.4:1 or 7.5:1; preferably, the mass ratio of the ligand-drug conjugate or its pharmaceutically acceptable salt to the pH regulator is 3:1 to 6.5:1, for example, 3.125:1, 3.5:1, 4.1:1, 4.5:1, 5.0:1, 5.5:1, 6.0:1, 6.25:1 or 6.5:1; more preferably, 3.125:1, 4.1:1 or 6.25:1.

[13] The pharmaceutical composition according to any one of [1] to [12], characterized in that the mass ratio of the ligand-drug conjugate or its pharmaceutically acceptable salt to the lyophilization excipient is 1.2:1 to 1:10, for example, 1.2:1, 1.1:1, 1:1, 1:1.5, 1:2, 1:2.5, 1:3, 1:3.5, 1:4, 1:4.5, 1:5, 1:5.5, 1:6, 1:7.5, 1:8.5, 1:9. 6.5, 1:7, 1:7.5, 1:8, 1:8.5, 1:9, 1:9.5 or 1:10; preferably, the mass ratio of the ligand-drug conjugate or its pharmaceutically acceptable salt to the pH regulator is 1:2 to 1:6, for example, 1:2, 1:2.5, 1:3, 1:3.5, 1:4, 1:4.5, 1:5, 1:5.5 or 1:6; more preferably, 1:2, 1:4 or 1:6.

[14] The pharmaceutical composition according to [1] to [13], characterized in that the pharmaceutical composition comprises a ligand-drug conjugate or a pharmaceutically acceptable salt thereof, a pH adjuster and a lyophilization excipient, and the mass ratio thereof is 5:(0.8-2.5):(10-30); preferably, the mass ratio thereof is 5:(1-1.5):(15:25); further preferably, the mass ratio thereof is 5:1.2:20; further preferably, the pharmaceutical composition comprises a ligand-drug conjugate or a pharmaceutically acceptable salt thereof, histidine and sucrose, The mass ratio is 5:1.2:20; further preferably, the pharmaceutical composition comprises a ligand-drug conjugate or a pharmaceutically acceptable salt thereof, histidine and trehalose in a mass ratio of 5:1.2:20; further preferably, the pharmaceutical composition comprises a ligand-drug conjugate or a pharmaceutically acceptable salt thereof, histidine and mannitol in a mass ratio of 5:1.2:20; further preferably, the pharmaceutical composition comprises a ligand-drug conjugate or a pharmaceutically acceptable salt thereof, tromethamine and mannitol in a mass ratio of 5:1:20; further preferably, the pharmaceutical composition The composition comprises a ligand-drug conjugate or a pharmaceutically acceptable salt thereof, sodium citrate and mannitol in a mass ratio of 5:2.1:20; further preferably, the pharmaceutical composition comprises a ligand-drug conjugate or a pharmaceutically acceptable salt thereof, disodium hydrogen phosphate and mannitol in a mass ratio of 5:1.1:20; further preferably, the pharmaceutical composition comprises a ligand-drug conjugate or a pharmaceutically acceptable salt thereof, histidine and mannitol in a mass ratio of 5:1.2:10; further preferably, the pharmaceutical composition comprises a ligand-drug conjugate or a pharmaceutically acceptable salt thereof , histidine and mannitol, the mass ratio of which is 5:1.2:30; further preferably, the pharmaceutical composition comprises a ligand-drug conjugate or a pharmaceutically acceptable salt thereof, histidine and mannitol, the mass ratio of which is 5:0.8:20; or, further preferably, the pharmaceutical composition comprises a ligand-drug conjugate or a pharmaceutically acceptable salt thereof, histidine and mannitol, the mass ratio of which is 5:1.6:20; more preferably, the pharmaceutical composition comprises 50 mg of compound X-1 or a pharmaceutically acceptable salt thereof, 12 mg of histidine and 200 mg of sucrose; more preferably, The pharmaceutical composition comprises 50 mg of compound X-1 or a pharmaceutically acceptable salt thereof, 12 mg of histidine and 200 mg of trehalose; more preferably, the pharmaceutical composition comprises 50 mg of compound X-1 or a pharmaceutically acceptable salt thereof, 12 mg of histidine and 200 mg of mannitol; more preferably, the pharmaceutical composition comprises 50 mg of compound X-1 or a pharmaceutically acceptable salt thereof, 12 mg of histidine and 100 mg of mannitol; more preferably, the pharmaceutical composition comprises 50 mg of compound X-1 or a pharmaceutically acceptable salt thereof, 12 mg of histidine and 300 mg of mannitol; more preferably, the pharmaceutical composition comprises 50 mg of compound X-1 or a pharmaceutically acceptable salt thereof, 8 mg of histidine and 200 mg of mannitol; or, more preferably, the pharmaceutical composition comprises 50 mg of compound X-1 or a pharmaceutically acceptable salt thereof, 16 mg of histidine and 200 mg of mannitol.

[15] The pharmaceutical composition according to any one of [1] to [14], characterized in that the pharmaceutical composition is a liquid composition, a freeze-dried solid composition, or a freeze-dried solid composition reconstituted into a liquid.

[16]. A liquid preparation, characterized in that it comprises the pharmaceutical composition according to any one of [1] to [15] and a solvent; the solvent is water; preferably, the solvent is purified water; more preferably, the purified water is sterile water, distilled water or deionized water; more preferably, the sterile water is sterile water for injection, single distilled water or double distilled water.

[17]. The liquid preparation according to [16], characterized in that the pH of the liquid preparation is 6.0 to 8.0, for example 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 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; preferably 6.5.

[18]. The liquid preparation according to [16] or [17], characterized in that the liquid preparation optionally contains an acidic substance or an alkaline substance; the acidic substance or the alkaline substance is used to adjust the pH value of the liquid preparation; the acidic substance is preferably hydrochloric acid; and the alkaline substance is preferably sodium hydroxide.

[19]. The liquid preparation according to any one of [16] to [18], characterized in that the concentration of the ligand-drug conjugate or its pharmaceutically acceptable salt is 10 mg/mL-15 mg/mL, for example, 10 mg/mL, 10.5 mg/mL, 11 mg/mL, 11.5 mg/mL, 12 mg/mL, 12.5 mg/mL, 13 mg/mL, 13.5 mg/mL, 14 mg/mL, 14.5 mg/mL or 15 mg/mL; preferably 12.5 mg/mL.

[20]. The liquid preparation according to any one of [16] to [19], characterized in that the concentration of the pH adjuster is 2 mg/mL-4 mg/mL, for example 2 mg/mL, 2.2 mg/mL, 2.4 mg/mL, 2.6 mg/mL, 2.8 mg/mL, 3 mg/mL, 3.2 mg/mL, 3.4 mg/mL, 3.6 mg/mL, 3.8 mg/mL or 4 mg/mL; preferably 2 mg/mL, 3 mg/mL or 4 mg/mL; more preferably 3 mg/mL.

[21]. The liquid preparation according to any one of [16] to [20], characterized in that the concentration of the lyophilized excipient is 12.5 mg/mL to 100 mg/mL, for example 12.5 mg/mL, 15 mg/mL, 17.5 mg/mL, 20 mg/mL, 22.5 mg/mL, 25 mg/mL, 27.5 mg/mL, 30 mg/mL, 32.5 mg/mL, 35 mg/mL, 37.5 mg/mL, 40 mg/mL, 42.5 mg/mL, 45 mg/mL, 47.5 mg/mL, 50 mg/mL, 52.5 mg/mL, 55 mg/mL, 57.5 mg/mL, 60 mg/mL, 62.5 mg/mL, 65mg/mL, 67.5mg/mL, 70mg/mL, 72.5mg/mL, 75mg/mL, 77.5mg/mL, 80mg/mL, 82.5mg/mL, 85mg/mL, 87.5mg/mL, 90mg/mL, 92.5mg/mL, 95mg/mL, 97.5mg/mL or 100mg/mL; preferably 25mg/mL to 75mg/mL, for example 25mg/mL, 27.5mg/mL, 30mg/mL, 32.5mg/mL, 35mg/mL, 37.5mg/mL, 40mg/mL, 42.5mg/mL, 45mg/mL, 47.5mg/mL, 50mg/mL, 52.5mg/mL, 55mg/mL, 57.5mg/mL, 60mg /mL, 62.5mg/mL, 65mg/mL, 67.5mg/mL, 70mg/mL, 72.5mg/mL, 75mg/mL25mg/mL, 27.5mg/mL, 30mg/mL, 32.5mg/mL, 35mg/mL, 37.5mg/mL, 40mg/mL, 42.5mg/mL, 45mg/mL, 47.5mg/mL, 50mg/mL, 52.5mg/mL, 55mg/mL, 57.5mg/mL, 60mg/mL, 62.5mg/mL, 65mg/mL, 67.5mg/mL, 70mg/mL, 72.5mg/mL or 75mg/mL; further preferably 25mg/mL, 50mg/mL or 75mg/mL; more preferably 50mg/mL.

[22] The liquid preparation according to any one of [16] to [21], characterized in that the liquid preparation comprises a ligand-drug conjugate or a pharmaceutically acceptable salt thereof, a lyophilization excipient, a pH adjuster and a solvent; wherein the pH of the pharmaceutical preparation is 6.0 to 8.0; preferably, each 1 mL of the pharmaceutical preparation comprises 12.5 mg of compound X-1 or a pharmaceutically acceptable salt thereof, 3 mg of histidine, 50 mg of sucrose and an optional acidic substance or alkaline substance and the remainder of water; wherein the pH of the pharmaceutical preparation is 6.0 to 8.0 ; Preferably, each 1 mL of the pharmaceutical preparation contains 12.5 mg of compound X-1 or a pharmaceutically acceptable salt thereof, 3 mg of histidine, 50 mg of trehalose and optionally an acidic substance or an alkaline substance and the remainder of water; wherein the pH of the pharmaceutical preparation is 6.0 to 8.0; Preferably, each 1 mL of the pharmaceutical preparation contains 12.5 mg of compound X-1 or a pharmaceutically acceptable salt thereof, 3 mg of histidine, 50 mg of mannitol and optionally an acidic substance or an alkaline substance and the remainder of water; wherein the pH of the pharmaceutical preparation is 6.0 to 8.0 ; Preferably, each 1 mL of the pharmaceutical preparation contains 12.5 mg of compound X-1 or a pharmaceutically acceptable salt thereof, 3 mg of histidine, 25 mg of mannitol and optionally an acidic substance or an alkaline substance and the remainder of water; wherein the pH of the pharmaceutical preparation is 6.0 to 8.0; Preferably, each 1 mL of the pharmaceutical preparation contains 12.5 mg of compound X-1 or a pharmaceutically acceptable salt thereof, 3 mg of histidine, 75 mg of mannitol and optionally an acidic substance or an alkaline substance and the remainder of water; wherein the pH of the pharmaceutical preparation is 6.0 to 8.0 ; Preferably, each 1 mL of the pharmaceutical preparation contains 12.5 mg of compound X-1 or a pharmaceutically acceptable salt thereof, 2 mg of histidine, 50 mg of mannitol and optionally an acidic or alkaline substance and the remainder is water; wherein the pH of the pharmaceutical preparation is 6.0 to 8.0; Preferably, each 1 mL of the pharmaceutical preparation contains 12.5 mg of compound X-1 or a pharmaceutically acceptable salt thereof, 4 mg of histidine, 50 mg of mannitol and optionally an acidic or alkaline substance and the remainder is water; wherein the pH of the pharmaceutical preparation is 6.0 to 8.0.

[23] The liquid preparation according to any one of [16] to [22], characterized in that the liquid preparation is sterile.

[24] The liquid preparation according to any one of [16] to [23], characterized in that the liquid preparation is stable when frozen and thawed in the dark.

[25] A method for preparing a liquid preparation according to any one of [16] to [24], comprising the steps of: Under light conditions, take a prescribed amount of a ligand-drug conjugate or a pharmaceutically acceptable salt thereof and optional pharmaceutically acceptable excipients, mix them evenly, and the mixture is obtained.

[26]. The preparation method according to [25] is characterized in that it comprises the following steps: taking a prescribed amount of a ligand-drug conjugate or a pharmaceutically acceptable salt thereof, a pH adjuster, a lyophilizing excipient and a solvent at room temperature and in the dark, dissolving compound X or a pharmaceutically acceptable salt thereof, a pH adjuster and a lyophilizing excipient in the solvent, adjusting the pH to 6.0 to 8.0, mixing, filtering, and obtaining the product.

[27]. A freeze-dried preparation, characterized in that it is obtained by freeze-drying the liquid preparation according to any one of [16] to [24].

[28] The freeze-dried preparation according to [27] is characterized in that the freeze-dried preparation is stable under refrigerated conditions at 2 to 8°C and away from light.

[29]. A method for preparing a freeze-dried preparation according to [27] or [28], comprising the step of freeze-drying the liquid preparation according to any one of [16] to [24] under light-proof conditions.

[30]. The preparation method according to [29] is characterized in that the freeze-drying comprises the following steps: (i) freezing the pharmaceutical preparation at -45°C; (ii) primary drying the pharmaceutical preparation at -20°C to -5°C; (iii) secondary drying the pharmaceutical preparation at 10°C to 40°C; for example, the primary drying temperature is -5°C, -10°C, -15°C or -20°C; and the secondary drying temperature is 10°C, 25°C or 40°C.

[31]. A reconstituted liquid preparation, characterized in that the reconstituted liquid preparation is reconstituted by using water from the lyophilized preparation according to [27] or [28].

[32] The reconstituted liquid preparation according to [31], characterized in that the water comprises one or more of distilled water, pure water, and sterile water; preferably, the pH of the lyophilized preparation after reconstitution with water is 6.0 to 8.0.

[33]. A method for preparing a reconstituted liquid preparation according to [31] or [32], characterized in that the reconstituted liquid preparation comprises the step of mixing the lyophilized preparation according to any one of [27] or [28] with sterile water.

[34]. A drug delivery device comprising one of the following: a pharmaceutical composition according to any one of [1] to [15], a liquid preparation according to any one of [16] to [24], a lyophilized preparation according to [27] or [28], or a reconstituted liquid preparation according to [31] or [32].

[35]. A prefilled syringe comprising one of the following: a pharmaceutical composition according to any one of [1] to [15], a liquid preparation according to any one of [16] to [24], a lyophilized preparation according to [27] or [28], or a reconstituted liquid preparation according to [31] or [32], preferably for intravenous injection or intramuscular injection.

[36] The pharmaceutical composition according to any one of [1] to [15], the liquid preparation according to any one of [16] to [24], the lyophilized preparation according to [27] or [28], or the reconstituted liquid preparation according to [31] or [32] in the preparation of Use in a delivery device or prefilled syringe or medicament to enhance immune effector cell response and/or reduce immunosuppression in a subject.

[37]. Use of the pharmaceutical composition according to any one of [1] to [15], the liquid preparation according to any one of [16] to [24], the lyophilized preparation according to [27] or [28], or the reconstituted liquid preparation according to [31] or [32] in the preparation of a delivery device or prefilled syringe or drug for treating and/or preventing cancer, immune diseases, metabolic diseases and neurological diseases in a subject.

[38]. The use according to [37] is characterized in that the cancer includes one or more of breast cancer, lung cancer, prostate cancer, kidney cancer, leukemia, ovarian cancer, gastric cancer, uterine cancer, endometrial cancer, liver cancer, thyroid cancer, pancreatic cancer, colorectal cancer, esophageal cancer, testicular cancer, skin cancer, biliary tract cancer, breast cancer, lymphoma, and multiple myeloma; the immune disease includes one or more of connective tissue disease, systemic sclerosis, rheumatoid arthritis, and systemic lupus erythematosus; the metabolic disease includes one or more of diabetes, gout, obesity, hypoglycemia, hyperglycemia, and dyslipidemia; the neurological disease includes one or more of Alzheimer's disease, Parkinson's disease, Huntington's disease, head injury, multiple sclerosis, vertigo, coma, and epilepsy.

Effects of the Invention

The pharmaceutical composition comprising a ligand-drug conjugate provided by the present invention, as well as the liquid preparation, lyophilized preparation and reconstituted liquid preparation comprising the pharmaceutical composition, are stable during storage, including properties, water content, content of related substances, pH value, etc., which can all maintain stable effects; at the same time, the preparation method provided by the present invention is controllable and suitable for process scale-up production.

Detailed ways

The following describes the embodiments of the present invention, but the present invention is not limited thereto. The present invention is not limited to the various structures described below, and various changes can be made within the scope of the invention claim, and the embodiments and embodiments obtained by appropriately combining the technical means disclosed in different embodiments and embodiments are also included in the technical scope of the present invention. In addition, all the documents recorded in this specification are cited in this specification as references.

Unless otherwise specified, the instruments, equipment, reagents, materials, etc. used in the present invention can be obtained through conventional commercial means.

Unless defined otherwise, technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

In the present invention, the "some specific/preferred embodiments", "other specific/preferred embodiments", "some specific/preferred technical solutions", "other specific/preferred technical solutions" and the like refer to the embodiments described in the present invention. Specific elements (e.g., features, structures, properties and/or characteristics) related to the formula are included in at least one embodiment described herein, and may or may not exist in other embodiments. In addition, it should be understood that the elements can be combined in various embodiments in any suitable manner.

In the present invention, a numerical range expressed using "a numerical value to a numerical value B" or "a numerical value - a numerical value B" means a range including the endpoints A and B.

In the present invention, when "%" appears, it means the mass or weight percentage, that is, "mass %" or "weight %", unless otherwise specified.

In the present invention, the meaning of "may" includes both the meaning of performing a certain process and the meaning of not performing a certain process. In this specification, "optional" or "optionally" means that the event or situation described below may or may not occur, and the description includes the situation where the event occurs and the situation where the event does not occur.

In the present invention, "room temperature" or "normal temperature" means an ambient temperature of about 25°C.

In the present invention, "refrigerated" means an ambient temperature of 2 to 8°C.

The terms "comprises", "comprising" and any variations thereof in the description and claims of the present invention are inclusive or open-ended and do not exclude additional, unrecited elements or method steps.

In the present invention, "pharmaceutical composition" refers to a mixture containing one or more conjugates described in the present invention or pharmaceutically acceptable salts thereof and at least one and optionally more than one other pharmaceutically acceptable chemical component (such as a carrier, stabilizer, diluent, dispersant, suspending agent, pH adjuster or excipient).

In the present invention, "pharmaceutically acceptable" means that it is suitable for contact with cells of humans and other animals without undue toxicity, irritation, allergic reaction, etc., within the scope of reasonable medical judgment, and is commensurate with a reasonable benefit/risk ratio.

In the present invention, "pharmaceutically acceptable excipients" refer to excipients and additives used in the production of drugs and the preparation of prescriptions, such as pH adjusters; they are substances other than active ingredients or precursors that have been reasonably evaluated in terms of safety and are included in pharmaceutical preparations. In addition to excipients, pH adjustment, acting as carriers, and improving stability, pharmaceutical excipients also have important functions such as solubilization, dissolution assistance, and release regulation, and are important components that may affect the quality, safety, and effectiveness of drugs.

In the present invention, "pharmaceutically acceptable salt" refers to relatively non-toxic, inorganic and organic acid addition salts and base addition salts of the conjugate compounds of the present application. Representative acid addition salts include hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, toluenesulfonate, citrate, maleate, fumarate, succinate, tartrate, naphthoate, methanesulfonate, glucoheptonate, lactobionate, aminosulfonate, malonic acid, hydroxyethyl ester, hydroxypropyl ... The base addition salts include pharmaceutically acceptable metal and amine salts. Suitable metal salts include sodium, potassium, calcium, barium, zinc, magnesium and aluminum salts. In some embodiments, sodium salts and potassium salts are preferred. Suitable inorganic base addition salts are prepared from metal bases, including, for example, sodium hydride, sodium hydroxide, potassium hydroxide, calcium hydroxide, aluminum hydroxide, lithium hydroxide, magnesium hydroxide and zinc hydroxide. Suitable amine base addition salts are prepared from amines having sufficient basicity to form stable salts, and preferably include the following amines commonly used in pharmaceutical chemistry because of their low toxicity and acceptable medical use: ammonia, ethylenediamine, N-methylglucamine, lysine, arginine, ornithine, choline, N,N'-dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine, diethylamine, piperazine, trishydroxymethylaminomethane, tetramethylammonium hydroxide, triethylamine, dibenzylamine, diphenylhydroxymethylamine, dehydroabietylamine, N-ethylpiperidine, benzylamine, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, ethylamine, basic amino acids (e.g., lysine and arginine) and dicyclohexylamine and the like.

In the present invention, a "ligand-drug conjugate" (LDC) is a drug with biological activity connected to a ligand through a chemical link, and the ligand is used as a carrier to transport small molecule drugs into target cells in a targeted manner, wherein the ligand can be a polypeptide or a small molecule, and the drug with biological activity can be a camptothecin drug, such as exotecan. Preferably, the ligand-drug conjugate is a dual-ligand drug conjugate, and preferably, the dual-ligand drug conjugate is a drug conjugate targeting folate receptors and TRPV6 receptors. More preferably, the ligand-drug conjugate of the present invention is a dual-ligand conjugate compound X-1, wherein the ligands target folate receptors and TRPV6 receptors, respectively, and the drug carrier is exotecan, and its structure is shown below:

Further preferably, the biligand-drug conjugate is an enantiomeric compound X having the following structure:

In the present invention, "pH adjusting agent" is an agent that can maintain the pH of the solution within an acceptable range, mainly acids, bases and salts with buffering effects, such as commonly used sodium citrate, tromethamine, histidine, sodium carbonate, ammonium chloride, hydrochloric acid, acetic acid, sodium hydroxide, sodium dihydrogen phosphate, sodium acetate, etc. In some embodiments, the pH adjusting agent used in the preparation of the present invention can control the pH of the preparation of the present invention within a pH range of about 6.0 to 8.0. In some specific embodiments, the preparation of the present invention has a pH of about 6.0, 6.5, 7.0, 7.5, 8.0.

In the present invention, "alkaline salt" refers to a salt in which the anions generated during ionization include not only acid ions but also hydroxide ions, and the cations are metal ions (or NH ₄ ⁺ ).

In the present invention, "purified water" refers to water with a resistivity greater than 0.1x10^6Ω*cm when the temperature is greater than 25°C. It is a colorless, clear liquid, odorless and tasteless. It is water for medicinal use prepared by distillation, ion exchange, reverse osmosis or other suitable methods and does not contain any additives.

In the present invention, "polyol" refers to a large class of alcohols containing two or more hydroxyl groups in the molecule, for example, mannitol, inositol, ethylene glycol, polyethylene glycol, sorbitol, xylitol, etc.

In the present invention, "acidic substance" refers to a substance that can provide a hydrogen proton or accept an electron pair, for example, it can be sulfuric acid, hydrochloric acid, cerium trichloride, ferric chloride, ferric chloride, etc.

In the present invention, the "alkaline substance" refers to a substance having the ability to donate electrons or accept protons, and examples thereof include sodium hydroxide, sodium carbonate, ammonia, triphenylphosphine, triethylamine, and the like.

In the present invention, "reconstitution" refers to dissolving and/or suspending a solid preparation (eg, a lyophilized preparation) in a physiologically acceptable solution.

In the present invention, "about" means that the specified numerical value is approximate, and a specific numerical value in the relevant data does not need to be very precise.

In the present invention, "lyophilized preparation" refers to a sterile solid for injection prepared by freeze drying.

In the present invention, "liquid preparation" refers to a liquid preparation for oral or external use composed of a drug dispersed in a liquid dispersion medium; it is also the basic dosage form of other dosage forms (such as injections, soft capsules, ointments, suppositories, aerosols, etc.).

In the present invention, the "reconstituted liquid preparation" refers to a liquid preparation obtained by re-dissolving a lyophilized preparation in a solvent.

In the present invention, "lyophilized excipients" are also called freeze-dried protective agents, which refer to additives added during the freeze-drying and storage process of food, medicine and organisms, in order to make the product still maintain stability and activity under the influence of many factors (such as chemical composition, freezing rate, freezing and dehydration stress, glass transition temperature, residual water in dry solids, temperature and humidity of storage environment, etc.). For example, lyophilized excipients can be polyols, sugars, amino acids, inorganic salts and proteins, such as mannitol, ethylene glycol, xylitol, glucose, fructose, sucrose, trehalose, lactose, maltose, dextran, hydroxypropyl methylcellulose, hydroxypropyl cellulose, sodium carboxymethyl cellulose, cyclodextrin, dextrorotatory Glucose anhydride, sodium glutamate, sodium acetate, polyoxyethylene pyrrolidone, calcium carbonate and bovine serum albumin, etc.

In the present invention, the "stability of the preparation" or the "stable preparation" means that the moisture content, properties, pH value, related substances, content, insoluble particles and properties after reconstitution remain basically unchanged, do not change significantly or change within a pharmaceutically acceptable range during the product preparation and storage process, and the quality of the preparation can be controlled for at least 24 months.

[Pharmaceutical composition comprising a ligand-drug conjugate]

The present invention provides a pharmaceutical composition, which may include a ligand-drug conjugate or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

In one embodiment, the pharmaceutical composition may include a pH adjuster and one or more auxiliary materials in a lyophilization excipient.

In one embodiment, the pharmaceutical composition may comprise a ligand-drug conjugate, a pH adjuster and a lyophilization excipient.

In one embodiment, the pharmaceutical composition may comprise a ligand-drug conjugate, a basic pH adjuster and a lyophilization excipient.

In one embodiment, the ligand-drug conjugate in the above pharmaceutical composition is a dual ligand-drug conjugate.

In a preferred embodiment, the ligand-drug conjugate in the above pharmaceutical composition is a drug conjugate targeting folate receptor and TRPV6 receptor.

In a more preferred embodiment, the ligand-drug conjugate in the above pharmaceutical composition is compound X-1, having the following structure:

In a more preferred embodiment, the ligand-drug conjugate in the above pharmaceutical composition is an enantiomeric compound X, having the following structure:

In one embodiment, the alkaline pH regulator in the above pharmaceutical composition can be selected from one or more of histidine, histidine hydrochloride, tromethamine, tromethamine hydrochloride or alkaline salts.

Furthermore, the alkaline pH regulator in the above pharmaceutical composition can be selected from hydroxide, citrate, phosphate, borate, acetate, bicarbonate or carbonate.

Further, the alkaline pH regulator in the above pharmaceutical composition can be selected from sodium salt, calcium salt or potassium salt. Further, the alkaline pH regulator in the above pharmaceutical composition is sodium hydroxide, potassium hydroxide, sodium citrate, sodium phosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, sodium hydrogen phosphate, sodium borate, sodium acetate, potassium acetate, sodium bicarbonate or sodium carbonate.

In a preferred embodiment, the alkaline pH regulator in the above pharmaceutical composition is tromethamine.

In another preferred embodiment, the alkaline pH regulator in the above pharmaceutical composition is histidine.

In another preferred embodiment, the alkaline pH regulator in the above pharmaceutical composition is sodium citrate.

In another preferred embodiment, the alkaline pH regulator in the above pharmaceutical composition is disodium bicarbonate.

In one embodiment, the lyophilization excipient in the above pharmaceutical composition can be selected from one or more of polyols or sugars.

Furthermore, the lyophilized excipient in the above pharmaceutical composition can be selected from one or more of mannitol, sorbitol or xylitol.

Furthermore, the lyophilized excipient in the above pharmaceutical composition can be selected from one or more of monosaccharides, disaccharides or polysaccharides.

Furthermore, the lyophilized excipient in the above pharmaceutical composition can be selected from glucose or fructose.

Furthermore, the lyophilized excipient in the above pharmaceutical composition can be selected from sucrose, trehalose, lactose or maltose.

Furthermore, the lyophilized excipient in the above pharmaceutical composition can be selected from dextran, cyclodextrin, hydroxypropyl methylcellulose, hydroxypropyl cellulose, sodium carboxymethyl cellulose or dextran.

In a preferred embodiment, the lyophilization excipient in the above pharmaceutical composition is mannitol.

In another preferred embodiment, the lyophilization excipient in the above pharmaceutical composition is sucrose.

In another preferred embodiment, the lyophilization excipient in the above pharmaceutical composition is trehalose.

In one embodiment, the mass ratio of the pH adjuster to the lyophilization excipient in the above pharmaceutical composition is 1:3 to 1:50, for example, 1:3.125, 1:4.2, 1:5, 1:5125, 1:6.125, 1:6.25, 1:7, 1:7125, 1:8.3, 1:9, 1:95, 1:10, 1:10.25, 1:11, 1:12.5, 1:13, 1:14, 1:15, 1:16.7, 1:17, 1:18.75, 1:1 9, 1:20, 1:21, 1:21.5, 1:22, 1:23, 1:24, 1:25, 1:25.175, 1:26, 1:27, 1:28, 1:29, 1:30, 1:31, 1:32, 1:33, 1:34, 1:35, 1:36, 1:37.5, 1:38, 1:39, 1:40, 1:41, 1:42, 1:43, 1:44, 1:45, 1:46, 1:47, 1:48, 1:49, or 1:50.

In a preferred embodiment, the mass ratio of the pH adjuster to the lyophilized excipient in the above pharmaceutical composition is 1:6 to 1:40, for example, 1:6.25, 1:8.3, 1:12.5, 1:15, 1:16.7, 1:17, 1:18.75, 1:19, 1:20, 1:25 or 1:37.5.

In another preferred embodiment, the mass ratio of the pH adjuster to the lyophilization excipient in the above pharmaceutical composition is 1:15 to 1:20, for example, 1:15, 1:16.7, 1:17, 1:18.75, 1:19 or 1:20.

In one embodiment, the molar mass ratio of the ligand-drug conjugate to the pH adjuster in the pharmaceutical composition is 1:3 to 1:7, for example, 1:3, 1:3.1, 1:3.2, 1:3.3, 1:3.4, 1:3.5, 1:3.6, 1:3.7, 1:3.8, 1:3.9, 1:4, 1:4.1, 1:4.2, 1:4.3, 1:4.4, 1:4.5, 1:4.6, 1:4.7, 1:4.8, 1:4.9, 1:5.10, 1:5.11, 1:5.12, 1:5.13, 1:5.14, 1:5.15 :4.6, 1:4.7, 1:4.8, 1:4.9, 1:5, 1:5.1, 1:5.2, 1:5.3, 1:5.4, 1:5.5, 1:5.6, 1:5.7, 1: 5.8, 1:5.9, 1:6, 1:6.1, 1:6.2, 1:6.3, 1:6.4, 1:6.5, 1:6.6, 1:6.7, 1:6.8, 1:6.9, 1:7.

In another preferred embodiment, the molar mass ratio of the ligand-drug conjugate to the pH regulator in the above pharmaceutical composition is 1:3.1, 1:4.8, or 1:6.2.

In one embodiment, when the pH adjuster is histidine, the mass ratio of the ligand-drug conjugate to the pH adjuster in the above pharmaceutical composition is 2.5:1 to 7.5:1, for example, 2.5:1, 2.6:1, 2.7:1, 2.8:1, 2.9:1, 3.0:1, 3.1:1, 3.125:1, 3.2:1, 3.3:1, 3.4:1, 3.5:1, 3.6:1, 3.75:1, 3.8:1, 3.9:1, 4.0:1, 4.1:1, 4.2:1, 4.3:1, 4.4:1 , 4.5:1, 4.6:1, 4.7:1, 4.8:1, 4.9:1, 5.0:1, 5.1:1, 5.2:1, 5.3:1, 5.4:1, 5.5:1, 5.6:1, 5.7:1, 5.8:1, 5.9:1, 6:1, 6.1:1, 6.2:1, 6.25:1, 6.3:1, 6.4:1, 6.5:1, 6.6:1, 6.7:1, 6.8:1, 6.9:1, 7.0:1, 7.1:1, 7.2:1, 7.3:1, 7.4:1, or 7.5:1.

In a preferred embodiment, when the pH adjuster is histidine, the mass ratio of the ligand-drug conjugate to the pH adjuster in the above pharmaceutical composition is 3:1 to 6.5:1, for example 3.125:1, 3.5:1, 4.1:1, 4.5:1, 5.0:1, 5.5:1, 6.0:1, 6.25:1 or 6.5:1.

In another preferred embodiment, when the pH adjuster is histidine, the mass ratio of the ligand-drug conjugate to the pH adjuster in the above pharmaceutical composition is 3.125:1, 4.1:1 or 6.25:1.

In one embodiment, the mass ratio of the ligand-drug conjugate to the lyophilized excipient in the above pharmaceutical composition is 1.2:1 to 1:10, for example, 1.2:1, 1.1:1, 1:1, 1:1.5, 1:2, 1:2.5, 1:3, 1:3.5, 1:4, 1:4.5, 1:5, 1:5.5, 1:6, 1:6.5, 1:7, 1:7.5, 1:8, 1:8.5, 1:9, 1:9.5 or 1:10.

In a preferred embodiment, the mass ratio of the ligand-drug conjugate to the lyophilized excipient in the above pharmaceutical composition is 1:2 to 1:6, for example, 1:2, 1:2.5, 1:3, 1:3.5, 1:4, 1:4.5, 1:5, 1:5.5 or 1:6.

In another preferred embodiment, the mass ratio of the ligand-drug conjugate to the lyophilized excipient in the above pharmaceutical composition is 1:2, 1:4 or 1:6.

In one embodiment, the pharmaceutical composition comprises a ligand-drug conjugate or a pharmaceutically acceptable salt thereof, a pH adjuster and a lyophilization excipient in a mass ratio of 5:(0.8-2.5):(10-30).

In a preferred embodiment, the pharmaceutical composition comprises a ligand-drug conjugate or a pharmaceutically acceptable salt thereof, a pH adjuster and a lyophilization excipient in a mass ratio of 5:(1-1.5):(15:25).

In another preferred embodiment, the pharmaceutical composition comprises a ligand-drug conjugate or a pharmaceutically acceptable salt thereof, a pH adjuster and a lyophilization excipient in a mass ratio of 5:1.2:20.

In a preferred embodiment, the pharmaceutical composition comprises a ligand-drug conjugate or a pharmaceutically acceptable salt thereof, histidine and sucrose in a mass ratio of 5:1.2:20.

In another preferred embodiment, the pharmaceutical composition comprises a ligand-drug conjugate or a pharmaceutically acceptable salt thereof, histidine and trehalose in a mass ratio of 5:1.2:20.

In another preferred embodiment, the pharmaceutical composition comprises a ligand-drug conjugate or a pharmaceutically acceptable salt thereof, histidine and mannitol in a mass ratio of 5:1.2:20.

In another preferred embodiment, the pharmaceutical composition comprises a ligand-drug conjugate or a pharmaceutically acceptable salt thereof, tromethamine and mannitol in a mass ratio of 5:1:20.

In another preferred embodiment, the pharmaceutical composition comprises a ligand-drug conjugate or a pharmaceutically acceptable salt thereof, sodium citrate and mannitol in a mass ratio of 5:2.1:20.

In another preferred embodiment, the pharmaceutical composition comprises a ligand-drug conjugate or a pharmaceutically acceptable salt thereof, disodium hydrogen phosphate and mannitol in a mass ratio of 5:1.1:20.

In another preferred embodiment, the pharmaceutical composition comprises a ligand-drug conjugate or a pharmaceutically acceptable salt thereof, histidine and mannitol in a mass ratio of 5:1.2:10.

In another preferred embodiment, the pharmaceutical composition comprises a ligand-drug conjugate or a pharmaceutically acceptable salt thereof, histidine and mannitol in a mass ratio of 5:1.2:30.

In another preferred embodiment, the above-mentioned pharmaceutical composition comprises a ligand-drug conjugate or a drug-linked The mass ratio of the salt, histidine and mannitol is 5:0.8:20.

In another preferred embodiment, the pharmaceutical composition comprises a ligand-drug conjugate or a pharmaceutically acceptable salt thereof, histidine and mannitol in a mass ratio of 5:1.6:20.

In a preferred embodiment, the pharmaceutical composition comprises 50 mg of a ligand-drug conjugate or a pharmaceutically acceptable salt thereof, 12 mg of histidine and 200 mg of sucrose.

In another preferred embodiment, the pharmaceutical composition comprises 50 mg of a ligand-drug conjugate or a pharmaceutically acceptable salt thereof, 12 mg of histidine and 200 mg of trehalose.

In another preferred embodiment, the pharmaceutical composition comprises 50 mg of a ligand-drug conjugate or a pharmaceutically acceptable salt thereof, 12 mg of histidine and 200 mg of mannitol.

In another preferred embodiment, the pharmaceutical composition comprises 50 mg of a ligand-drug conjugate or a pharmaceutically acceptable salt thereof, 12 mg of histidine and 100 mg of mannitol.

In another preferred embodiment, the pharmaceutical composition comprises 50 mg of a ligand-drug conjugate or a pharmaceutically acceptable salt thereof, 12 mg of histidine and 300 mg of mannitol.

In another preferred embodiment, the pharmaceutical composition comprises 50 mg of a ligand-drug conjugate or a pharmaceutically acceptable salt thereof, 8 mg of histidine and 200 mg of mannitol.

In another preferred embodiment, the pharmaceutical composition comprises 50 mg of a ligand-drug conjugate or a pharmaceutically acceptable salt thereof, 16 mg of histidine and 200 mg of mannitol.

In one embodiment, the above pharmaceutical composition is a liquid composition.

In one embodiment, the above pharmaceutical composition is a lyophilized solid composition.

In one embodiment, the above pharmaceutical composition is a lyophilized solid composition that is reconstituted into a liquid.

[Liquid preparation and preparation method thereof]

The present invention provides a liquid preparation comprising the above pharmaceutical composition and a solvent.

In one embodiment, the solvent in the above liquid formulation is water.

In a preferred embodiment, the solvent in the above liquid preparation is purified water.

In another preferred embodiment, the solvent in the above liquid preparation is sterile water, distilled water or deionized water.

In a more preferred embodiment, the solvent in the above liquid preparation is sterile water for injection, single distilled water or double distilled water.

In one embodiment, the pH value of the liquid preparation may be 6.0-8.0, for example, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 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, 8.0.

In a preferred embodiment, the pH value of the above pharmaceutical preparation is 6.5.

In one embodiment, the liquid preparation optionally comprises an acidic substance or an alkaline substance.

In a preferred embodiment, the liquid preparation does not contain other acidic or alkaline substances except the pH adjuster.

In another preferred embodiment, the liquid preparation comprises an acidic substance, and the acidic substance is used to adjust the pH value of the liquid preparation to 6.0-8.0.

In a more preferred embodiment, the liquid preparation comprises hydrochloric acid.

In another preferred embodiment, the liquid preparation comprises an alkaline substance other than the pH adjuster, and the alkaline substance is used to adjust the pH value of the liquid preparation to 6.0-8.0.

In a more preferred embodiment, the liquid preparation comprises sodium hydroxide.

In one embodiment, the concentration of the ligand-drug conjugate or its pharmaceutically acceptable salt in the above liquid formulation is 10 mg/mL-15 mg/mL, for example, 10 mg/mL, 10.5 mg/mL, 11 mg/mL, 11.5 mg/mL, 12 mg/mL, 12.5 mg/mL, 13 mg/mL, 13.5 mg/mL, 14 mg/mL, 14.5 mg/mL or 15 mg/mL.

In a preferred embodiment, the active drug concentration in the above liquid preparation is 12.5 mg/mL.

In one embodiment, the concentration of the pH adjuster in the above liquid preparation is 2 mg/mL-4 mg/mL, for example, 2 mg/mL, 2.2 mg/mL, 2.4 mg/mL, 2.6 mg/mL, 2.8 mg/mL, 3 mg/mL, 3.2 mg/mL, 3.4 mg/mL, 3.6 mg/mL, 3.8 mg/mL or 4 mg/mL.

In a preferred embodiment, the concentration of the pH adjuster in the above liquid preparation is 2 mg/mL.

In another preferred embodiment, the concentration of the pH adjuster in the above liquid preparation is 3 mg/mL.

In yet another preferred embodiment, the concentration of the pH adjuster in the above liquid preparation is 4 mg/mL.

In one embodiment, the concentration of the lyophilized excipient in the above liquid formulation is 12.5 mg/mL-100 mg/mL, for example, 12.5 mg/mL, 15 mg/mL, 17.5 mg/mL, 20 mg/mL, 22.5 mg/mL, 25 mg/mL, 27.5 mg/mL, 30 mg/mL, 32.5 mg/mL, 35 mg/mL, 37.5 mg/mL, 40 mg/mL, 42.5 mg/mL, 45 mg/mL, 47.5 mg/mL, 50 mg/mL, g/mL, 52.5mg/mL, 55mg/mL, 57.5mg/mL, 60mg/mL, 62.5mg/mL, 65mg/mL, 67.5mg/mL, 70mg/mL, 72.5mg/mL, 75mg/m L, 77.5mg/mL, 80mg/mL, 82.5mg/mL, 85mg/mL, 87.5mg/mL, 90mg/mL, 92.5mg/mL, 95mg/mL, 97.5mg/mL or 100mg/mL.

In a preferred embodiment, the concentration of the lyophilized excipient in the above liquid preparation is 25 mg/mL-75 mg/mL, for example, 25 mg/mL, 27.5 mg/mL, 30 mg/mL, 32.5 mg/mL, 35 mg/mL, 37.5 mg/mL, 40 mg/mL, 42.5 mg/mL, 45 mg/mL, 47.5 mg/mL, 50 mg/mL, 52.5 mg/mL, 55 mg/mL, 57.5 mg/mL, 60 mg/mL, 62.5 mg/mL, 65 mg/mL, 67.5 mg/mL, 70 mg/mL, 72.5 mg/mL, 75 mg/mL 42.5mg/mL, 45mg/mL, 47.5mg/mL, 50mg/mL, 52.5mg/mL, 55mg/mL, 57.5mg/mL, 60mg/mL, 62.5mg/mL, 65mg/mL, 67.5mg/mL, 70mg/mL, 72.5mg/mL or 75mg/mL.

In another preferred embodiment, the concentration of the lyophilized excipient in the above liquid preparation is 25 mg/mL.

In another preferred embodiment, the concentration of the lyophilized excipient in the above liquid preparation is 50 mg/mL.

In yet another preferred embodiment, the concentration of the lyophilized excipient in the above liquid preparation is 75 mg/mL.

In one embodiment, the liquid preparation comprises a ligand-drug conjugate or a pharmaceutically acceptable salt thereof, a lyophilization excipient, a pH adjuster and a solvent; wherein the pH of the liquid preparation is 6.0 to 8.0.

In a preferred embodiment, each 1 mL of the above liquid preparation contains 12.5 mg of a ligand-drug conjugate or a pharmaceutically acceptable salt thereof, 3 mg of histidine, 50 mg of sucrose and optionally an acidic or alkaline substance and the balance water; wherein the pH of the liquid preparation is 6.0 to 8.0.

In a preferred embodiment, each 1 mL of the above liquid preparation contains 12.5 mg of a ligand-drug conjugate or a pharmaceutically acceptable salt thereof, 3 mg of histidine, 50 mg of trehalose and optionally an acidic or alkaline substance and the balance water; wherein the pH of the liquid preparation is 6.0-8.0.

In a preferred embodiment, each 1 mL of the above liquid preparation contains 12.5 mg of a ligand-drug conjugate or a pharmaceutically acceptable salt thereof, 3 mg of histidine, 50 mg of mannitol and optionally an acidic or alkaline substance and the remainder of water; wherein the pH of the liquid preparation is 6.0 to 8.0.

In a preferred embodiment, each 1 mL of the above liquid preparation contains 12.5 mg of a ligand-drug conjugate or a pharmaceutically acceptable salt thereof, 3 mg of histidine, 25 mg of mannitol and optionally an acidic or alkaline substance and the balance water; wherein the pH of the liquid preparation is 6.0 to 8.0.

In a preferred embodiment, each 1 mL of the above liquid preparation contains 12.5 mg of a ligand-drug conjugate or a pharmaceutically acceptable salt thereof, 3 mg of histidine, 75 mg of mannitol and optionally an acidic or alkaline substance and the balance water; wherein the pH of the liquid preparation is 6.0 to 8.0.

In a preferred embodiment, each 1 mL of the above liquid preparation contains 12.5 mg of a ligand-drug conjugate or a pharmaceutically acceptable salt thereof, 2 mg of histidine, 50 mg of mannitol and optionally an acidic or alkaline substance and the balance water; wherein the pH of the liquid preparation is 6.0 to 8.0.

In a preferred embodiment, each 1 mL of the above liquid preparation contains 12.5 mg of a ligand-drug conjugate or a pharmaceutically acceptable salt thereof, 4 mg of histidine, 50 mg of mannitol and optionally an acidic or alkaline substance and the balance water; wherein the pH of the liquid preparation is 6.0 to 8.0.

In one embodiment, the above liquid formulation is sterile.

In one embodiment, the above liquid formulation is stable when frozen in the dark and thawed in the dark.

In one embodiment, the preparation method of the above liquid preparation comprises the following steps: taking a prescribed amount of a ligand-drug conjugate or a pharmaceutically acceptable salt thereof and optional pharmaceutically acceptable excipients at room temperature and in the dark, and mixing them uniformly to obtain the liquid preparation.

In one embodiment, the preparation method of the above-mentioned liquid preparation comprises the following steps: taking a prescribed amount of a ligand-drug conjugate or a pharmaceutically acceptable salt thereof, a pH adjuster, a lyophilized excipient and a solvent at room temperature and in the dark, dissolving the ligand-drug conjugate or a pharmaceutically acceptable salt thereof, a pH adjuster and a lyophilized excipient in a solvent, adjusting the pH to 6.0-8.0, mixing, filtering, and obtaining the liquid preparation.

In a preferred embodiment, the preparation method of the above-mentioned liquid preparation comprises the following steps: taking a prescribed amount of a ligand-drug conjugate or a pharmaceutically acceptable salt thereof, a pH adjuster, a lyophilized excipient and a solvent at room temperature and in the dark, dissolving the pH adjuster and the lyophilized excipient in the solvent, and then adding the ligand-drug conjugate or a pharmaceutically acceptable salt thereof, mixing, and obtaining the liquid preparation.

In a preferred embodiment, the preparation method of the above-mentioned liquid preparation comprises the following steps: taking a prescribed amount of a ligand-drug conjugate or a pharmaceutically acceptable salt thereof, a pH adjuster, a lyophilized excipient and a solvent at room temperature and in the dark, dissolving the pH adjuster in the solvent, then dissolving the ligand-drug conjugate or a pharmaceutically acceptable salt thereof in the above-mentioned solvent, and finally adding the lyophilized excipient and mixing to obtain the liquid preparation.

In a preferred embodiment, the preparation method of the above-mentioned liquid preparation comprises the following steps: taking a prescribed amount of a ligand-drug conjugate or a pharmaceutically acceptable salt thereof, a pH adjuster, a lyophilized excipient and a solvent at room temperature and in the dark, dissolving the lyophilized excipient in the solvent, then dissolving the ligand-drug conjugate or a pharmaceutically acceptable salt thereof in the above-mentioned solvent, and finally adding a pH adjuster and mixing to obtain the liquid preparation.

In a preferred embodiment, the preparation method of the above-mentioned liquid preparation comprises the following steps: taking a prescribed amount of a ligand-drug conjugate or a pharmaceutically acceptable salt thereof, a pH adjuster, a lyophilizing excipient and a solvent at room temperature and in the dark, and dissolving the ligand-drug conjugate or a pharmaceutically acceptable salt thereof, a pH adjuster and a lyophilizing excipient in the solvent at the same time.

[Lyophilized preparation and preparation method thereof]

The present invention provides a lyophilized preparation obtained by freeze-drying the liquid preparation of the present invention.

The present invention also provides a method for preparing the above-mentioned freeze-dried preparation, which comprises the following steps: freeze-drying the liquid preparation of the present invention under light-proof conditions to obtain the freeze-dried preparation.

In one embodiment, the freeze-drying comprises the following steps: (i) freezing the pharmaceutical preparation at -45°C; (ii) drying the pharmaceutical preparation once at -20°C to -5°C; (iii) drying the pharmaceutical preparation twice at 10°C to 40°C.

In a preferred embodiment, the primary drying temperature in the above preparation method is -5°C.

In another preferred embodiment, the primary drying temperature in the above preparation method is -10°C.

In another preferred embodiment, the primary drying temperature in the above preparation method is -15°C.

In another preferred embodiment, the primary drying temperature in the above preparation method is -20°C.

In a preferred embodiment, the secondary drying temperature in the above preparation method is 10°C.

In another preferred embodiment, the secondary drying temperature in the above preparation method is 25°C.

In another preferred embodiment, the secondary drying temperature in the above preparation method is 40°C.

In one embodiment, the lyophilized preparation is stable under refrigerated conditions at 2-8°C and protected from light.

[Reconstituted liquid preparation and preparation method thereof]

The present invention provides a reconstituted liquid preparation, which is prepared by reconstructing the above-mentioned lyophilized preparation with water.

In one embodiment, the water used in the above-mentioned reconstituted liquid preparation is one or more of distilled water, purified water or sterile water.

In one embodiment, the pH of the reconstituted liquid preparation after the lyophilized preparation is reconstituted with water is 6.0-8.0.

The present invention also provides a method for preparing the above-mentioned reconstituted liquid preparation, which comprises the step of mixing the lyophilized preparation of the present invention with sterile water.

[Device]

The present invention provides a drug-containing delivery device, which comprises one of the above-mentioned pharmaceutical composition, the above-mentioned liquid preparation, the above-mentioned lyophilized preparation or the above-mentioned reconstituted liquid preparation.

The present invention also provides a prefilled syringe, which comprises one of the above-mentioned pharmaceutical composition, the above-mentioned liquid preparation, the above-mentioned lyophilized preparation or the above-mentioned reconstituted liquid preparation.

In one embodiment, the above-described prefilled syringe is for intravenous injection.

In one embodiment, the above-described prefilled syringe is for intramuscular injection.

[Medical Use]

The present invention provides use of the above pharmaceutical composition, the above liquid preparation, the above lyophilized preparation or the above reconstituted liquid preparation containing an active drug in preparing a delivery device or a pre-filled syringe or a drug.

In one embodiment, the delivery device or prefilled syringe or medicament in the above use is used to enhance immune effector cell response in a subject.

In one embodiment, the delivery device or prefilled syringe or medicament for use as described above is for reducing immunosuppression in a subject.

In one embodiment, the delivery device or prefilled syringe or medicament for use above is used in a subject. Treating and/or preventing cancer.

Furthermore, the cancers used in the above-mentioned purposes include one or more of breast cancer, lung cancer, prostate cancer, kidney cancer, leukemia, ovarian cancer, gastric cancer, uterine cancer, endometrial cancer, liver cancer, thyroid cancer, pancreatic cancer, colorectal cancer, esophageal cancer, testicular cancer, skin cancer, biliary tract cancer, breast cancer, lymphoma, and multiple myeloma.

In one embodiment, the delivery device or prefilled syringe or medicament in the above use is for treating and/or preventing an immune disease in a subject.

Furthermore, the immune diseases in the above use include one or more of connective tissue disease, systemic sclerosis, rheumatoid arthritis and systemic lupus erythematosus.

In one embodiment, the delivery device or prefilled syringe or medicament for use as described above is for treating and/or preventing a metabolic disease in a subject.

Furthermore, the metabolic diseases in the above use include one or more of diabetes, gout, obesity, hypoglycemia, hyperglycemia and dyslipidemia.

In one embodiment, the delivery device or prefilled syringe or medicament for use as described above is for treating and/or preventing a neurological disease in a subject.

Furthermore, the neurological diseases in the above use include one or more of Alzheimer's disease, Parkinson's disease, Huntington's disease, head injury, multiple sclerosis, vertigo, coma and epilepsy.

The technical solution of the present invention will be further described below in conjunction with specific embodiments.

Embodiment 1:

Compound X is unstable to acid and alkali, so it is necessary to investigate the appropriate pH adjuster and dosage to ensure the preparation and stability of the product.

1.1 Screening of pH adjusters

1.1.1 Preparation method

Dissolve compound X and mannitol in water for injection, add pH regulators to the aqueous solution respectively, so that the concentration of the added pH regulators is 20 mM; adjust the pH value of the final solution to 6.5 with hydrochloric acid and/or sodium hydroxide; filter and dispense into vials, half-stopper, and freeze-dry to obtain a freeze-dried product.

1.1.2 Prescription

Table 1. Prescription composition for screening of pH adjuster types

Note: “/” means the component is not added.

1.1.3 Stability study

The freeze-dried preparation prepared according to the above prescription and preparation method was subjected to a high temperature test at 40°C for 10 days. The test results are as follows:

Table 2. Investigation of factors affecting high temperature of 40℃ for 10 days

Note: “N/A” means the item was not tested.

The results show that the finished products of each pH regulator formulation have no significant degradation under high temperature conditions after 10 days of testing of influencing factors at 40°C, and the pH has no significant change after lyophilization. The composition of each formulation meets the stability requirements of the formulation and has equivalent quality. Considering that the pH of formulation 1 is still 6.5 after reconstitution, which has no significant change from before lyophilization; and the pH of histidine is close to neutral after dissolving in water, histidine is selected as the pH regulator in the following examples.

1.2 pH adjuster dosage screening

1.2.1 Preparation method

Prepare the freeze-dried product using a method similar to 1.1.1.

1.2.2 pH adjuster dosage screening

Effects of different histidine dosages (1 mg/mL, 2 mg/mL, 3 mg/mL, 4 mg/mL) on the dissolution of compound X.

1.2.3 Results

Table 3. pH adjuster dosage screening

Note: “N/A” means the item was not tested.

The results showed that except for 1 mg/mL, all other components were completely soluble in water for injection. In order to ensure that compound X was completely dissolved in water in a short time and to use as few excipients as possible, the following example selected a histidine dosage of 20 mM (3 mg/mL).

Embodiment 2:

The type and dosage of lyophilized excipients have an impact on the properties and stability of the product. Therefore, it is necessary to examine the appropriate lyophilized excipients and dosage to ensure the properties and stability of the product.

2.1 Screening of lyophilized excipients

2.1.1 Preparation method

Dissolve histidine in water for injection, add compound X, stir to dissolve, then add the prescribed amount of freeze-drying protective agent; if necessary, adjust the pH to 6.5 with 0.1M hydrochloric acid and/or sodium hydroxide, filter and dispense into vials, half-stopper, freeze-dry, and cap to obtain a freeze-dried product.

2.1.2 Prescription

Table 4. Lyophilized excipient type screening formula composition

2.1.3 Stability study

The freeze-dried preparation prepared according to the above prescription and preparation method was subjected to a high temperature test of 60°C for 5 days. The test results are as follows:

Table 5. Investigation of factors affecting high temperature of 60℃ for 5 days

The above experimental results show that the freeze-dried products of prescriptions 10 and 11 on day 0 have slight defects in their properties, and the freeze-dried products of prescription 12 have the best properties; the freeze-dried products of each prescription were examined after influencing factors at 60°C for 5 days, and the product quality was equivalent; considering that the freeze-dried product of prescription 12 has better properties, mannitol was selected as the freeze-dried excipient in the following embodiments.

2.2 Screening of freeze-dried excipient dosage

2.2.1 Preparation method

Prepare the freeze-dried product using a method similar to 2.1.1.

2.2.2 Prescription

Effect of different lyophilized excipient dosages (0 mg/mL, 25 mg/mL, 50 mg/mL, 75 mg/mL) on the prescription.

Table 6. Lyophilized excipient dosage screening formula composition

2.2.3 Stability study

Table 7. Stability test results

The results showed that the freeze-dried product of prescription 13 was atrophied, the freeze-dried product of prescription 14 had slight defects, and the freeze-dried products of prescriptions 12 and 15 were of similar quality. Considering the use of excipients as little as possible, 200 mg of mannitol was selected as the amount of freeze-dried excipient in the following examples;

At the same time, according to the above stability test results, the total impurities of the freeze-dried finished product increased under high temperature (60°C) and strong light (4500lx±500lx) conditions. Therefore, the freeze-dried finished product described in the following examples is stored under refrigerated and light-proof conditions to ensure the stability of the product.

Embodiment 3:

Different raw and auxiliary materials have different acidity, alkalinity and stability. Therefore, it is necessary to examine the feeding sequence, pH adjustment process, light intensity and temperature of different raw and auxiliary materials to ensure the preparation and stability of the product.

3.1 Screening of the feeding order of raw and auxiliary materials

3.1.1 Prescription

Prescription 12 was used to investigate the effect of the order of feeding on the product.

3.1.2 Investigation of feeding process

1) Add about 80% of the prescribed amount of water for injection into each preparation container;

2) Feeding process;

Table 8. Feeding process

3) Add 0.1M hydrochloric acid and/or sodium hydroxide to adjust the pH to 6.5. Add injection water to the full amount and filter with a 0.22μm PES filter membrane to obtain the product.

3.1.3 Investigation of solvent phenomena in the feeding process

Table 9. Dissolution phenomenon of feeding process

3.1.4 Results of the feeding process investigation

Table 10. Investigation results

The results showed that, regardless of the order of adding the materials, compound X was completely dissolved after stirring for 10 to 25 minutes after addition; and the properties, pH value, content and related substances of the obtained intermediate solutions were all comparable.

3.2 pH adjustment process investigation

3.2.1 Prescription

Formulation 12 was used to investigate the effect of pH adjustment process on liquid dosage forms.

3.2.2 pH adjustment process investigation

Liquid preparations were prepared, and the pH values of the liquid preparations were adjusted to 6.0, 6.5, 7.0, 7.5 and 8.0 respectively with 0.1 M hydrochloric acid and/or sodium hydroxide solution.

3.2.3 Stability study

The liquid preparations with different pH values prepared according to the above prescription and preparation method were placed at 25±5℃ in the dark for 0h, 14h, and 24h. The results are as follows:

Table 11. Results of 24-hour stability study of liquid preparations with different pH values

The results showed that when the pH value of the liquid preparation was between 6.0 and 8.0 and the temperature was 25±5℃ and away from light, the total impurities did not increase significantly within 24 hours, and the pH of the pH8.0 group decreased slightly. Therefore, the acceptable pH adjustment range of the liquid preparation is 6.0 to 8.0.

3.3 Effect of light on products

3.3.1 Prescription

Prescription 12 was used to investigate the effect of light on the product.

3.3.2 Preparation method

Compound X, mannitol and pH adjuster are dissolved in water for injection; the pH value of the final solution is adjusted to 6.5 with hydrochloric acid and/or sodium hydroxide.

3.2.3 Stability study

The liquid preparation prepared according to the above prescription and preparation method was placed under light-proof conditions and strong light irradiation conditions for 0h, 4h, 6h, and 24h. The results are as follows:

Table 12. Survey results

The results show that under 4500lx±500lx conditions within 24 hours, the total impurity growth rate of samples under strong light conditions is much higher than that of samples under light-proof conditions. Therefore, in order to ensure product quality, the following embodiments are protected from light during the production process.

3.4 Screening of liquid preparation temperature

3.4.1 Prescription

Use prescription 3.2.1 to investigate the effect of preparation temperature on the product.

3.4.2 Preparation method

Prepared in a similar manner to 3.2.2.

3.4.3 Stability study

The liquid preparation prepared according to the above prescription and preparation method was placed under light-proof conditions at 5℃±3℃, 25℃±2℃, and 40℃±2℃ for 25h, and samples were taken for testing at 0h, 6h, and 25h. The results are as follows:

Table 13. Investigation results

The results show that the above-mentioned preparation is relatively stable under the temperature conditions of 5℃±3℃ and 25℃±2℃, and there is no obvious change in properties, pH value, content and related substances; considering the actual process conditions, the following examples are prepared at below 25℃, which is suitable for process-scaled production and can well guarantee product quality.

Embodiment 4:

The freeze-drying process can remove the solvent in the preparation and obtain a freeze-dried product that can be reconstituted before injection. The key properties of freeze-drying are moisture, properties and reconstitution time; therefore, different freeze-drying processes are examined to obtain a preparation product that meets the requirements.

4.1 Prescription

4.2 Freeze-drying process investigation

Table 14. Freeze-drying process investigation

4.3 Results

Table 15. Results of freeze-drying process investigation

The above results show that the moisture content after freeze-drying in process 1 to process 7 can be controlled below 2.00%, which can ensure storage stability; the reconstitution time does not exceed 3 minutes, the pH is close to neutral, and it is suitable for clinical use. In the actual freeze-drying process operation, the freeze-drying time, drying temperature, etc. can be appropriately changed according to the freeze-drying equipment, freeze-drying batch, freeze-drying scale, etc., and the appropriate freeze-drying process is selected according to the freeze-drying residual moisture content, and the moisture content after freeze-drying meets the requirements (moisture content ≤ 5%).

Embodiment 5:

During the production, storage and use of drug preparations, they may decompose and deteriorate due to various factors, which may lead to reduced drug efficacy or increased side effects. Therefore, the stability of drug preparations is investigated.

5.1 Prescription

Prescription 12 was used to investigate the stability of the drug preparation under light-protected conditions.

5.2 Stability test plan

Table 16. Stability test plan

5.3 Experimental Results

Table 17. Long-term stability test results (2-8°C, protected from light)

Table 18. Accelerated stability test results (25℃±2℃, protected from light)

The results showed that the samples were kept at 2-8℃ and 25℃±2℃ in the dark, and the moisture, total impurities, content, pH value, properties and reconstitution time did not undergo significant changes within 6 months, which was in line with expectations; this indicates that the product can be stably stored at 2-8℃ and 25℃±2℃ in the dark for at least 6 months.

It should be understood that the embodiments described in the present invention are only examples, and various changes or modifications may be made to the essential embodiments without departing from the principle and essence of the present invention.

Claims

A pharmaceutical composition comprising compound X-1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient;

The compound X-1 has the following structure:

The pharmaceutically acceptable excipients include one or more of a pH adjuster and a lyophilization excipient;

Preferably, the compound X-1 is an enantiomeric compound X having the following structure:

Further preferably, the pH adjuster is an alkaline pH adjuster;

More preferably, the lyophilization excipient is one or more of polyols or sugars.
The pharmaceutical composition according to claim 1, characterized in that the alkaline pH regulator is one or more of histidine, histidine hydrochloride, tromethamine, tromethamine hydrochloride or an alkaline salt; preferably, the alkaline salt is sodium hydroxide, potassium hydroxide, sodium citrate, sodium phosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, sodium hydrogen phosphate, sodium borate, sodium acetate, potassium acetate, sodium bicarbonate or sodium carbonate.
The pharmaceutical composition according to claim 1 or 2, characterized in that the pH regulator is tromethamine, histidine, sodium citrate or disodium hydrogen phosphate, preferably histidine.
The pharmaceutical composition according to claim 1, characterized in that the polyol is one or more of mannitol, sorbitol or xylitol, and the sugar is glucose, fructose, lactose, dextran, sucrose, trehalose, maltose, cyclodextrin, hydroxypropyl methylcellulose, hydroxypropyl cellulose, sodium carboxymethyl cellulose or dextran; preferably, the polyol is mannitol, and the sugar is sucrose or trehalose.
The pharmaceutical composition according to any one of claims 1 to 4, characterized in that the molar mass ratio of the compound X-1 to the pH regulator is 1:3 to 1:7, for example, 1:3, 1:3.1, 1:3.2, 1:3.3, 1:3.4, 1:3.5, 1:3.6, 1:3.7, 1:3.8, 1:3.9, 1:4, 1:4.1, 1:4.2, 1:4.3, 1:4.4, 1:4.5, 1:4.6, 1:4.7, 1:4.8, 1:4.9, 1:5, 1:5.1, 1:5.2, 1:5.3, 1:5.4, 1:5.5, 1:5.6, 1:5.7, 1:5.8, 1:5.9, 1:6, 1:6.1, 1:6.2, 1:6.3, 1:6.4, 1:6.5, 1:6.6, 1:6.7, 1:6.8, 1:6.9, 1:7; preferably, the molar mass ratio of the compound X-1 to the pH regulator is 1:3.1, 1:4.8, 1:6.2.
The pharmaceutical composition according to any one of claims 1 to 5, characterized in that the mass ratio of the compound X-1 to the lyophilized excipient is 1.2:1 to 1:10, for example, 1.2:1, 1.1:1, 1:1, 1:1.5, 1:2, 1:2.5, 1:3, 1:3.5, 1:4, 1:4.5, 1:5, 1:5.5, 1:6, 1:6.5, 1:7, 1:7.5, 1:8, 1:8.5, 1:9, 1:9.5 or 1:10;

Preferably, the mass ratio of the compound X-1 to the lyophilized excipient is 1:2, 1:4 or 1:6.
The pharmaceutical composition according to any one of claims 1 to 6, characterized in that the pharmaceutical composition comprises compound X-1 or a pharmaceutically acceptable salt thereof, a pH regulator and a lyophilization excipient, and the mass ratio thereof is 5:(0.8-2.5):(10-30); preferably, the mass ratio thereof is 5:(1-1.5):(15:25); further preferably, the mass ratio thereof is 5:1.2:20;

Further preferably, the pharmaceutical composition comprises compound X-1, histidine and sucrose in a mass ratio of 5:1.2:20;

Further preferably, the pharmaceutical composition comprises compound X-1, histidine and trehalose in a mass ratio of 5:1.2:20;

Further preferably, the pharmaceutical composition comprises compound X-1, histidine and mannitol in a mass ratio of 5:1.2:20;

Further preferably, the pharmaceutical composition comprises compound X-1, tromethamine and mannitol in a mass ratio of 5:1:20;

Further preferably, the pharmaceutical composition comprises compound X-1, sodium citrate and mannitol in a mass ratio of 5:2.1:20;

Further preferably, the pharmaceutical composition comprises compound X-1, disodium hydrogen phosphate and mannitol in a mass ratio of 5:1.1:20;

Further preferably, the pharmaceutical composition comprises compound X-1, histidine and mannitol in a mass ratio of 5:1.2:10;

Further preferably, the pharmaceutical composition comprises compound X-1, histidine and mannitol in a mass ratio of 5:1.2:30;

Further preferably, the pharmaceutical composition comprises compound X-1, histidine and mannitol in a mass ratio of 5:0.8:20; or,

Further preferably, the pharmaceutical composition comprises compound X-1, histidine and mannitol in a mass ratio of 5:1.6:20.
A liquid preparation, characterized in that it comprises the pharmaceutical composition according to any one of claims 1 to 7 and a solvent; the solvent is water;

Preferably, the solvent is purified water;

More preferably, the purified water is sterile water, distilled water or deionized water;

More preferably, the sterile water is sterile water for injection, single-distilled water or double-distilled water.
The liquid preparation according to claim 8, characterized in that the pH of the liquid preparation is 6.0 to 8.0, for example 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 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;

Preferably, the pH of the liquid preparation is 6.5.
The liquid preparation according to claim 8 or 9 is characterized in that the liquid preparation optionally contains an acidic substance or an alkaline substance; the acidic substance or the alkaline substance is used to adjust the pH value of the liquid preparation; the acidic substance is preferably hydrochloric acid; the alkaline substance is preferably sodium hydroxide.
The liquid preparation according to any one of claims 8 to 10, characterized in that the concentration of the compound X-1 is 10 mg/mL-15 mg/mL, for example, 10 mg/mL, 10.5 mg/mL, 11 mg/mL, 11.5 mg/mL, 12 mg/mL, 12.5 mg/mL, 13 mg/mL, 13.5 mg/mL, 14 mg/mL, 14.5 mg/mL or 15 mg/mL;

Preferably, the concentration of compound X-1 is 12.5 mg/mL.
The liquid preparation according to any one of claims 8 to 11, characterized in that the concentration of the pH regulator is 2 mg/mL-4 mg/mL, for example, 2 mg/mL, 2.2 mg/mL, 2.4 mg/mL, 2.6 mg/mL, 2.8 mg/mL, 3 mg/mL, 3.2 mg/mL, 3.4 mg/mL, 3.6 mg/mL, 3.8 mg/mL or, 4 mg/mL;

Preferably, the concentration of the pH adjuster is 2 mg/mL, 3 mg/mL, 4 mg/mL;

More preferably, the concentration of the pH adjuster is 3 mg/mL.
The liquid preparation according to any one of claims 8 to 12, characterized in that the concentration of the lyophilized excipient is 12.5 mg/mL to 100 mg/mL, for example 12.5 mg/mL, 15 mg/mL, 17.5 mg/mL, 20 mg/mL, 22.5 mg/mL, 25 mg/mL, 27.5 mg/mL, 30 mg/mL, 32.5 mg/mL, 35 mg/mL, 37.5 mg/mL, 40 mg/mL, 42.5 mg/mL, 45 mg/mL, 47.5 mg/mL mL, 50mg/mL, 52.5mg/mL, 55mg/mL, 57.5mg/mL, 60mg/mL, 62.5mg/mL, 65mg/mL, 67.5mg/mL, 70mg/mL, 72.5mg/mL, 75m g/mL, 77.5mg/mL, 80mg/mL, 82.5mg/mL, 85mg/mL, 87.5mg/mL, 90mg/mL, 92.5mg/mL, 95mg/mL, 97.5mg/mL or 100mg/mL;

Preferably, the concentration of the lyophilized excipient is 25 mg/mL to 75 mg/mL, for example 25 mg/mL, 27.5 mg/mL, 30 mg/mL, 32.5 mg/mL, 35 mg/mL, 37.5 mg/mL, 40 mg/mL, 42.5 mg/mL, 45 mg/mL, 47.5 mg/mL, 50 mg/mL, 52.5 mg/mL, 55 mg/mL, 57.5 mg/mL, 60 mg/mL, 62.5 mg/mL, 65 mg/mL, 67.5 mg/mL, 70 mg/mL, 72.5 mg/mL, or 75 mg/mL;

Further preferably, the concentration of the lyophilized excipient is 25 mg/mL, 50 mg/mL or 75 mg/mL.
The liquid preparation according to any one of claims 8 to 13, characterized in that the liquid preparation comprises compound X-1 or a pharmaceutically acceptable salt thereof, a lyophilization excipient, a pH adjuster and a solvent; wherein the pH of the liquid preparation is 6.0 to 8.0;

Preferably, each 1 mL of the liquid preparation contains 12.5 mg of compound X-1 or a pharmaceutically acceptable salt thereof, 3 mg of histidine, 50 mg of sucrose and an optional acidic substance or alkaline substance and the balance of water; wherein the pH of the liquid preparation is 6.0 to 8.0;

Preferably, each 1 mL of the liquid preparation contains 12.5 mg of compound X-1 or a pharmaceutically acceptable salt thereof, 3 mg of histidine, 50 mg of trehalose and an optional acidic substance or alkaline substance and the remainder of water; wherein the pH of the liquid preparation is 6.0 to 8.0;

Preferably, each 1 mL of the liquid preparation contains 12.5 mg of compound X-1 or a pharmaceutically acceptable salt thereof, 3 mg of histidine, 50 mg of mannitol and an optional acidic substance or alkaline substance and the remainder of water; wherein the pH of the liquid preparation is 6.0 to 8.0;

Preferably, each 1 mL of the liquid preparation contains 12.5 mg of compound X-1 or a pharmaceutically acceptable salt thereof, 3 mg of histidine, 25 mg of mannitol and an optional acidic substance or alkaline substance and the remainder of water; wherein the pH of the liquid preparation is 6.0 to 8.0;

Preferably, each 1 mL of the liquid preparation contains 12.5 mg of compound X-1 or a pharmaceutically acceptable salt thereof, 3 mg of histidine, 75 mg of mannitol and an optional acidic substance or alkaline substance and the remainder of water; wherein the pH of the liquid preparation is 6.0 to 8.0;

Preferably, each 1 mL of the liquid preparation contains 12.5 mg of compound X-1 or a pharmaceutically acceptable salt thereof, 2 mg of histidine, 50 mg of mannitol and optionally an acidic substance or an alkaline substance and the remainder of water; wherein the pH of the liquid preparation is 6.0 to 8.0; or,

Preferably, each 1 mL of the liquid preparation contains 12.5 mg of compound X-1 or a pharmaceutically acceptable salt thereof, 4 mg of histidine, 50 mg of mannitol and optionally an acidic or alkaline substance and the balance of water; wherein the pH of the liquid preparation is 6.0 to 8.0.
A freeze-dried preparation, characterized in that it is obtained by freeze-drying the liquid preparation according to any one of claims 8 to 14.
A method for preparing a lyophilized preparation according to claim 15, comprising the step of freeze-drying the liquid preparation according to any one of claims 8 to 14 under light-proof conditions; the freeze-drying comprises the following steps: (i) -45°C The pharmaceutical preparation is frozen; (ii) the pharmaceutical preparation is dried once at -20°C to -5°C; (iii) the pharmaceutical preparation is dried twice at 10°C to 40°C; for example, the primary drying temperature is -5°C, -10°C, -15°C or -20°C; the secondary drying temperature is 10°C, 25°C or 40°C.
A reconstituted liquid preparation, characterized in that it is reconstituted from the lyophilized preparation according to claim 15 with water; preferably, the water comprises one or more of distilled water, pure water, and sterile water; more preferably, the pH of the reconstituted liquid preparation after the lyophilized preparation is reconstituted with water is 6.0 to 8.0.
A drug delivery device comprising one of the following: the pharmaceutical composition according to any one of claims 1 to 7, the liquid preparation according to any one of claims 8 to 14, the lyophilized preparation according to claim 15, or the reconstituted liquid preparation according to claim 17.
A prefilled syringe comprising one of the following: a pharmaceutical composition according to any one of claims 1 to 7, a liquid preparation according to any one of claims 8 to 14, a lyophilized preparation according to claim 15, or a reconstituted liquid preparation according to claim 17, preferably for intravenous injection or intramuscular injection.
Use of the pharmaceutical composition according to any one of claims 1 to 7, the liquid preparation according to any one of claims 8 to 14, the lyophilized preparation according to claim 15 or the reconstituted liquid preparation according to claim 17 in the preparation of a delivery device or prefilled syringe or medicament for treating and/or preventing cancer, immune diseases, metabolic diseases and neurological diseases in a subject;

The cancer includes one or more of breast cancer, lung cancer, prostate cancer, kidney cancer, leukemia, ovarian cancer, stomach cancer, uterine cancer, endometrial cancer, liver cancer, thyroid cancer, pancreatic cancer, colorectal cancer, esophageal cancer, testicular cancer, skin cancer, biliary tract cancer, breast cancer, lymphoma, and multiple myeloma;

The immune disease includes one or more of connective tissue disease, systemic sclerosis, rheumatoid arthritis and systemic lupus erythematosus;

The metabolic disease includes one or more of diabetes, gout, obesity, hypoglycemia, hyperglycemia and dyslipidemia;

The neurological disease includes one or more of Alzheimer's disease, Parkinson's disease, Huntington's disease, head injury, multiple sclerosis, vertigo, coma and epilepsy.