Conjugate drug formulations, their manufacturing methods and uses

Abstract

A conjugate drug formulation in the biopharmaceutical field and its manufacturing method and use. The formulation contains a ligand-drug conjugate, a pH adjuster and a freeze-drying excipient. The pH screening is performed on the above-mentioned formulation containing the ligand-drug conjugate, and the pH adjuster and freeze-drying excipient used are limited. At the same time, the administration order and the liquid distribution environment during drug production are considered, and the freeze-drying process parameters are screened, thereby finally achieving the effect of keeping the properties, water content, impurity content, pH value, etc. of the formulation stable during the storage period.

Description

[Technical Field]

[0001] <Priority rights and related applications> This application claims priority to a Chinese patent application submitted to the China Patent Office on October 19, 2021, bearing application number 202111215700.9 and titled "Conjugate drug formulations and their manufacturing methods and uses," the entire contents of which are incorporated herein by reference.

[0002] <Technical field> The present invention relates to the field of biomedicine, specifically, the present invention relates to conjugate drug formulations, specifically drug formulations containing ligand-drug conjugates, and the preparation methods and uses thereof. [Background technology]

[0003] Although significant progress has been made in tumor chemotherapy in recent years, satisfactory results have not been achieved in the treatment of solid tumors, which pose the most serious threat to human life and health and account for more than 90% of malignant tumors. Pharmacists and oncologists in the industry are increasingly aware that to improve the therapeutic efficacy of tumor treatment, breakthroughs cannot be achieved unless we start from the mechanism of tumor development and development.

[0004] Research into the molecular mechanisms of tumor development and progression has revealed that tumor cells exhibit uncontrolled regulation of various fundamental intracellular processes. Therefore, researchers have focused on identifying specific molecules and biological targets that affect the pathological process of cancer. Tumor cells and lesion-bearing cells have multiple specific or overexpressed receptors on their surfaces. The ligands for these receptors can be divided into proteins, polypeptides, and small molecules. These ligands exhibit good specificity, moderate affinity, and clear biological effects when binding to receptors. By coupling with therapeutic drugs to form ligand-drug conjugates (LDCs), they can significantly improve the targeting and efficacy of drugs while simultaneously reducing toxicity.

[0005] Ligand-drug conjugates mediate cellular endocytosis, enabling the binding of targets to endocytic structures. By utilizing dual-targeting ligands to enhance the affinity and targeting of drug conjugates to diseased cells, they can carry highly effective anti-toxic drugs, such as monomethyl auristatin E (MMAE). The connector prevents the conjugate from releasing the drug molecule outside the cell (interstitial space, blood circulation, etc.), ensuring the stability of the drug during circulation in the body, reducing drug toxicity and preventing toxic effects on normal cells. After entering the target cells, the connector decomposes, releasing the therapeutic drug molecule, thereby avoiding the development of multidrug resistance (MDR).

[0006] It is necessary to ensure that LDC formulations maintain good stability during their manufacture, long-term storage, and subsequent use. The stability of LDC in a formulation depends on the pH adjusters, stabilizers, surfactants, etc. used in the formulation. If LDC is not properly formulated in a liquid, the LDC in the liquid solution is prone to degradation, aggregation, or undesirable chemical modification. There is a need in the art for new drug formulations containing LDC that are sufficiently stable and suitable for administration to subjects, and therefore, there is a need to produce LDC formulations suitable for the treatment or prevention of diseases. Summary of the Invention [Problem to be solved by the invention]

[0007] In response to the above-mentioned demand in the art for novel LDC drug formulations that are stable and suitable for administration to subjects, the present invention aims to provide a conjugate drug formulation, specifically a drug formulation containing a ligand-drug conjugate, as well as its preparation method and use, which satisfies the demand for maintaining good stability during storage by limiting the pH value, the type and amount of pH adjuster used, the lyophilization excipients, the administration sequence and distribution environment during drug production, and the parameters of the lyophilization process. [Means for solving the problem]

[0008] [1]. A drug formulation comprising an active drug and optionally a pharmaceutically acceptable excipient.

[0009] [2] The drug formulation of [1], wherein the active drug comprises a ligand-drug conjugate or a pharmaceutically acceptable salt thereof, and the pharmaceutically acceptable excipient comprises one or more of a lyophilization excipient and a pH adjuster.

[0010] [3] The drug formulation of [1] or [2], wherein the active drug comprises a ligand-drug conjugate or a pharmaceutically acceptable salt thereof, and the pharmaceutically acceptable excipient comprises one or more of a lyophilization excipient, a pH adjuster, and a solvent.

[0011] [4] The pharmaceutical formulation according to [3], wherein 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, monodistilled water or bidistilled water.

[0012] [5]. The drug formulation according to [3], characterized in that the concentration of the active drug is 2 mg / mL to 8 mg / mL, for example, 2.0 mg / mL, 2.2 mg / mL, 2.4 mg / mL, 2.6 mg / mL, 2.8 mg / mL, 3.0 mg / mL, 3.2 mg / mL, 3.4 mg / mL, 3.6 mg / mL, 3.8 mg / mL, 4.0 mg / mL, 4.2 mg / mL, 4.4 mg / mL, 4.6 mg / mL, 4.8 mg / mL, 5.0 mg / mL, 5.2 mg / mL, 5.4 mg / mL, 5.6 mg / mL, 5.8 mg / mL, 6.0 mg / mL, 6.2 mg / mL, 6.4 mg / mL, 6.6 mg / mL, 6.8 mg / mL, 7.0 mg / mL, 7.2 mg / mL, 7.4 mg / mL, 7.6 mg / mL, 7.8 mg / mL, or 8.0 mg / mL.

[0013] [6] The pharmaceutical formulation according to [2] or [3], characterized in that the pH adjuster comprises a buffer salt.

[0014] [7] The pharmaceutical formulation described in [6], characterized in that the pH adjuster further contains an acidic substance and / or a basic substance.

[0015] [8] The pharmaceutical formulation of [6], wherein the buffer salt comprises one or more of acetate, phosphate, citrate or hydrates thereof, preferably the hydrates containing 0.5, 1, 1.5, 2.0, 2.5 or 3 molecules of water per molecule, and preferably the buffer salt is one or more of sodium acetate, anhydrous sodium citrate, sodium citrate dihydrate or sodium dihydrogen phosphate.

[0016] [9]. The pharmaceutical formulation of [7], wherein the acidic substance comprises an acid, preferably one or more of hydrochloric acid, acetic acid, or citric acid, and the basic substance comprises a base or a salt, preferably one or more of sodium hydroxide, sodium carbonate, or sodium bicarbonate.

[0017]

[10] The pharmaceutical formulation according to any one of [6] to [9], wherein when the buffer salt is selected from anhydrous sodium citrate or sodium citrate dihydrate, the concentration of the buffer salt is 2.85 mg / mL to 11.4 mg / mL, for example, 2.85 mg / mL, 3.5 mg / mL, 4.2 mg / mL, 5.7 mg / mL, 6.5 mg / mL, 7.6 mg / mL, 8.5 mg / mL, 9.8 mg / mL, 10.5 mg / mL, or 11.4 mg / mL.

[0018]

[11] The drug formulation according to [2] or [3], wherein the lyophilization excipient comprises one or more of a polyol, such as mannitol or xylitol, and preferably the lyophilization excipient is mannitol, and preferably the concentration thereof is 20 mg / mL to 150 mg / mL, for example, 20 mg / mL, 30 mg / mL, 40 mg / mL, 50 mg / mL, 60 mg / mL, 70 mg / mL, 80 mg / mL, 90 mg / mL, 100 mg / mL, 110 mg / mL, 120 mg / mL, 130 mg / mL, 140 mg / mL, or 150 mg / mL, and more preferably the concentration thereof is 40 to 60 mg / mL.

[0019]

[12] The drug formulation according to

[11] , wherein the lyophilization excipient further comprises one or more saccharides, such as monosaccharides, disaccharides, and polysaccharides, and preferably, the mass ratio of the saccharides to the polyol is 1:1 to 1:5, such as 1:1, 1:1.5, 1:2, 1:2.5, 1:3, 1:3.5, 1:4, 1:4.5, or 1:5, and more preferably, the mass ratio of the saccharides to the polyol is 1:2 to 1:4.

[0020]

[13] The pharmaceutical formulation according to

[12] , characterized in that the monosaccharides include one or more of glucose and fructose, the disaccharides include one or more of sucrose, trehalose and maltose, and the polysaccharides include one or more of cyclodextrin and dextran.

[0021]

[14] The drug formulation according to any one of

[11] to

[13] , characterized in that the lyophilized excipients are mannitol and sucrose, preferably in a mass ratio of sucrose to mannitol of 1:4.

[0022]

[15] The pharmaceutical formulation according to any one of [3] to

[14] , characterized in that the pH value of the pharmaceutical formulation is 5.0 to 8.0, for example, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 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.

[0023]

[16] . The drug formulation comprises a ligand-drug conjugate or a pharmaceutically acceptable salt thereof, a lyophilized excipient, a pH adjuster, and a solvent, wherein the pH of the drug formulation is 5.0 to 8.0. Preferably, the drug formulation comprises, per mL, 5 mg of a biligand-drug conjugate or a pharmaceutically acceptable salt thereof, 50 mg of mannitol, 5.7 mg of sodium citrate dihydrate, and an optional acidic or basic substance, and the balance is water, wherein the pH of the drug formulation is 5.0 to 8.0. Preferably, the drug formulation comprises, per mL, 5 mg of a biligand-drug conjugate or a pharmaceutically acceptable salt thereof, 40 mg of mannitol, 10 mg of sucrose, 4.5 mg of anhydrous sodium citrate, and an optional acidic substance. or a basic substance, and the remainder water, wherein the pH of the drug formulation is 5.0 to 8.0; preferably, the drug formulation contains, per mL, 4 mg of the biligand-drug conjugate or a pharmaceutically acceptable salt thereof, 50 mg of mannitol, a suitable amount of sodium acetate and an optional acidic or basic substance, and the remainder water; wherein the pH of the drug formulation is 5.0 to 8.0; preferably, the drug formulation contains, per mL, 6 mg of the biligand-drug conjugate or a pharmaceutically acceptable salt thereof, 50 mg of mannitol, a suitable amount of sodium dihydrogen phosphate and an optional acidic or basic substance, and the remainder water; wherein the pH of the drug formulation is 5.0 to 8.0.

[0024]

[17] . The ligand-drug conjugate is a biligand-drug conjugate, preferably a drug conjugate that targets the PSMA receptor and the TRPV6 receptor, and preferably the biligand-drug conjugate has the following structure: [ka] and More preferably, the biligand-drug conjugate has the structure: [ka] The drug formulation according to any one of [2] to

[16] , characterized in that it has:

[0025]

[18] . A drug formulation described in any one of [1] to

[17] , characterized in that the drug formulation is sterile.

[0026]

[19] . A drug formulation described in any one of [1] to

[17] , characterized in that the drug formulation is stable when frozen and thawed.

[0027]

[20] . A method for producing a drug formulation according to any one of [1] to

[19] , comprising the steps of taking a prescribed amount of an active drug and optionally a pharmaceutically acceptable excipient and mixing them uniformly to obtain the drug formulation.

[0028]

[21] The method according to

[20] , comprising the steps of: taking a prescribed amount of a ligand-drug conjugate or a pharmaceutically acceptable salt thereof, a lyophilized excipient, a pH adjuster, and a solvent; dissolving each component in the solvent all at once or in portions; optionally adjusting the pH to 5.0-8.0 using an acidic or basic substance in the pH adjuster; and uniformly mixing the components to obtain the product; preferably, when dissolving each component in the solvent, the pH adjuster is dissolved in the solvent simultaneously with or preferentially to the ligand-drug conjugate or a pharmaceutically acceptable salt thereof.

[0029]

[22] The manufacturing method described in

[20] or

[21] , wherein the manufacturing method is optionally carried out under light-shielded conditions, and preferably, the manufacturing method is carried out under light-shielded conditions.

[0030]

[23] The method according to any one of

[20] to

[22] , characterized in that the method is carried out at a temperature of 15°C to 40°C.

[0031]

[24] . The method of any one of

[20] to

[23] , wherein the method is optionally carried out under nitrogen gas protection conditions, and preferably, the method is carried out under conditions without nitrogen gas protection.

[0032]

[25] . A freeze-dried preparation, characterized in that it is produced by freeze-drying the drug formulation described in any one of [1] to

[19] .

[0033]

[26] A method for producing a freeze-dried formulation according to

[25] , comprising the steps of: (i) freezing the drug formulation at -45°C; (ii) primary drying the drug formulation at -15°C to -5°C; and (iii) secondary drying the drug formulation at 15°C to 25°C; for example, the primary drying temperature is -15°C, -10°C, or -5°C, and the secondary drying temperature is 15°C or 25°C; preferably, the production method comprises the steps of: (i) freezing the drug formulation at -45°C; (ii) primary drying the drug formulation at -15°C; and (iii) secondary drying the drug formulation at 25°C.

[0034]

[27] The freeze-dried formulation described in

[25] , characterized in that the freeze-dried formulation is stable at room temperature.

[0035]

[28] . A liquid formulation obtained by reconstituting the freeze-dried formulation described in

[25] with water.

[0036]

[29] The liquid formulation according to

[28] , characterized in that the water comprises one or more of distilled water, pure water, and sterile water, and preferably the pH of the lyophilized formulation after reconstitution with water is 5.0 to 8.0.

[0037]

[30] . A method for producing a liquid formulation according to

[28] or

[29] , comprising the step of mixing the freeze-dried formulation with sterile water.

[0038]

[31] . A drug-containing delivery device comprising one of the following formulations: a drug formulation described in any one of [1] to

[19] , a freeze-dried formulation described in

[25] , or a liquid formulation described in

[28] or

[29] .

[0039]

[32] A pre-filled syringe containing one of the drug formulations described in any one of [1] to

[19] , the lyophilized formulation described in

[25] , or the liquid formulation described in

[28] or

[29] , preferably for intravenous or intramuscular injection.

[0040]

[33] . Use of a drug formulation described in any one of [1] to

[19] , a lyophilized formulation described in

[25] , or a liquid formulation described in

[28] or

[29] in the manufacture of a delivery device or pre-filled syringe or drug for enhancing immune effector cell responses and / or reducing immunosuppression in a subject.

[0041]

[34] . Use of a drug formulation according to any one of [1] to

[19] , a lyophilized formulation according to

[25] , or a liquid formulation according to

[28] or

[29] in the manufacture of a delivery device or pre-filled syringe or drug for treating and / or preventing cancer, immune disorders, cardiovascular diseases, metabolic disorders and neurological disorders in a subject.

[0042]

[35] . 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, colon cancer, thyroid cancer, pancreatic cancer, colorectal cancer, esophageal cancer, testicular cancer, skin 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 cardiovascular disease includes angina, myocardial infarction, stroke, heart attack, hypertension, and rheumatoid arthritis. The use according to

[34] , wherein the metabolic diseases include one or more of hypertensive heart disease, rheumatic heart disease, cardiomyopathy, cardiac arrhythmia and congenital heart disease, the metabolic diseases include one or more of diabetes, gout, obesity, hypoglycemia, hyperglycemia and dyslipidemia, and the neurological diseases include one or more of Alzheimer's disease, Parkinson's disease, Huntington's disease, head trauma, multiple sclerosis, dizziness, coma and epilepsy. [Effects of the Invention]

[0043] The present invention performs pH screening on formulations containing ligand-drug conjugates, limits the pH adjusters and lyophilization excipients used, and simultaneously considers the administration order and liquid distribution environment during drug production, and screens lyophilization process parameters, thereby ultimately achieving the effect of maintaining stable properties, water content, impurity content, pH value, etc. of the formulation throughout its storage period. [Brief explanation of the drawings]

[0044] [Figure 1] FIG. 1 is a DSC curve diagram of a drug formulation solution containing CR19213. DETAILED DESCRIPTION OF THE INVENTION

[0045] The following describes embodiments of the present invention, but the present invention is not limited thereto. The present invention is not limited to the configurations described below, and various modifications can be made within the scope of protection of the invention. However, embodiments and examples obtained by appropriately combining the technical means disclosed in different embodiments and examples are also included in the technical scope of the present invention. In addition, all documents described in this specification are incorporated herein by reference.

[0046] Unless otherwise specified, all instruments, reagents, materials, etc. used in the present invention are available through conventional commercial means.

[0047] Unless otherwise defined, 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.

[0048] As used herein, references to "some specific / preferred embodiments," "some other specific / preferred embodiments," "some specific / preferred technical solutions," "some other specific / preferred technical solutions," etc., mean that particular elements (e.g., features, structures, properties, and / or characteristics) described in connection with the embodiments are included in at least one embodiment described herein and may or may not be present in other embodiments. It should also be understood that the elements may be combined in any suitable manner in various embodiments.

[0049] In this specification, a numerical range expressed using "numeric value A to numerical value B" or "numeric value A minus numerical value B" is a range that includes the endpoint numerical values ​​A and B.

[0050] In this specification, unless otherwise specified, "%" refers to mass or weight content, i.e., "mass %" or "wt %".

[0051] In this specification, the meaning expressed by "may" includes both the meaning of performing some processing and the meaning of not performing some processing. In this specification, "optionally" or "optionally" means that the event or situation described below may or may not occur, and the description includes a situation in which the event occurs and a situation in which the event does not occur.

[0052] As used herein, "room temperature" or "normal temperature" refers to an ambient temperature of approximately 25°C.

[0053] The term "comprises" and any variations thereof in the present specification and claims and the above drawings are intended to cover a non-exclusive "comprises."

[0054] For purposes of the present invention, "pharmaceutically acceptable" means, within the scope of sound medical judgment, suitable for contact with the cells of humans and other animals without undue toxicity, irritation, allergic response, etc., and commensurate with a reasonable benefit / risk ratio.

[0055] In the present invention, "pharmaceutically acceptable excipients" refer to excipients and additives used in the production and formulation of pharmaceuticals, such as pH adjusters, which are substances other than active ingredients or precursors that have been reasonably evaluated for safety and are included in pharmaceutical formulations. Pharmaceutical excipients have important functions such as shape, pH adjustment, carrier function, and stability improvement, as well as solubilization, solubilization, and release control, and are important components that may affect the quality, safety, and efficacy of pharmaceuticals.

[0056] In the present invention, "pharmaceutically acceptable salts" refer 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, hydrogensulfate, phosphate, nitrate, acetate, oxalate, pentanoate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, toluenesulfonate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, methanesulfonate, glucoheptanoate, lactosate, sulfamate, malonate, salicylate, propionate, methylene-bis-b-hydroxynaphthoate, loncholate, hydroxyethylsulfonate, di-p-toluyltartrate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, cyclohexylsulfamate, and quinacyl laurylsulfonate. 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 and potassium salts are preferred. Suitable inorganic base addition salts are prepared from metal bases, such as 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 which are sufficiently basic to form stable salts, and preferably include the following amines which are commonly used in pharmaceutical chemistry because of their low toxicity and medical acceptability: ammonia, ethylenediamine, N-methylglucosamine, lysine, arginine, ornithine, choline, N,N'-dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N-benzylphenylethylamine, diethylamine, piperazine, trimethylolaminomethane, tetramethylammonium hydroxide, triethylamine, dibenzylamine, diphenylhydroxymethine, dehydroabietylamine, N-ethylpiperidine, benzylamine, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, ethylamine, basic amino acids (e.g., lysine and arginine), and dicyclohexylamine.

[0057] In the present invention, a "ligand-drug conjugate" (LDC) refers to a biologically active drug linked to a ligand via a chemical bond, and the ligand serves as a carrier for targeting and transporting a small molecule drug to a target cell. The ligand may be a polypeptide or a small molecule, and the biologically active drug may be monomethyl auristatin E (MMAE). Preferably, the ligand-drug conjugate is a biligand drug conjugate, and preferably, the biligand drug conjugate targets the PSMA receptor and the TRPV6 receptor. More preferably, the ligand-drug conjugate of the present invention is the biligand conjugate CR19213, in which the ligand targets the PSMA receptor and the TRPV6 receptor, respectively, and the carrier drug is MMAE, the structure of which is shown as follows: [ka] More preferably, the biligand-drug conjugate has the structure: [ka] It has.

[0058] In the present invention, a "pH adjuster" refers to a reagent capable of maintaining the pH of a solution within an acceptable range, and is primarily an acid, base, or salt with buffering properties, such as commonly used salts such as hydrochloric acid, acetic acid, sodium hydroxide, sodium dihydrogen phosphate, and sodium acetate. In some embodiments, the pH adjuster used in the formulations of the present invention can control the pH of the formulations of the present invention within a pH range of about 5.0 to 8.0. In some specific embodiments, the formulations of the present invention have a pH of about 5.0, 5.5, 6.0, 6.5, 7.0, or 8.0.

[0059] In the present invention, the term "polyol" refers to an alcohol containing two or more hydroxyl groups in the molecule, and may be, for example, mannitol, inositol, ethylene glycol, polyethylene glycol, or the like.

[0060] In the present invention, "reconstitution" refers to dissolving and / or suspending a solid formulation (e.g., a lyophilized formulation) in a physiologically acceptable solution.

[0061] In the present invention, "about" means that the qualified numerical value is approximate, and does not require that a particular numerical value in the relevant data be highly precise.

[0062] In the present invention, a "lyophilized preparation" is a sterile solid for injection obtained by freeze-drying.

[0063] In the present invention, the term "lyophilization excipient," also known as a lyoprotectant, refers to an additive added during the freeze-drying and storage of foods, drugs, and organisms, with the aim of maintaining the stability and activity of the product despite the influence of many factors (e.g., chemical components, freezing rate, freezing and dehydration stress, glass transition temperature, residual moisture in the dried solid, temperature and humidity of the storage environment, etc.) For example, the lyophilization excipient may be polyols, sugars, amino acids, inorganic salts, and proteins, such as mannitol, ethylene glycol, sucrose, monosodium glutamate, sodium acetate, calcium carbonate, and bovine serum albumin.

[0064] In the present invention, "stable" in "stabilization of a formulation" or "stable formulation" means that the water content, appearance, pH value, related substances, content, insoluble particulates, and resolubility properties of the product do not change fundamentally, do not change obviously, or change within a pharmaceutically acceptable range during the manufacturing and storage process, and the formulation can be quality-controlled for at least 24 months.

[0065] In this invention, "DSC" refers to differential scanning calorimetry, a thermal analysis method. It measures the relationship between the temperature and the difference in power input between a sample and a reference at a programmable temperature. The curve recorded by a differential scanning calorimeter is called a DSC curve. It measures the rate of heat absorption or release from the sample, i.e., the heat flow rate, on the ordinate, and temperature T or time t on the abscissa. It can measure various thermodynamic and kinetic parameters. This method has a wide temperature range, high resolution, and requires little sample. It is applicable to the analysis of inorganic substances, organic compounds, and pharmaceuticals.

[0066] [Drug formulations containing CR19213 and their manufacturing methods] The present invention provides drug formulations, which may include an active drug and optionally a pharmaceutically acceptable excipient.

[0067] In one embodiment, the drug formulation may include a ligand-drug conjugate, a lyophilization excipient, and a pH adjusting agent.

[0068] In one embodiment, the drug formulation may include a ligand-drug conjugate, a lyophilization excipient, a pH adjuster, and a solvent.

[0069] In one embodiment, the ligand-drug conjugate in the drug formulation may be a dual ligand-drug conjugate that targets the PSMA receptor and the TRPV6 receptor.

[0070] In one embodiment, the solvent in the drug formulation is water.

[0071] In one preferred embodiment, the solvent in the drug formulation is purified water.

[0072] In another preferred embodiment, the solvent in the drug formulation is sterile water, distilled water or deionized water.

[0073] In one more preferred embodiment, the solvent in the above drug formulation is sterile water for injection, single distilled water or double distilled water.

[0074] In one embodiment, the active drug concentration in the drug formulation is 2 mg / mL to 8 mg / mL, e.g., 2.0 mg / mL, 2.2 mg / mL, 2.4 mg / mL, 2.6 mg / mL, 2.8 mg / mL, 3.0 mg / mL, 3.2 mg / mL, 3.4 mg / mL, 3.6 mg / mL, 3.8 mg / mL, 4.0 mg / mL, 4.2 mg / mL, 4.4 mg / mL, 4.6 mg / mL, 4.8 mg / mL, 5.0 mg / mL, 5.2 mg / mL, 5.4 mg / mL, 5.6 mg / mL, 5.8 mg / mL, 6.0 mg / mL, 6.2 mg / mL, 6.4 mg / mL, 6.6 mg / mL, 6.8 mg / mL, 7.0 mg / mL, 7.2 mg / mL, 7.4 mg / mL, 7.6 mg / mL, 7.8 mg / mL, or 8.0 mg / mL.

[0075] In one embodiment, the pH adjusting agent in the drug formulation may include a buffer salt.

[0076] Furthermore, the buffer salt contained in the pH adjusting agent in the drug formulation may be selected from one or more of acetate, phosphate, citrate, or hydrates thereof.

[0077] Furthermore, the buffer salt hydrate in the drug formulation contains 0.5, 1, 1.5, 2.0, 2.5 or 3 molecules of water per molecule.

[0078] In one preferred embodiment, the pH adjuster in the drug formulation may include sodium acetate.

[0079] In another preferred embodiment, the pH adjuster in the drug formulation may include sodium dihydrogen phosphate.

[0080] In one preferred embodiment, the pH adjuster in the drug formulation may include anhydrous sodium citrate.

[0081] In one preferred embodiment, the pH adjuster in the drug formulation may include sodium citrate dihydrate.

[0082] In one embodiment, when the buffer salt contained in the pH adjuster in the drug formulation is selected from anhydrous sodium citrate or sodium citrate dihydrate, the concentration of the buffer salt is 2.85 mg / mL to 11.4 mg / mL, for example, 2.85 mg / mL, 5.7 mg / mL, or 11.4 mg / mL.

[0083] In one embodiment, the pH adjusting agent in the drug formulation may include a buffer salt and an acidic and / or basic substance.

[0084] Furthermore, the buffer salt contained in the pH adjuster in the above drug formulation may be selected from one or more of acetate, phosphate, citrate or hydrates thereof; the acidic substance may be selected from one or more of acids, such as hydrochloric acid, acetic acid or citric acid; and the basic substance may be selected from one or more of bases or salts, such as sodium hydroxide, sodium carbonate or sodium bicarbonate.

[0085] In one preferred embodiment, the pH adjuster in the drug formulation may include sodium acetate and hydrochloric acid or sodium hydroxide.

[0086] In another preferred embodiment, the pH adjuster in the above drug formulation may comprise sodium dihydrogen phosphate and hydrochloric acid or sodium hydroxide.

[0087] In another preferred embodiment, the pH adjuster in the drug formulation may comprise anhydrous sodium citrate and hydrochloric acid or sodium hydroxide, and the concentration of the anhydrous sodium citrate is 2.85 mg / mL to 11.4 mg / mL, for example, 2.85 mg / mL, 3.5 mg / mL, 4.2 mg / mL, 5.7 mg / mL, 6.5 mg / mL, 7.6 mg / mL, 8.5 mg / mL, 9.8 mg / mL, 10.5 mg / mL, or 11.4 mg / mL.

[0088] In another preferred embodiment, the pH adjuster in the drug formulation may comprise sodium citrate dihydrate and hydrochloric acid or sodium hydroxide, and the concentration of the sodium citrate dihydrate is 2.85 mg / mL to 11.4 mg / mL, for example, 2.85 mg / mL, 3.5 mg / mL, 4.2 mg / mL, 5.7 mg / mL, 6.5 mg / mL, 7.6 mg / mL, 8.5 mg / mL, 9.8 mg / mL, 10.5 mg / mL, or 11.4 mg / mL.

[0089] In one embodiment, the lyophilization excipients in the drug formulation may include one or more of the following polyols: mannitol, xylitol.

[0090] In one preferred embodiment, the lyophilized excipient in the drug formulation comprises mannitol, and preferably, the concentration of the mannitol is 20 to 150 mg / mL, for example, 20 mg / mL, 30 mg / mL, 40 mg / mL, 50 mg / mL, 60 mg / mL, 70 mg / mL, 80 mg / mL, 90 mg / mL, 100 mg / mL, 110 mg / mL, 120 mg / mL, 130 mg / mL, 140 mg / mL, or 150 mg / mL, and more preferably, the concentration is 40 to 60 mg / mL.

[0091] In one embodiment, the lyophilization excipient in the drug formulation comprises a polyol and a saccharide, wherein the saccharide is one or more of a monosaccharide, a disaccharide, and a polysaccharide, and preferably the mass ratio of the saccharide to the polyol is 1:1 to 1:5, for example, 1:1, 1:1.5, 1:2, 1:2.5, 1:3, 1:3.5, 1:4, 1:4.5, or 1:5, and preferably the mass ratio of the saccharide to the polyol is 1:2 to 1:4.

[0092] Furthermore, the monosaccharides in the lyophilized excipients in the drug formulation include one or more of glucose and fructose, the disaccharides include one or more of sucrose, trehalose, and maltose, and the polysaccharides include one or more of cyclodextrin and dextran.

[0093] In one preferred embodiment, the lyophilized excipients in the drug formulation may include mannitol and sucrose, and preferably, the mass ratio of the sucrose to the mannitol is 1:4.

[0094] In one embodiment, the pH value of the drug formulation may be 5.0 to 8.0, for example, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 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.

[0095] In one preferred embodiment, the pH value of the drug formulation may be 5.5 to 6.5, for example, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, or 6.5.

[0096] In one embodiment, the drug formulation 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 drug formulation is 5.0 to 8.0.

[0097] In one preferred embodiment, the drug formulation contains, per mL, 5 mg of the biligand-drug conjugate or a pharmaceutically acceptable salt thereof, 50 mg of mannitol, 5.7 mg of sodium citrate dihydrate, and an optional acidic or basic substance, with the remainder being water, and the pH of the drug formulation is 5.0 to 8.0.

[0098] In one preferred embodiment, the drug formulation contains, per mL, 5 mg of the biligand-drug conjugate or a pharmaceutically acceptable salt thereof, 40 mg of mannitol, 10 mg of sucrose, 4.5 mg of anhydrous sodium citrate, and an optional acidic or basic substance, and the balance is water, wherein the pH of the drug formulation is 5.0 to 8.0.

[0099] In one preferred embodiment, the drug formulation contains, per mL, 4 mg of the biligand-drug conjugate or a pharmaceutically acceptable salt thereof, 50 mg of mannitol, a suitable amount of sodium acetate and an optional acidic or basic substance, and the remainder water, wherein the pH of the drug formulation is 5.0 to 8.0.

[0100] In one preferred embodiment, the drug formulation contains, per mL, 6 mg of the biligand-drug conjugate or a pharmaceutically acceptable salt thereof, 50 mg of mannitol, an appropriate amount of sodium dihydrogen phosphate and an optional acidic or basic substance, and the remainder water, wherein the pH of the drug formulation is 5.0 to 8.0.

[0101] In one embodiment, the drug formulation is sterile.

[0102] In one embodiment, the drug formulation is stable upon freezing and thawing.

[0103] In one embodiment, the method for preparing the drug formulation comprises the steps of taking a prescribed amount of active drug and optionally pharmaceutically acceptable excipients and mixing them uniformly.

[0104] In one preferred embodiment, the method for preparing the drug formulation includes the steps of taking a prescribed amount of a ligand-drug conjugate or a pharmaceutically acceptable salt thereof, a lyophilization excipient, a pH adjuster, and a solvent, dissolving each component in the solvent all at once, and mixing them uniformly to obtain the drug formulation. Preferably, when dissolving each component in the solvent, the pH adjuster is dissolved in the solvent simultaneously with or preferentially to the ligand-drug conjugate or a pharmaceutically acceptable salt thereof.

[0105] In one preferred embodiment, the method for preparing the drug formulation includes the steps of taking a prescribed amount of a ligand-drug conjugate or a pharmaceutically acceptable salt thereof, a lyophilized excipient, a pH adjuster, and a solvent, dissolving each component separately in the solvent, and mixing them uniformly to obtain the drug formulation. Preferably, when dissolving each component in the solvent, the pH adjuster is dissolved in the solvent simultaneously with or preferentially to the ligand-drug conjugate or a pharmaceutically acceptable salt thereof.

[0106] In another preferred embodiment, the method for preparing the above-mentioned drug formulation comprises the steps of taking a prescribed amount of a ligand-drug conjugate or a pharmaceutically acceptable salt thereof, a lyophilized excipient, a pH adjuster, and a solvent, dissolving each component in the solvent all at once, adjusting the pH to 5.0-8.0 using an acidic or basic substance in the pH adjuster, and mixing them uniformly to obtain the drug formulation. Preferably, when dissolving each component in the solvent, the pH adjuster is dissolved in the solvent simultaneously with or preferentially to the ligand-drug conjugate or a pharmaceutically acceptable salt thereof.

[0107] In another preferred embodiment, the method for preparing the drug formulation includes the steps of taking a prescribed amount of a ligand-drug conjugate or a pharmaceutically acceptable salt thereof, a lyophilized excipient, a pH adjuster, and a solvent, separately dissolving each component in the solvent, adjusting the pH to 5.0-8.0 using an acidic or basic substance in the pH adjuster, and mixing the components uniformly to obtain the drug formulation. Preferably, when dissolving each component in the solvent, the pH adjuster is dissolved in the solvent simultaneously with or preferentially to the ligand-drug conjugate or a pharmaceutically acceptable salt thereof.

[0108] In one embodiment, the method for producing the drug formulation is carried out under non-light-shielded conditions.

[0109] In one embodiment, the method for producing the drug formulation is carried out in the dark.

[0110] In one embodiment, the method for producing the drug formulation is carried out at a temperature of 15°C to 40°C, for example, 15°C, 20°C, 25°C, 30°C, 35°C, or 40°C.

[0111] In one embodiment, the manufacturing method of the drug formulation is carried out under nitrogen gas protection conditions.

[0112] In one embodiment, the manufacturing method of the drug formulation is carried out in the absence of nitrogen gas protection.

[0113] In one preferred embodiment, the method for producing the drug formulation is carried out in the dark at a temperature of 15°C to 40°C without nitrogen gas protection.

[0114] [Lyophilized preparation and its manufacturing method] The present invention provides a lyophilized formulation, which is obtained by freeze-drying the drug formulation of the present invention.

[0115] The present invention further provides a method for producing the above-mentioned lyophilized formulation, the method comprising the step of freeze-drying the drug formulation of the present invention to obtain the formulation.

[0116] In one embodiment, in the above manufacturing method, the freeze-drying comprises the steps of freezing the drug formulation at -45°C, primary drying the drug formulation at -15°C to -5°C, and secondary drying the drug formulation at 15°C to 25°C.

[0117] In one preferred embodiment, in the above manufacturing method, the freeze-drying comprises the steps of freezing the drug formulation at -45°C, primary drying the drug formulation at -5°C, and secondary drying the drug formulation at 15°C.

[0118] In another preferred embodiment, in the above manufacturing method, the freeze-drying comprises the steps of freezing the drug formulation at -45°C, primary drying the drug formulation at -10°C, and secondary drying the drug formulation at 15°C.

[0119] In another preferred embodiment, in the above manufacturing method, the freeze-drying comprises the steps of freezing the drug formulation at -45°C, primary drying the drug formulation at -15°C, and secondary drying the drug formulation at 25°C.

[0120] In one more preferred embodiment, in the above manufacturing method, the freeze-drying comprises the steps of freezing the drug formulation at −45° C. for 120 minutes, primary drying the drug formulation at −15° C. for 720 minutes, and secondary drying the drug formulation at 25° C. for 720 minutes.

[0121] In one embodiment, the lyophilized formulation is stable at room temperature.

[0122] [Liquid formulation and its manufacturing method] The present invention provides a liquid formulation, which is obtained by reconstituting the lyophilized formulation of the present invention with water.

[0123] The present invention further provides a method for producing the above liquid formulation, the method comprising the step of mixing the lyophilized formulation of the present invention with water to obtain the liquid formulation.

[0124] In one embodiment, in the above manufacturing method, the reconstitution is completed using distilled water, purified water or sterile water.

[0125] In one embodiment, the pH of the lyophilized formulation after reconstitution with water is 5.0 to 8.0.

[0126] [Device] The present invention provides a drug-containing delivery device, which comprises one of the drug formulations, the lyophilized formulations, or the liquid formulations.

[0127] The present invention further provides a pre-filled syringe, which contains one of the above drug formulations, the above lyophilized formulations, or the above liquid formulations.

[0128] [Medicinal uses] The present invention provides the use of the drug formulation, the lyophilized formulation or the liquid formulation comprising an active drug in the manufacture of a delivery device or a pre-filled syringe or drug.

[0129] In one embodiment, the delivery device or pre-filled syringe or drug in the above uses is used to enhance an immune effector cell response in a subject.

[0130] In one embodiment, the delivery device or pre-filled syringe or drug in the above uses is used to reduce immunosuppression in a subject.

[0131] In one embodiment, the delivery device or pre-filled syringe or drug in the above uses is used for the treatment and / or prevention of cancer in a subject.

[0132] Furthermore, the cancer in the above applications includes one or more of breast cancer, lung cancer, prostate cancer, kidney cancer, leukemia, ovarian cancer, gastric cancer, uterine cancer, endometrial cancer, liver cancer, colon cancer, thyroid cancer, pancreatic cancer, colorectal cancer, esophageal cancer, testicular cancer, skin cancer, lymphoma, and multiple myeloma.

[0133] In one embodiment, the delivery device or pre-filled syringe or drug in the above uses is used for the treatment and / or prevention of an immune-mediated disease in a subject.

[0134] Furthermore, the immune-mediated disease in the above applications includes one or more of connective tissue disease, systemic sclerosis, rheumatoid arthritis, and systemic lupus erythematosus.

[0135] In one embodiment, the delivery device or pre-filled syringe or drug in the above uses is used for the treatment and / or prevention of cardiovascular disease in a subject.

[0136] Furthermore, cardiovascular disease in the above applications includes one or more of angina pectoris, myocardial infarction, stroke, heart attack, hypertensive heart disease, rheumatic heart disease, cardiomyopathy, cardiac arrhythmia and congenital heart disease.

[0137] In one embodiment, the delivery device or pre-filled syringe or drug in the above uses is used for the treatment and / or prevention of a metabolic disease in a subject.

[0138] Furthermore, the metabolic disease in the above applications includes one or more of diabetes, gout, obesity, hypoglycemia, hyperglycemia and dyslipidemia.

[0139] In one embodiment, the delivery device or the pre-filled syringe or the drug in the above uses is used for the treatment and / or prevention of a neurological disorder in a subject.

[0140] Furthermore, the neurological disorders in the above applications include one or more of Alzheimer's disease, Parkinson's disease, Huntington's disease, head trauma, multiple sclerosis, vertigo, coma, and epilepsy.

[0141] The following further describes the technical solution of the present invention in conjunction with specific examples.

[0142] Example 1 1.1 Screening of pH adjuster types CR19213 has poor solubility in water and is unstable in acids and alkalis, so it is necessary to add an appropriate pH adjuster to drug formulations containing CR19213 to ensure the manufacturing and stability of the product.

[0143] Injection-grade pH adjusters are primarily buffer salts, with the commonly used Tris, acetate, citrate, and phosphate salts selected, with a provisional concentration of 0.5%. Because CR19213 is sensitive to both acid and alkali, the pH of the buffer salt solution is provisionally set to 7.0 (adjusted with 1M hydrochloric acid or sodium hydroxide), and the lyophilization excipient is provisionally the commonly used 5% mannitol. Samples were prepared by dissolving CR19213 in the above buffer salt solutions, and then immersed in high temperature (40°C) and strong light (4500 lx, near-ultraviolet light 85 μW / cm). 2 ) was subjected to a 10-day impact factor test, and the product properties, acidity, reconstitution time, moisture, reconstitution properties, content and related substances were considered.

[0144] 1.1.1 Prescription [Table 1]

[0145] 1.1.2 Process (1) Prepare a 0.5% Tris solution, 0.5% sodium acetate solution, 0.5% sodium citrate solution, and 0.5% sodium dihydrogen phosphate solution at pH 7.0 (adjusted with 0.1 M hydrochloric acid or sodium hydroxide) as spares. (2) Weigh out the prescribed amount of mannitol, add 70% of the corresponding buffer salt solution, stir and dissolve, then add the prescribed amount of raw material CR19213, stir and dissolve at room temperature in the dark, (3) Add the appropriate amount of buffer salt solution to the total amount. (4) Fill 2 mL per bottle and press the stopper halfway. (5) freeze-drying, and then pressing the stopper under vacuum conditions; (6) The lid was closed and the result was obtained.

[0146] [Table 2]

[0147] 1.1.3 Detection Results [Table 3]

[0148] Results: Formula 1 (pH 7.0 0.5% Tris solution) CR19213 was not dissolved, but the remaining formulas were all dissolved. The finished product was exposed to high temperature (40°C) and strong light (4500 lx, near-ultraviolet light 85 μW / cm 2 After a 10-day impact factor test, it was found that there was some decomposition at high temperatures and significant decomposition under strong light conditions (the decomposition at high temperatures and strong light is mainly related to the sensitivity of CR19213 to temperature and strong light). Here, the impurity level of Formulation 3 (pH 7.0 0.5% sodium citrate solution) is the lowest, so the pH adjuster is preferably sodium citrate.

[0149] 1.2 pH value screening The pH value is of particular importance to the stability of drugs. Therefore, in the process of preparing the intermediates of injections, the pH value must be controlled as necessary to ensure the mass stability of the injections during the freeze-drying and storage processes.

[0150] Experiments were designed to adjust the pH values ​​of the intermediate solutions to 4.0, 5.0, 5.5, 6.0, 6.5, 7.0 and 8.0, respectively, and the quality of the finished products was compared using the pH value, content and related substances of the finished products as the main consideration indexes.

[0151] 1.2.1 Prescription [Table 4]

[0152] 1.2.2 Process (1) Add 70% of the prescribed amount of water for injection to a preparation container, add the prescribed amount of sodium citrate, and stir to dissolve it. (2) Weigh out the prescribed amount of mannitol, add it to a preparation vessel, stir and dissolve it, then add the prescribed amount of CR19213, stir and dissolve it at room temperature in the dark, (3) Adjust the pH to the selected value with hydrochloric acid / sodium hydroxide, add water to the full volume, (4) Fill 2 mL per bottle and press the stopper halfway. (5) Freeze-drying, and then press the stopper under vacuum conditions. The specific parameters for freeze-drying are the same as those in Table 2. (6) The lid was closed and the result was obtained.

[0153] 1.2.3 Study results [Table 5]

[0154] As a result, insoluble matter precipitated during the manufacturing process for formulation 13 (pH 4.0). The quality of the samples for the remaining formulations (intermediate pH 5.0-8.0) was comparable, and after 10 days of influencing factor analysis at 40°C, there was no significant change in product quality. Because the pH value after adding the raw materials and excipients was approximately 6.0 (not adjusted with acid or alkali), the product quality at this acidity was stable. Therefore, the target value for intermediate acidity was set at pH 6.0, with an acceptable range of 5.5-6.5.

[0155] 1.3 Screening of pH adjuster usage amount The solubility of CR19213 is related to the pH of the solution, and the amount of pH adjuster (expressed as the concentration of buffer salt) directly affects the pH of the solution, so the buffer salt concentration must be screened. When CR19213 was added to a sodium citrate solution with a pH of 7.0, it exhibited an acidic reaction after complete dissolution. To make the final product closer to neutral, a 1.0% sodium citrate solution (11.4 mg / mL) with a pH of 7.5 (adjusted by citric acid) was prepared and diluted with water to obtain sodium citrate solutions with concentrations of 0.1%, 0.25%, and 0.5%. The sodium citrate solutions with different concentrations were used to prepare intermediate solutions, and the dissolution behavior during the preparation process was examined.

[0156] 1.3.1 Prescription [Table 6]

[0157] 1.3.2 Process (1) Prepare a 1.0% sodium citrate solution at pH 7.5 (adjusted with citric acid) as a backup. (2) Dilute with water to 0.1%, 0.25%, and 0.5% sodium citrate solutions, respectively; (3) Weigh out the prescribed amount of mannitol, add 70% of the total amount of sodium citrate solution, stir to dissolve, add the prescribed amount of CR19213, and stir to dissolve at room temperature in the dark. (4) The total amount was obtained by adding the corresponding amount of sodium citrate solution.

[0158] 1.3.3 Study results [Table 7]

[0159] According to the dissolution phenomenon, 0.1% sodium citrate solution could not completely dissolve CR19213, 0.25% sodium citrate solution (formulation 6) required 3 hours to dissolve CR19213, and 0.5% (formulation 7) and 1.0% (formulation 8) sodium citrate solutions could dissolve CR19213 within half an hour.

[0160] After testing, the pH value of the 0.5% sodium citrate solution is 8.42, and the pH value after adding and dissolving mannitol and CR19213 is 5.95. Because the raw material is acidic, there is no need to pre-adjust the pH value with citric acid to make the finished product closer to neutral.

[0161] Example 2 To obtain a lyophilized product that is beautiful, easy to reconstitute, and stable, it is necessary to screen protectants.Mannitol, sucrose, lactose, and sorbitol, which are commonly used as lyophilization excipients, were selected and compared.

[0162] 2.1 Prescription [Table 8]

[0163] 2.2 Process (1) Add 70% of the prescribed amount of water for injection to a preparation container, add the prescribed amount of sodium citrate (dihydrate), and stir to dissolve it. (2) Weigh out the prescribed amount of lyophilized excipients, add them to a preparation container, stir to dissolve, then add the prescribed amount of CR19213, stir to dissolve at room temperature in the dark, (3) If necessary, adjust the pH to 5-7 with 0.1M hydrochloric acid / sodium hydroxide, and add water to the full volume. (4) Fill 2 mL per bottle and press the stopper halfway. (5) Freeze-drying, and then press the stopper under vacuum conditions. The specific parameters for freeze-drying are the same as those in Table 2. (6) The lid was closed and the result was obtained.

[0164] 2.3 Study results [Table 9]

[0165] Results: When lactose (formula 11) and sorbitol (formula 12) were used as excipients in this product, the finished product shrunk. The finished products of formulas 9 and 10 were subjected to influence factor testing at 40°C for 10 days, and the product quality was equivalent.

[0166] Example 3 In order to obtain a lyophilized formulation for injection that can be stably manufactured, a formulation determined through research was selected and process considerations were carried out.

[0167] [Table 10]

[0168] 3.1 Consideration of input order Different excipients have different acid-alkali and stability properties. The order in which the ingredients and excipients are added can affect the quality of the injection. We designed different orders of adding ingredients and excipients and considered the impact of the order of adding ingredients and excipients on product quality.

[0169] [Table 11]

[0170] The quality attributes of the intermediates output from the input process are content, acidity, properties and related substances.

[0171] [Table 12]

[0172] The results showed that the properties, acidity and content of the intermediate solutions obtained with different addition sequences were all comparable.

[0173] 3.2 Liquid distribution environment The dispensing environment includes the oxygen content of the solution, the light environment to which the dispensing is exposed, and the temperature and time of dispensing.

[0174] 3.2.1 Solution oxygen content CR19213 is sensitive to 1% H2O2 and is prone to oxidation in solution. Therefore, it is necessary to consider whether nitrogen gas protection is necessary to achieve a reduced oxygen content during the manufacturing process of the product.

[0175] The intermediate solutions were prepared using both nitrogen gas protection and non-nitrogen gas protection processes, and then left for 24 hours to examine the stability of the intermediate solutions. The main focus was on whether there were any significant differences in the properties, content, pH, and related substances of the intermediate solutions.

[0176] 3.2.1.1 Process [Table 13]

[0177] 3.2.1.2 Study results [Table 14]

[0178] The results showed that there were no significant differences in the properties, content, pH, or related substances within 24 hours regardless of whether or not nitrogen gas was injected into the pharmaceutical intermediate, indicating that there is no need to use a nitrogen gas protection process.

[0179] 3.2.2 Consideration of the effect of light on liquid distribution Considering that the CR19213 raw material is light sensitive and comes into contact with room lighting during the actual dispensing process, an experiment was designed to examine the influence of light during the preparation process and the effect of room lighting on the stability of the product during the dispensing process.

[0180] An intermediate solution was prepared and left for 24 hours under dark and indoor lighting conditions, and the properties, pH, content, and related substances of the intermediate drug solution were detected.

[0181] [Table 15]

[0182] As a result, within 24 hours, there was no significant difference in the properties, pH, content and related substances of the intermediate solution under indoor lighting conditions compared to the intermediate solution under dark conditions.

[0183] 3.2.3 Temperature control of liquid distribution CR19213 is sensitive to temperature, so to determine the temperature control during the production preparation process, the prepared intermediate solution was kept at 15°C, 25°C, and 40°C, and samples were taken at 0, 8, 20, and 24 hours for detection. The effects of temperature on the properties, pH, content, and related substances of the intermediate solution were considered.

[0184] [Table 16]

[0185] The results showed that after the intermediate solution was incubated at 15°C, 25°C and 40°C for 24 hours, there were no significant changes in the properties, pH, content and related substances of the intermediate solution.

[0186] 3.3 Freeze-drying parameters To further optimize the freeze-drying parameters, DSC detection was performed on the formulation solution, and the results are shown in Figure 1.

[0187] According to the results of DSC detection, the eutectic point is −19.72° C. and the eutectic temperature is −3.90° C., so the pre-freezing temperature was determined to be −45° C. (approximately 25° C. lower than the eutectic point).

[0188] The freeze-drying process parameters were mainly the primary and secondary drying temperatures. The primary drying temperatures were -15°C, -10°C, and -5°C, respectively, and the secondary drying temperatures were 25°C, 15°C, and 15°C, respectively. Samples were prepared and the product properties, acidity, moisture, reconstitution time, reconstitution properties, content, and related substances were investigated.

[0189] [Table 17]

[0190] [Table 18]

[0191] Results: There were no significant differences in the properties, acidity, moisture content, reconstitution time, reconstitution properties, content, and related substances of the samples produced using freeze-drying processes 12, 13, and 14. Process 12 had a relatively low moisture content, so it was selected as the freeze-drying parameter for CR19213 for injection.

[0192] [Table 19]

[0193] Example 4 A formulation determined through research was selected and stability was examined.

[0194] [Table 20]

[0195] A freeze-dried formulation of CR19213 was prepared according to the above formulation and the process of Examples 1-3, and allowed to stand at 25° C. The results of stability testing were as follows:

[0196] [Table 21]

[0197] The results showed that there were no significant changes in the properties, moisture content, pH value, related substances, content and insoluble particles within 6 months at 25°C, demonstrating that the determined formulation and process can produce a product that can be stored stably at 25°C for at least 6 months.

Claims

1. A drug formulation comprising an active drug and a pharmaceutically acceptable excipient, wherein: the active drug comprises a ligand-drug conjugate or a pharmaceutically acceptable salt thereof; the pharmaceutically acceptable excipients include a lyophilization excipient and a pH adjusting agent; the lyophilization excipient is mannitol; the pH adjusting agent comprises a buffer salt, the buffer salt being sodium acetate, sodium citrate, or sodium dihydrogen phosphate; the ligand-drug conjugate is a biligand-drug conjugate; The biligand-drug conjugate has the structure: 【Chemistry 1】 A drug formulation comprising:

2. 10. The drug formulation of claim 1, wherein the excipient further comprises a solvent.

3. 3. The drug formulation of claim 2, wherein the solvent is water.

4. The biligand-drug conjugate has the structure: 【Chemistry 2】 2. The pharmaceutical formulation of claim 1, wherein

5. 3. The pharmaceutical formulation of claim 2, wherein the concentration of the active drug is 2 mg / mL to 8 mg / mL.

6. 6. The pharmaceutical formulation of claim 5, wherein the concentration of the active drug is 2.0 mg / mL, 2.2 mg / mL, 2.4 mg / mL, 2.6 mg / mL, 2.8 mg / mL, 3.0 mg / mL, 3.2 mg / mL, 3.4 mg / mL, 3.6 mg / mL, 3.8 mg / mL, 4.0 mg / mL, 4.2 mg / mL, 4.4 mg / mL, 4.6 mg / mL, 4.8 mg / mL, 5.0 mg / mL, 5.2 mg / mL, 5.4 mg / mL, 5.6 mg / mL, 5.8 mg / mL, 6.0 mg / mL, 6.2 mg / mL, 6.4 mg / mL, 6.6 mg / mL, 6.8 mg / mL, 7.0 mg / mL, 7.2 mg / mL, 7.4 mg / mL, 7.6 mg / mL, 7.8 mg / mL, or 8.0 mg / mL.

7. The pH adjuster further comprises an acidic substance and / or a basic substance; 2. The pharmaceutical formulation of claim 1, wherein the acidic substance is one or more of hydrochloric acid, acetic acid, or citric acid, and the basic substance is one or more of sodium hydroxide, sodium carbonate, or sodium bicarbonate.

8. 3. The pharmaceutical formulation of claim 2, wherein when the buffer salt is sodium citrate, and the sodium citrate is selected from anhydrous sodium citrate or sodium citrate dihydrate, the concentration of the buffer salt is from 2.85 mg / mL to 11.4 mg / mL.

9. 3. The pharmaceutical formulation according to claim 2, wherein the concentration of mannitol is 20 mg / mL to 150 mg / mL.

10. 10. The pharmaceutical formulation of claim 9, wherein the concentration of mannitol is 20 mg / mL, 30 mg / mL, 40 mg / mL, 50 mg / mL, 60 mg / mL, 70 mg / mL, 80 mg / mL, 90 mg / mL, 100 mg / mL, 110 mg / mL, 120 mg / mL, 130 mg / mL, 140 mg / mL, or 150 mg / mL.

11. The lyophilization excipient further comprises a sugar; 9. The pharmaceutical formulation according to claim 8, wherein the mass ratio of the saccharide to the mannitol is 1:1 to 1:

5.

12. 12. The pharmaceutical formulation of claim 11, wherein the mass ratio of the saccharide to the mannitol is 1:1, 1:1.5, 1:2, 1:2.5, 1:3, 1:3.5, 1:4, 1:4.5, or 1:

5.

13. the sugars are monosaccharides and include one or more of glucose and fructose; the sugars are disaccharides and include one or more of sucrose, trehalose, and maltose; 12. The pharmaceutical formulation of claim 11, wherein the saccharide is a polysaccharide, including one or more of cyclodextrin and dextran.

14. 14. The pharmaceutical formulation of claim 13, wherein the disaccharide is sucrose.

15. 2. The drug formulation of claim 1, wherein the pH value of the drug formulation is 5.0 to 8.

0.

16. the drug formulation comprises, per mL, 5 mg of a biligand-drug conjugate or a pharmaceutically acceptable salt thereof, 50 mg of mannitol, 5.7 mg of sodium citrate dihydrate, an acidic or basic substance, and the balance water, wherein the pH value of the drug formulation is 5.0 to 8.0; or the drug formulation comprises, per mL, 5 mg of a biligand-drug conjugate or a pharmaceutically acceptable salt thereof, 40 mg of mannitol, 10 mg of sucrose, 4.5 mg of anhydrous sodium citrate, an acidic or basic substance, and the balance water, wherein the pH value of the drug formulation is 5.0 to 8.0; or The drug formulation contains, per mL, 4 mg of the biligand-drug conjugate or a pharmaceutically acceptable salt thereof, 50 mg of mannitol, an appropriate amount of sodium acetate and an acidic or basic substance, and the balance being water, wherein the pH value of the drug formulation is 5.0 to 8.0; or 3. The drug formulation of claim 2, wherein the drug formulation contains, per mL, 6 mg of the biligand-drug conjugate or a pharmaceutically acceptable salt thereof, 50 mg of mannitol, an appropriate amount of sodium dihydrogen phosphate, an acidic or basic substance, and the remainder water, and the pH value of the drug formulation is 5.0 to 8.

0.

17. 17. A manufacturing method for producing the drug formulation of any one of claims 1 to 16, the manufacturing method comprising the steps of using a prescribed amount of an active drug, adding pharmaceutically acceptable excipients, and uniformly mixing to obtain the drug formulation; The preparation method is characterized by comprising the steps of using a prescribed amount of a ligand-drug conjugate or a pharmaceutically acceptable salt thereof, a lyophilized excipient, a pH adjuster, and a solvent, dissolving each component in the solvent all at once or in portions, adjusting the pH value to 5.0 to 8.0 using an acidic or basic substance in the pH adjuster, and mixing uniformly to obtain the drug formulation.

18. A manufacturing method for producing the pharmaceutical formulation according to any one of claims 1 to 16, comprising the steps of: A method for producing the drug formulation, comprising the steps of: (i) freezing the drug formulation at −45°C; (ii) primary drying the drug formulation at −15°C to −5°C; and (iii) secondary drying the drug formulation at 15°C to 25°C.

19. A drug-containing delivery device comprising a drug formulation according to any one of claims 1 to 16.

20. A pre-filled syringe, characterized in that it contains a drug formulation according to any one of claims 1 to 16.

21. 17. The pharmaceutical formulation of any one of claims 1 to 16, for use in enhancing immune effector cell responses and / or reducing immunosuppression, or for the treatment or prevention of cancer, immune disorders, cardiovascular diseases, metabolic disorders and neurological disorders.

22. the cancer is one or more of breast cancer, lung cancer, prostate cancer, kidney cancer, leukemia, ovarian cancer, stomach cancer, uterine cancer, endometrial cancer, liver cancer, colon cancer, thyroid cancer, pancreatic cancer, colorectal cancer, esophageal cancer, testicular cancer, skin cancer, lymphoma, multiple myeloma; the immune disease is one or more of connective tissue disease, systemic sclerosis, rheumatoid arthritis, and systemic lupus erythematosus; the cardiovascular disease is one or more of angina pectoris, myocardial infarction, stroke, heart attack, hypertensive heart disease, rheumatic heart disease, cardiomyopathy, cardiac arrhythmia, and congenital heart disease; the metabolic disease is one or more of diabetes, gout, obesity, hypoglycemia, hyperglycemia, and dyslipidemia; 22. The pharmaceutical formulation of claim 21, wherein the neurological disorder is one or more of Alzheimer's disease, Parkinson's disease, Huntington's disease, head trauma, multiple sclerosis, dizziness, coma, and epilepsy.

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