Drug formulations, their manufacturing methods, and uses

Abstract

A drug formulation comprising a ligand-drug conjugate, a lyophilized excipient, and a buffer, the formulation is subjected to pH screening to limit the buffer and lyophilized excipient used, and the lyophilization process is screened at the same time, so that the appearance, water content, impurity content, and redissolution time of the formulation can all be kept stable during storage.

Description

Technical Field

[0001] <Priority and Related Applications> This application claims the priority of a Chinese patent application with application number 202111051190.6 and invention title "Drug Preparation and Its Manufacturing Method and Use", which was filed with the Chinese Patent Office on September 8, 2021, and all of its content is incorporated herein by reference.

[0002] <Technical Field> The present invention relates to the field of biopharmaceuticals. Specifically, the present invention relates to a drug preparation, specifically a drug preparation containing a ligand-drug conjugate, and its manufacturing method and use.

Background Art

[0003] The surfaces of tumor cells and other cells that develop lesions (e.g., vascular endothelial cells, leukocytes, brain capillary endothelial cells) contain a variety of specific or overexpressed receptors, such as transferrin receptors (TFRs), low-density lipoprotein receptors, folate receptors, uric acid kinase receptors, tumor necrosis factor receptors, intercellular adhesion molecules (ICAMs), and integrin receptor LFA-1. The ligands for these receptors are classified into proteins (ferritin, apolipoproteins, LRP1, a low-density lipoprotein receptor-associated protein 1, etc.), polypeptides (insulin, SOR-C13, luteinizing hormone-releasing hormone LHRH, somatostatin SST-14, etc.), and small molecules (folate and its analogs, glycosphingopropyl alcohols). These ligands possess characteristics such as good specificity when binding to receptors, moderate affinity, and clear biological effects. By coupling with therapeutic drugs to form ligand-drug conjugates (LDCs), they can clearly improve drug targeting and efficacy while simultaneously reducing toxicity. Ligand-drug conjugates possess cellular endocytosis-mediated functions and can be applied to the treatment of tumors, immunomodulation, and cardiovascular diseases. Their advantages are as follows: (1) The binding of the target to the endocytosis structure allows for the induction of polypeptides that target any ligand, thereby broadening the target range of this type of drug; (2) By utilizing dual-target ligands, the affinity and targeting of drug conjugates to diseased cells are enhanced, enabling the delivery of highly efficient toxic drugs, such as monomethyl auristatin E (MMAE), thereby enhancing drug efficacy, increasing the therapeutic pathway, and avoiding drug side effects; (3) The connector cannot release drug molecules outside the cell (interstitium, blood circulation system, etc.), ensuring the stability of the drug as it circulates in the body, reducing drug toxicity, and preventing toxic effects on normal cells. After entering the target cell, the connector degrades, releasing therapeutic drug molecules, thus avoiding the development of multidrug resistance (MDR).

[0004] In addition to formulating the conjugate in a manner suitable for administration to the subject, LDC formulations must be formulated in a manner that maintains their stability during storage and subsequent use. For example, if LDC is not properly formulated in liquid, the LDC in the liquid solution tends to decompose, aggregate, or undergo undesirable chemical modifications. The stability of LDC formulations depends on the buffers, stabilizers, and surfactants used in the formulation.

[0005] In this field, there is a demand for novel drug formulations containing LDCs that are sufficiently stable and suitable for administration to subjects. Therefore, it is necessary to manufacture appropriate LDC formulations for the treatment or prevention of diseases. [Overview of the project] [Problems that the invention aims to solve]

[0006] In response to the demand in the aforementioned field for novel LDC drug formulations that are stable and suitable for administration to subjects, the present invention aims to provide formulations containing ligand-drug conjugates, as well as methods for producing the same and its applications. By limiting parameters such as pH value, buffers and lyophilization excipients, and the lyophilization process, the invention satisfies the demand for LDC formulations to maintain good stability during storage. [Means for solving the problem]

[0007] According to a first aspect, the present invention provides a drug formulation comprising an active drug and optionally pharmaceutically acceptable excipients.

[0008] Furthermore, in the above drug formulation, 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 lyophilized excipient and a buffer.

[0009] Furthermore, in the above-mentioned drug formulation, the pharmaceutically acceptable excipient further comprises a solvent.

[0010] Furthermore, in the above drug formulation, the ligand-drug conjugate is a dual ligand-drug conjugate, preferably the dual ligand-drug conjugate is a drug conjugate that targets the folate receptor and the TRPV6 receptor, and more preferably the dual ligand-drug conjugate has the following structure [ka] It has, More preferably, the dual ligand-drug conjugate has the following structure [ka] It has.

[0011] Furthermore, in the above drug formulation, the solvent is water, preferably purified water, more preferably sterile water, distilled water, or deionized water, and more preferably sterile water is sterile water for injection, simply distilled water, or redistilled water.

[0012] Furthermore, in the above-mentioned drug formulation, the concentration of the active drug is 4.75 mg / mL to 6 mg / mL, and preferably the concentration of the active drug is 4.75 mg / mL, 5 mg / mL, 5.25 mg / mL, 5.5 mg / mL, 5.75 mg / mL, or 6 mg / mL.

[0013] Furthermore, the pH value of the drug formulation is 6.5 to 8.5, preferably 6.9 to 8.0, for example 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, and more preferably 6.9 to 7.7, for example 6.9, 7.0, 7.3, 7.5, 7.7.

[0014] Furthermore, in the above drug formulation, the lyophilized excipient comprises one or more polyols, such as mannitol, sorbitol, inositol, and xylitol, and preferably comprises mannitol.

[0015] Furthermore, in the above-mentioned drug formulation, the freeze-dried excipient further comprises one or more sugars, such as monosaccharides, disaccharides, and polysaccharides, preferably the mass ratio of the sugars to the polyol is 1:1 to 1:5, and more preferably the mass ratio of the sugars to the polyol is 1:2 to 1:4.

[0016] Preferably, in the above drug formulation, the monosaccharide comprises one or more of glucose and fructose, the disaccharide comprises one or more of sucrose, trehalose, maltose, and lactose, and the polysaccharide comprises one or more of cyclodextrin and dextran.

[0017] More preferably, in the above drug formulation, the freeze-dried excipient comprises mannitol and sucrose, and preferably the mass ratio of sucrose to mannitol is 1:2 to 1:5, for example 1:2, 1:2.4, 1:2.5, 1:4, 1:4.5, 1:4.7, 1:5, and more preferably the mass ratio of sucrose to mannitol is 1:4.

[0018] More preferably, in the above drug formulation, the lyophilized excipient comprises mannitol and trehalose, and preferably the mass ratio of trehalose to mannitol is 1:2 to 1:4, and more preferably the mass ratio of trehalose to mannitol is 1:4.

[0019] Furthermore, in the above drug formulation, the buffer contains tromethamine and an acidic substance, and the mass ratio of tromethamine to the active drug is 1:4 to 1:10, preferably 1:5 to 1:8.5.

[0020] Preferably, in the above drug formulation, the acidic substance comprises one or more of hydrochloric acid, acetic acid, sodium dihydrogen phosphate, and tromethamine hydrochloride.

[0021] More preferably, in the above drug preparation, the buffer contains tromethamine and hydrochloric acid. Preferably, the mass ratio of the tromethamine to the active drug is 1:5 to 1:8.5, for example, 1:5, 1:5.5, 1:6, 1:6.5, 1:7, 1:8, 1:8.5, and more preferably, the ratio of the tromethamine to the active drug is 1:6.5.

[0022] Furthermore, in the above drug preparation, the drug preparation contains 4.75 - 6 mg of a ligand-drug conjugate or a pharmaceutically acceptable salt thereof, 25 - 55 mg of mannitol, 0 - 55 mg of sucrose, 0.5 - 1.25 mg of tromethamine, hydrochloric acid and the balance of the solvent per mL. Here, the pH of the drug preparation is 6.5 - 8.5, preferably 6.9 - 8.0. For example, the drug preparation contains 5 mg of a ligand-drug conjugate or a pharmaceutically acceptable salt thereof, 40 mg of mannitol, 10 mg of sucrose, 0.765 mg of tromethamine, hydrochloric acid and the balance of water per mL. Here, the pH of the drug preparation is 6.5 - 8.5, preferably 6.9 - 8.0.

[0023] Furthermore, the above drug preparation is sterile.

[0024] Furthermore, the above drug preparation is stable upon freezing and thawing.

[0025] According to a second aspect, the present invention provides a method for manufacturing the above drug preparation, and the manufacturing method includes the step of obtaining the above drug preparation by taking a prescribed amount of an active drug and optionally a pharmaceutically acceptable excipient and uniformly mixing them.

[0026] Furthermore, the above manufacturing method includes the step of obtaining the above drug preparation by taking a prescribed amount of a ligand-drug conjugate or a pharmaceutically acceptable salt thereof, a lyophilization excipient, a buffer and a solvent, dissolving the ligand-drug conjugate or a pharmaceutically acceptable salt thereof and the lyophilization excipient using the solvent, adjusting the pH value to 6.9 - 7.7 using the buffer, uniformly mixing and filtering.

[0027] According to a third aspect, the present invention provides a lyophilized formulation, which is manufactured by lyophilizing the above-mentioned drug formulation.

[0028] According to a fourth aspect, the present invention provides a method for producing the above-mentioned freeze-dried formulation, the method comprising the steps of (i) freezing the drug formulation at -45°C, (ii) annealing the drug formulation at -25°C, (iii) freezing the drug formulation again at -45°C, (iv) primary drying the drug formulation at -15°C, and (v) secondary drying the drug formulation at 25°C.

[0029] Furthermore, in the above manufacturing method, the primary drying time is 800 to 3000 minutes, and the secondary drying time is 300 to 600 minutes.

[0030] According to a fifth aspect, the present invention provides a liquid formulation obtained by reconstituting the above-mentioned freeze-dried formulation with water.

[0031] Furthermore, in the above liquid formulation, the water includes one or more of distilled water, pure water, and sterile water, and preferably the pH after reconstitution of the freeze-dried formulation with water is 6.5 to 8.5.

[0032] According to a sixth aspect, the present invention provides a method for producing the above-mentioned liquid formulation, the method comprising the step of mixing the lyophilized formulation with sterile water to obtain the above-mentioned liquid formulation.

[0033] According to a seventh aspect, the present invention provides a drug-containing delivery device, the drug-containing delivery device comprising one of the drug formulations, the lyophilized formulations, or the liquid formulations.

[0034] According to the eighth aspect, the present invention provides a pre-filled syringe containing one of the above-mentioned drug formulations, lyophilized formulations, or liquid formulations, and is preferably used for intravenous or intramuscular injection.

[0035] According to the ninth aspect, the present invention provides a delivery device or pre-filled syringe or a drug manufacturing application for the above-mentioned drug formulation, the above-mentioned lyophilized formulation and the above-mentioned liquid formulation to enhance and / or reduce immunosuppression in a subject.

[0036] According to the tenth aspect, the present invention provides a delivery device or pre-filled syringe or a drug manufacturing application for the above-mentioned drug formulation, the above-mentioned lyophilized formulation and the above-mentioned liquid formulation for treating or preventing cancer, immune diseases, cardiovascular diseases, metabolic diseases and neurological diseases in a subject.

[0037] Furthermore, in the above uses, the cancer includes one or more of the following: 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, skin cancer, lymphoma, and multiple myeloma; the immune disease includes one or more of the following: connective tissue disease, systemic sclerosis, rheumatoid arthritis, and systemic lupus erythematosus; the cardiovascular disease includes one or more of the following: angina pectoris, myocardial infarction, stroke, heart attack, hypertensive heart disease, rheumatic heart disease, cardiomyopathy, cardiac arrhythmia, and congenital heart disease; the metabolic disease includes one or more of the following: diabetes mellitus, gout, obesity, hypoglycemia, hyperglycemia, and dyslipidemia; and the neurological disease includes one or more of the following: Alzheimer's disease, Parkinson's disease, Huntington's disease, head injury, multiple sclerosis, dizziness, coma, and epilepsy. [Effects of the Invention]

[0038] The present invention achieves the effect of maintaining stability in appearance, moisture content, impurity content, and redissolution time of a formulation throughout its storage period by performing pH screening on a formulation containing a ligand-drug conjugate, limiting the buffering agent and lyophilization excipient used, and simultaneously screening the lyophilization process. [Modes for carrying out the invention]

[0039] 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 inventive requirements. 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. Furthermore, all documents mentioned herein are incorporated herein by reference.

[0040] Unless otherwise defined, the technical and scientific terms used in this invention have the same meanings as those generally understood by those skilled in the art in which this invention pertains.

[0041] In this specification, a numerical range expressed using "numerical value A to numerical value B" or "numerical value A - numerical value B" is a range that includes the endpoint numerical values ​​A and B.

[0042] In this specification, whereever "%" appears, it represents the percentage of mass or weight, i.e., "mass%" or "weight%", unless otherwise specified.

[0043] In this specification, "room temperature" or "ambient temperature" refers to an ambient temperature of approximately 25°C.

[0044] In this specification, the use of "may" includes both the meaning of performing some action and the meaning of not performing some action. In this specification, "optional" or "optionally" means that the following events or situations may or may not occur, and such descriptions include the circumstances under which the event occurs and the circumstances under which the event does not occur.

[0045] In this specification, “several specific / preferred embodiments,” “other specific / preferred embodiments,” “several specific / preferred technical proposals,” “other specific / preferred technical proposals,” etc., refer to any particular element (e.g., feature, structure, property, and / or characteristic) described in relation to such embodiment is included in at least one embodiment described herein and may be present in other embodiments, or may not be present in other embodiments. It should also be understood that such elements may be combined in various embodiments in any suitable manner.

[0046] The term “inclusive” and any variations thereof in the specification and claims of this invention are intended to intentionally cover non-exclusive “inclusive.”

[0047] In this invention, "pharmaceutically acceptable" means that, within the bounds of reasonable medical judgment, it is applicable to contact with human and other animal cells without causing inappropriate toxicity, irritation, allergic reactions, etc., and is commensurate with a reasonable benefit / risk ratio.

[0048] In this invention, "pharmacoagulably acceptable salts" refer to relatively non-toxic inorganic and organic acid addition salts and base addition salts of the conjugate compound of this application. Typical acid addition salts include hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, oxalate, pentanoate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, toluenesulfonate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, methanesulfonate, glucoheptanoate, lactoseate, sulfamate, malonate, salicylate, propionate, methylene-bis-β-hydroxynaphthoate, loncholate, hydroxyethylsulfonate, di-p-toluyltartrate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, cyclohexylsulfamate, and lauryl quinate. Base addition salts include pharmaceutically acceptable metals 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, which include, 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 produced from amines that are sufficiently basic to form a stable salt and are preferably low in toxicity and acceptable for medical use, and therefore commonly used amines in medicamental chemistry, including: ammonia, ethylenediamine, N-methylglucosamine, lysine, arginine, ornithine, choline, N,N'-dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N-benzylphenylethylamine, diethylamine, piperazine, trimethylolaminomethane, tetramethylammonium hydroxide, triethylamine, dibenzylamine, diphenylhydroxymethine, dehydroabiethylamine, N-ethylpiperidine, benzylamine, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, ethylamine, basic amino acids (e.g., lysine and arginine), and dicyclohexylamine.

[0049] In the present invention, a "ligand-drug conjugate" (LDC) links a biologically active drug to a ligand via chemical bonding, and the ligand acts as a carrier to target the delivery of a small molecule drug to a target cell, where the ligand may be a polypeptide or a small molecule. Preferably, the ligand-drug conjugate is a biligand-drug conjugate, and preferably, the biligand-drug conjugate is a drug conjugate that targets the folate receptor and the TRPV6 receptor. More preferably, the ligand-drug conjugate of the present invention is the ligand-drug conjugate described in the patent application with application number 201680045855.3 and the title of the invention "Multiligand Drug Conjugate and Uses thereof", and more preferably, the ligand-binding compound is a biligand coupling product LDC10B, the ligands target the TRPV6 receptor and the folate receptor, respectively, the carrier drug is MMAE, and its structure is shown below. [ka] , More preferably, the dual ligand-drug conjugate has the following structure [ka] It has.

[0050] In the present invention, a "buffer" is a reagent that can maintain the pH of a solution within an acceptable range. In some embodiments, the buffer used in the formulation of the present invention can control the pH of the formulation to a pH range of about 6.5 to 8.5, for example, about 6.9 to 8.0. In some specific embodiments, the formulation of the present invention has pH values ​​of about 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, and 8.0.

[0051] In this invention, "polyol" refers to alcohols containing two or more hydroxyl groups in their molecule.

[0052] In this invention, "reconstitution" means dissolving and / or suspending a solid dosage form (e.g., a lyophilized dosage form) in a physiologically acceptable solution.

[0053] In this invention, "approximately" means that a limited numerical value is approximate, and it is not necessary for a particular numerical value in the related data to be extremely accurate.

[0054] In this invention, "formulation" refers to a drug that is prepared according to certain dosage form requirements and can ultimately be provided for use by a target person.

[0055] In this invention, "freeze-dried formulation" refers to a sterile solid for injection obtained by freeze-drying.

[0056] In this invention, "freeze-drying excipients," also known as freeze-drying protective agents, are additives added during the freeze-drying and storage processes of foods, pharmaceuticals, and living organisms, with the aim of ensuring that the product maintains stability and activity even under the influence of many factors (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.).

[0057] In this invention, a "stable formulation" is a formulation in which the moisture content, appearance, pH value, impurity content, and resolubility do not fundamentally change during the manufacturing and storage processes of the product, or change within a pharmaceutically acceptable range.

[0058] In this invention, "HPLC" refers to High Performance Liquid Chromatography, an important branch of chromatography. It uses a liquid as the mobile phase and employs a high-pressure infusion system to pump the mobile phase, such as a single solvent or a mixture of solvents with different polarities or buffers in different proportions, into a column containing the stationary phase. After each component is separated in the column, it is detected by a detector to perform the analysis of the sample.

[0059] [Drug formulations containing LDC and methods for manufacturing the same] The present invention provides a drug formulation which may comprise an active drug and optionally pharmaceutically acceptable excipients.

[0060] In one embodiment, the drug formulation may include a ligand-drug conjugate, a lyophilized excipient, and a buffer.

[0061] In one embodiment, the drug formulation may include a ligand-drug conjugate, a lyophilized excipient, a buffer, and a solvent.

[0062] In one preferred embodiment, the ligand-drug conjugate in the drug formulation may be a dual ligand-drug conjugate targeting the folate receptor and the TRPV6 receptor.

[0063] In one embodiment, the solvent in the above drug formulation is water.

[0064] In one preferred embodiment, the solvent in the drug formulation is purified water.

[0065] In another preferred embodiment, the solvent in the drug formulation is sterile water, distilled water, or deionized water.

[0066] In one more preferred embodiment, the solvent in the drug formulation is sterile water for injection, simple distilled water, or redistilled water.

[0067] In one embodiment, the active drug concentration in the above drug formulation is 4.75 mg / mL to 6 mg / mL, for example, 4.75 mg / mL, 5 mg / mL, 5.25 mg / mL, 5.5 mg / mL, 5.75 mg / mL, and 6 mg / mL.

[0068] In one preferred embodiment, the active drug concentration of the drug formulation is 5 mg / mL.

[0069] In one embodiment, the pH value of the drug formulation may be 6.5 to 8.5.

[0070] In one preferred embodiment, the pH value of the drug formulation may be 6.9 to 8.0, for example, 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.

[0071] In one more preferred embodiment, the pH value of the drug formulation may be 6.9 to 7.7, for example, 6.9, 7.0, 7.3, 7.5, or 7.7.

[0072] In one embodiment, the lyophilized excipient in the above drug formulation may include one or more polyols, such as mannitol, sorbitol, inositol, and xylitol.

[0073] In one preferred embodiment, the lyophilized excipient in the drug formulation comprises mannitol.

[0074] In one embodiment, the lyophilized excipient in the drug formulation comprises a polyol and one or more sugars, such as monosaccharides, disaccharides, and polysaccharides.

[0075] Furthermore, in the above drug formulation, the monosaccharide in the freeze-dried excipient includes one or more of glucose and fructose; the disaccharide includes one or more of sucrose, trehalose, maltose, and lactose; and the polysaccharide includes one or more of cyclodextrin and dextran.

[0076] Furthermore, the mass ratio of the sugars to the polyol is 1:1 to 1:5, preferably 1:2 to 1:4.

[0077] In one preferred embodiment, the lyophilized excipient in the above drug formulation may include mannitol and sucrose, preferably the mass ratio of sucrose to mannitol is 1:2 to 1:5, for example, 1:2, 1:2.4, 1:2.5, 1:4, 1:4.5, 1:4.7, or 1:5.

[0078] In one more preferred embodiment, the lyophilized excipient in the drug formulation may contain mannitol and sucrose, preferably with a mass ratio of sucrose to mannitol of 1:4.

[0079] In another preferred embodiment, the lyophilized excipient in the drug formulation may include mannitol and trehalose, preferably with a mass ratio of trehalose to mannitol of 1:2 to 1:4.

[0080] In another, more preferred embodiment, the lyophilized excipient in the drug formulation may include mannitol and trehalose, preferably with a mass ratio of trehalose to mannitol of 1:4.

[0081] In one embodiment, the buffer in the drug formulation may include tromethamine and an acidic substance, and the mass ratio of tromethamine to the active drug is 1:4 to 1:10, preferably 1:5 to 1:8.5.

[0082] Furthermore, the acidic substance contained in the buffering agent in the above drug formulation may be selected from one or more of hydrochloric acid, acetic acid, sodium dihydrogen phosphate, and tromethamine hydrochloride.

[0083] In one preferred embodiment, the buffer in the drug formulation may include tromethamine and hydrochloric acid, and preferably the mass ratio of tromethamine to the active drug is 1:5 to 1:8.5, for example, 1:5, 1:5.5, 1:6, 1:6.5, 1:7, 1:8, or 1:8.5.

[0084] In one more preferred embodiment, the buffer in the drug formulation may include tromethamine and hydrochloric acid, preferably in a ratio of tromethamine to the active drug of 1:6.5.

[0085] In another preferred embodiment, the buffer in the drug formulation may include tromethamine and acetic acid, wherein the ratio of tromethamine to the active drug is 1:6.5.

[0086] In another preferred embodiment, the buffer in the drug formulation may include tromethamine and sodium dihydrogen phosphate, and the ratio of tromethamine to the active drug is 1:6.5.

[0087] In another preferred embodiment, the buffer in the drug formulation may include tromethamine and tromethamine hydrochloride, and the ratio of tromethamine to the active drug is 1:6.5.

[0088] In one embodiment, the drug formulation comprises 4.75 to 6 mg of a ligand-drug conjugate or a pharmaceutically acceptable salt thereof, 25 to 55 mg of mannitol, 0 to 55 mg of sucrose, 0.5 to 1.25 mg of tromethamine, hydrochloric acid, and the remainder of a solvent per 1 mL, wherein the pH of the drug formulation is 6.5 to 8.5, preferably 6.9 to 8.0.

[0089] In one preferred embodiment, the drug formulation comprises 5 mg of ligand-drug conjugate or a pharmaceutically acceptable salt thereof, 40 mg of mannitol, 10 mg of sucrose, 0.765 mg of tromethamine, hydrochloric acid, and the remainder water per 1 mL, wherein the pH of the drug formulation is 6.5 to 8.5, preferably 6.9 to 8.0.

[0090] In one embodiment, the drug formulation is sterile.

[0091] In one embodiment, the above drug formulation is stable during freezing and thawing.

[0092] In one embodiment, the method for producing the drug formulation includes the step of taking a prescribed amount of active drug and optionally pharmaceutically acceptable excipients and mixing them uniformly to obtain the drug formulation.

[0093] In one preferred embodiment, the method for producing the drug formulation includes the steps of taking a prescribed amount of ligand-drug conjugate or a pharmaceutically acceptable salt thereof, a lyophilized excipient, a buffer, and a solvent; using the solvent to dissolve the ligand-drug conjugate or a pharmaceutically acceptable salt thereof and the lyophilized excipient; using the buffer to adjust the pH to 6.9 to 7.7; mixing uniformly; and filtering to obtain the drug formulation.

[0094] [Lyophilized preparation and method for producing the same] The present invention provides a lyophilized formulation, which is obtained by lyophilizing the drug formulation of the present invention.

[0095] The present invention further provides a method for producing the above-mentioned lyophilized formulation, the method comprising the step of obtaining the above-mentioned lyophilized formulation by lyophilizing the drug formulation of the present invention.

[0096] In one embodiment, the above manufacturing method includes the steps of freezing the drug formulation at -45°C, annealing the drug formulation at -25°C, freezing the drug formulation again at -45°C, primary drying the drug formulation at -15°C, and secondary drying the drug formulation at 25°C.

[0097] In one preferred embodiment, the above manufacturing method includes the steps of freezing the drug formulation at -45°C, annealing the drug formulation at -25°C, freezing the drug formulation again at -45°C, primary drying the drug formulation at -15°C for 800 to 3000 minutes, and secondary drying the drug formulation at 25°C for 300 to 600 minutes.

[0098] In one more preferred embodiment, the above manufacturing method comprises the following steps: Freezing: the formulation solution is placed in a freeze-drying chamber and cooled to -45°C under atmospheric pressure and held for 120 min; Annealing: the temperature is raised to -25°C under atmospheric pressure and held for 180 min; Freezing: the temperature is lowered to -45°C under atmospheric pressure and held for 120 min; Pre-vacuum evacuation: the atmospheric pressure of the chamber is changed to 0.2 mbar; Primary drying: the temperature is raised to -15°C at 0.13 mbar and held for 800 to 3000 min; Secondary drying: the temperature is raised to 25°C at 0.13 mbar and held for 300 to 600 min.

[0099] In one more preferred embodiment, the above manufacturing method comprises the following steps: Freezing: the formulation solution is placed in a freeze-drying chamber and cooled to -45°C under atmospheric pressure and held for 120 min; Annealing: the temperature is raised to -25°C under atmospheric pressure and held for 180 min; Freezing: the temperature is lowered to -45°C under atmospheric pressure and held for 120 min; Pre-vacuum evacuation: the atmospheric pressure of the chamber is changed to 0.2 mbar; Primary drying: the temperature is raised to -15°C at 0.13 mbar and held for 800 min; Secondary drying: the temperature is raised to 25°C at 0.13 mbar and held for 600 min.

[0100] [Liquid formulation and method for manufacturing the same] The present invention provides a liquid formulation, which is obtained by reconstituting the lyophilized formulation of the present invention with water.

[0101] The present invention further provides a method for producing the above-mentioned liquid formulation, the method comprising the step of mixing the freeze-dried formulation of the present invention with water.

[0102] In one embodiment, the above-described manufacturing method completes the reconstruction using distilled water, pure water, or sterile water.

[0103] In one embodiment, the pH of the freeze-dried formulation after reconstitution with water is 6.5 to 8.5.

[0104] [Device] The present invention provides a drug-containing delivery device, the device comprising one of the above-mentioned drug formulation, the above-mentioned lyophilized formulation, or the above-mentioned liquid formulation.

[0105] The present invention further provides a pre-filled syringe comprising one of the above-mentioned drug formulation, lyophilized formulation, or liquid formulation.

[0106] [Medical Use] The present invention provides a delivery device or pre-filled syringe or a drug manufacturing application for the drug formulation, lyophilized formulation or liquid formulation containing an active drug.

[0107] In one embodiment, the delivery device, pre-filled syringe, or drug in the above-described application is used to enhance the immune effector cell response in a subject.

[0108] In one embodiment, the delivery device, pre-filled syringe, or drug in the above-described application is used to reduce immunosuppression in the subject.

[0109] In one embodiment, the delivery device, pre-filled syringe, or drug in the above-described application is used for the treatment or prevention of cancer in a subject.

[0110] Furthermore, the cancers used in the above applications include one or more of the following: 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, skin cancer, lymphoma, and multiple myeloma.

[0111] In one embodiment, the delivery device, pre-filled syringe, or drug in the above-described application is used for the treatment or prevention of an immune disorder in a subject.

[0112] Furthermore, the immune diseases in the above-mentioned uses include one or more of connective tissue diseases, systemic sclerosis, rheumatoid arthritis, and systemic lupus erythematosus.

[0113] In one embodiment, the delivery device, pre-filled syringe, or drug in the above-described application is used for the treatment or prevention of cardiovascular disease in a subject.

[0114] Furthermore, the cardiovascular diseases in the above-mentioned uses include one or more of the following: angina pectoris, myocardial infarction, stroke, heart attack, hypertensive heart disease, rheumatic heart disease, cardiomyopathy, cardiac arrhythmias, and congenital heart diseases.

[0115] In one embodiment, the delivery device, pre-filled syringe, or drug in the above-described application is used for the treatment or prevention of a metabolic disorder in a subject.

[0116] Furthermore, metabolic diseases in the above-mentioned applications include one or more of diabetes, gout, obesity, hypoglycemia, hyperglycemia, and dyslipidemia.

[0117] In one embodiment, the delivery device, pre-filled syringe, or drug in the above-described application is used for the treatment or prevention of a neurological disorder in a subject.

[0118] Furthermore, the neurological disorders in the above-mentioned uses include one or more of the following: Alzheimer's disease, Parkinson's disease, Huntington's disease, head injury, multiple sclerosis, dizziness, coma, and epilepsy.

[0119] Unless otherwise specified, the instruments, reagents, materials, etc. used in this invention can all be obtained through conventional commercial means. The following describes the technical aspects of this invention in conjunction with specific examples.

[0120] Example 1 To investigate the stability of formulations containing LDC10B at pH 6.9 to 8.0, five pH values ​​were designed: 6.9, 7.2, 7.5, 7.8, and 8.0.

[0121] 1.1 Experimental Steps Aqueous solutions containing LDC10B (5 mg / mL), mannitol (40 mg / mL), sucrose (10 mg / mL), and tromethamine (0.765 mg / mL) were prepared. The pH of each solution was adjusted to 6.9, 7.2, 7.5, 7.8, and 8.0 with dilute hydrochloric acid, filtered, dispensed into vials, and sealed. Each sample was subjected to a 12-hour stability test at room temperature.

[0122] 1.2 Experimental Plan The specific plan is as shown in the table below.

[0123] [Table 1]

[0124] 1.3 Experimental Results [Table 2]

[0125] After standing at room temperature for different durations at pH 6.9, 7.2, 7.5, 7.8, and 8.0, the relevant substances in each sample were measured by HPLC. As can be seen, after 12 hours of observation under room temperature conditions, the total impurities in the samples at each pH value increased. Compared to the relevant substance levels in the sample at 0 hours, the total impurities in the samples at pH 6.9, 7.2, 7.5, 7.8, and 8.0 increased by 0.17%, 0.37%, 0.58%, 0.68%, and 1.28%, respectively.

[0126] According to the experimental results above, the total amount of impurities was within acceptable limits at pH levels between 6.9 and 8.0.

[0127] 1.4 Prepare the sample in its final formulation (lyophilized form) and confirm the pH. 1.4.1 Experimental Steps Aqueous solutions containing LDC10B (5 mg / mL), mannitol (40 mg / mL), sucrose (10 mg / mL), and tromethamine (0.765 mg / mL) were prepared. The pH was adjusted to 6.9, 7.3, and 7.7, respectively, using dilute hydrochloric acid. The solutions were filtered, dispensed into vials, the stoppers were partially pressed, freeze-dried, and capped. Each sample was subjected to a stability study at 30°C for one month.

[0128] 1.4.2 Experimental Plan The specific plan is as shown in the table below.

[0129] [Table 3]

[0130] 1.4.3 Experimental Results [Table 4]

[0131] The experimental results are shown in the table above. According to the data, the quality of the lyophilized formulation containing LDC10B remained stable within the pH range of 6.9 to 7.7.

[0132] Example 2 To study the effects of tromethamine buffering systems, phosphate buffering systems, and acetate buffering systems on the stability of formulations containing LDC10B, four formulations were designed. Detailed formulation information is shown in the table below.

[0133] [Table 5]

[0134] 2.1 Experimental Steps Aqueous solutions of each of the above formulations were prepared, filtered, dispensed into vials, the stoppers were partially pressed, freeze-dried, and the caps were applied. The stability of each sample was examined under conditions of 40°C.

[0135] 2.2 Experimental Plan The specific plan is as shown in the table below, and the detection indicators are appearance and related substances.

[0136] [Table 6]

[0137] 2.3 Experimental Results [Table 7]

[0138] According to the experimental results above, under the condition of 40°C, the changes in the total impurities of each formulation were all within acceptable limits.

[0139] Example 3 In the resulting buffer system, the amount of tromethamine used (0.615–1.00 mg / mL) was screened and optimized to obtain better product quality.

[0140] [Table 8]

[0141] 3.1 Experimental Steps Aqueous solutions of each of the above formulations were prepared, filtered, dispensed into vials, the stoppers were partially pressed, freeze-dried, and capped. The stability of each sample was examined under conditions of 2 to 8°C.

[0142] 3.2 Experimental Results [Table 9]

[0143] The results showed that when the amount of tromethamine used was between 0.615 mg / mL and 1.00 mg / mL, there were no significant differences in the redissolution time, properties, moisture content, and related substances of the product, indicating that 0.615 mg / mL to 1.00 mg / mL is within the acceptable usage range.

[0144] Example 4 To study the effects of mannitol as a polyol and sucrose and trehalose as sugars on formulations containing LDC10B, four formulations were designed, and detailed formulation information is shown in the table below.

[0145] [Table 10]

[0146] 4.1 Experimental Steps Aqueous solutions of each of the above formulations were prepared, filtered, dispensed into vials, the stoppers were partially pressed, freeze-dried, and the caps were applied. After freeze-drying and removal from the box, formulations 9 and 10 products withered, but the remaining formulations did not exhibit this phenomenon.

[0147] 4.2 Experimental Plan The specific plan is as shown in the table below, and the detection indicators are appearance, moisture content, and related substances.

[0148] [Table 11]

[0149] 4.3 Experimental Results [Table 12]

[0150] According to the experimental results above, when sucrose (Formulation 9) and trehalose (Formulation 10) are used as fillers, the product shrinks. However, after adding mannitol, a freeze-dried formulation that meets the requirements for appearance, moisture content, and quality can be obtained. Therefore, it is possible to choose to use mannitol and sucrose, or mannitol and trehalose together, as excipients.

[0151] Example 5 In the resulting excipient lines, the amounts of mannitol and sucrose used were screened and optimized to obtain better product quality.

[0152] [Table 13]

[0153] 5.1 Experimental Steps Aqueous solutions of each of the above formulations were prepared, filtered, dispensed into vials, the stoppers were partially pressed, freeze-dried, and the caps were applied. The stability of each sample was examined under conditions of 40°C.

[0154] 5.2 Experimental Results [Table 14]

[0155] The results showed that when mannitol was used alone, the amount of impurities in the product increased significantly, while when sucrose and mannitol were used together as excipients, the increase in impurities decreased significantly. Therefore, the amount of excipients used in this product is 20 mg to 33.5 mg of sucrose and 80 mg to 93.5 mg of mannitol.

[0156] Example 6 6.1 Process Selection [Table 15]

[0157] 6.2 Experimental Results [Table 16]

[0158] All processes yielded products with good appearance, passing moisture tests, and meeting re-dissolution time and pH values ​​suitable for clinical use. The allowable freezing temperature for the freeze-drying process was -45°C, followed by annealing at -25°C. The primary drying temperature was -15°C for 800-3000 mins, and the secondary drying temperature was 25°C for 300-600 mins.

[0159] Example 7 We combined the results of prescription screening experiments to conduct prescription process verification experiments and examined the stability of the final prescription.

[0160] The prescription information is as shown in the table below.

[0161] [Table 17]

[0162] The process information is as shown in the table below.

[0163] [Table 18]

[0164] The experimental plan is as shown in the table below.

[0165] [Table 19]

[0166] The experimental results are as follows:

[0167] [Table 20]

[0168] The results showed that the products manufactured using the determined formulation and process exhibited acceptable changes in appearance, moisture content (<5%), redissolution pH (6.9-7.7), and associated substances (total impurities <5%) after 6 months at 25°C and 1 month at high temperatures of 40°C.

Claims

1. A drug formulation comprising an active drug and pharmaceutically acceptable excipients, The active drug comprises a ligand-drug conjugate or a pharmaceutically acceptable salt thereof. The pharmaceutically acceptable excipient comprises a lyophilized excipient, the lyophilized excipient comprises a polyol and a sugar, the polyol being mannitol, the sugar being sucrose or trehalose, and the mass ratio of the sugar to the polyol being 1:1 to 1:

5. The ligand-drug conjugate is a dual ligand-drug conjugate, The aforementioned dual ligand-drug conjugate is a drug conjugate that targets the folate receptor and the TRPV6 receptor. The aforementioned dual ligand-drug conjugate has the following structure 【Chemistry 1】 A drug formulation characterized by having [a certain characteristic].

2. The aforementioned dual ligand-drug conjugate has the following structure 【Chemistry 2】 A drug formulation according to claim 1, characterized by having the following:

3. The drug formulation according to claim 1, characterized in that the pharmaceutically acceptable excipient further comprises one or more of a buffer and a solvent.

4. The drug formulation according to claim 1, characterized in that the solvent is water.

5. The drug formulation according to claim 1, characterized in that the concentration of the active drug is 4.75 mg / mL to 6 mg / mL.

6. The drug formulation according to claim 5, characterized in that the concentration of the active drug is 4.75 mg / mL, 5 mg / mL, 5.25 mg / mL, 5.5 mg / mL, 5.75 mg / mL, or 6 mg / mL.

7. The drug preparation according to claim 1, characterized in that the pH value of the drug preparation is 6.5 to 8.

5.

8. The drug preparation according to claim 7, characterized in that the pH value of the drug preparation is 6.9 to 7.

7.

9. The drug formulation according to claim 1, characterized in that the mass ratio of the sugars to the polyol is 1:2 to 1:

4.

10. The drug formulation according to claim 1, characterized in that the freeze-dried excipient comprises mannitol and sucrose, or mannitol and trehalose.

11. The drug preparation according to claim 10, characterized in that the mass ratio of sucrose to mannitol is 1:2 to 1:5, and the mass ratio of trehalose to mannitol is 1:2 to 1:

4.

12. The drug preparation according to claim 11, characterized in that the mass ratio of sucrose to mannitol is 1:2, 1:2.4, 1:2.5, 1:4, 1:4.5, 1:4.7, or 1:

5.

13. The drug formulation according to claim 3, characterized in that the buffering agent comprises tromethamine and an acidic substance, and the mass ratio of tromethamine to the active drug is 1:4 to 1:

10.

14. The drug formulation according to claim 13, characterized in that the mass ratio of tromethamine to the active drug is 1:5 to 1:8.

5.

15. The drug preparation according to claim 13, characterized in that the acidic substance includes one or more of hydrochloric acid, acetic acid, sodium dihydrogen phosphate, and tromethamine hydrochloride.

16. The drug formulation according to claim 13, characterized in that the buffering agent comprises tromethamine and hydrochloric acid.

17. The drug formulation according to claim 16, characterized in that the mass ratio of tromethamine to the active drug is 1:5 to 1:8.

5.

18. The pharmaceutically acceptable excipient further comprises one or more of a buffer and a solvent. The polyol is mannitol, the sugars are sucrose, and the buffer contains tromethamine and hydrochloric acid. The drug preparation according to claim 1, characterized in that the drug preparation contains 4.75 to 6 mg of a ligand-drug conjugate or a pharmaceutically acceptable salt thereof, 25 to 55 mg of mannitol, 0 to 55 mg of sucrose, 0.5 to 1.25 mg of tromethamine, and the remainder of a solvent per 1 mL, and contains hydrochloric acid such that the pH of the drug preparation is 6.5 to 8.

5.

19. The drug preparation according to claim 18, characterized in that the drug preparation contains 5 mg of ligand-drug conjugate or a pharmaceutically acceptable salt thereof, 40 mg of mannitol, 10 mg of sucrose, 0.765 mg of tromethamine, hydrochloric acid, and the remainder of water per 1 mL, wherein the hydrochloric acid is included such that the pH of the drug preparation is 6.5 to 8.

5.

20. A method for producing a drug preparation according to claim 3, The process includes the step of taking a prescribed amount of active drug and optionally pharmaceutically acceptable excipients and mixing them uniformly to obtain a drug formulation, A method for producing a drug formulation, comprising the steps of taking a prescribed amount of ligand-drug conjugate or a pharmaceutically acceptable salt thereof, a lyophilized excipient, a buffer, and a solvent; using the solvent, dissolving the ligand-drug conjugate or a pharmaceutically acceptable salt thereof and the lyophilized excipient; using the buffer, adjusting the pH to 6.9 to 7.7; mixing uniformly; and filtering to obtain a drug formulation.

21. A lyophilized preparation characterized by comprising a drug preparation according to any one of claims 1 to 19.

22. A method for producing a freeze-dried preparation according to claim 21, Step (i) of freezing the drug preparation at -45°C, (ii) A step of annealing the drug formulation at -25°C, The step of refreezing the drug preparation at -45°C (iii), (iv) A step of primary drying the drug formulation at -15°C, A method for manufacturing a drug preparation, comprising the step (v) of secondarily drying the drug preparation at 25°C.

23. The manufacturing method according to claim 22, wherein the time for the primary drying is 800 to 3000 mins, and the time for the secondary drying is 300 to 600 mins.

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

25. A drug-containing delivery device comprising the lyophilized preparation according to claim 21.

26. A pre-filled syringe comprising a drug formulation according to any one of claims 1 to 19.

27. A pre-filled syringe comprising the lyophilized formulation described in claim 21.

28. A pharmaceutical composition comprising a drug formulation according to any one of claims 1 to 19, comprising a drug that enhances and / or reduces immunosuppression, or a drug for treating or preventing cancer, autoimmune diseases, cardiovascular diseases, metabolic diseases and neurological diseases in a subject.

29. A pharmaceutical composition comprising a lyophilized preparation according to claim 21, comprising a drug for enhancing and / or reducing immunosuppression of immune effector cell responses, or for treating or preventing cancer, autoimmune diseases, cardiovascular diseases, metabolic diseases and neurological diseases in a subject.

30. The aforementioned cancers include one or more of the following: 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, skin cancer, lymphoma, and multiple myeloma. The aforementioned immune diseases include one or more of connective tissue diseases, systemic sclerosis, rheumatoid arthritis, and systemic lupus erythematosus. The aforementioned cardiovascular diseases include one or more of the following: angina pectoris, myocardial infarction, stroke, heart attack, hypertensive heart disease, rheumatic heart disease, cardiomyopathy, cardiac arrhythmia, and congenital heart disease. The aforementioned metabolic disorders include one or more of diabetes, gout, obesity, hypoglycemia, hyperglycemia, and dyslipidemia. The pharmaceutical composition according to claim 28, characterized in that the neurological disease includes one or more of Alzheimer's disease, Parkinson's disease, Huntington's disease, head injury, multiple sclerosis, dizziness, coma, and epilepsy.

31. The aforementioned cancers include one or more of the following: 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, skin cancer, lymphoma, and multiple myeloma. The aforementioned immune diseases include one or more of connective tissue diseases, systemic sclerosis, rheumatoid arthritis, and systemic lupus erythematosus. The aforementioned cardiovascular diseases include one or more of the following: angina pectoris, myocardial infarction, stroke, heart attack, hypertensive heart disease, rheumatic heart disease, cardiomyopathy, cardiac arrhythmia, and congenital heart disease. The aforementioned metabolic disorders include one or more of diabetes, gout, obesity, hypoglycemia, hyperglycemia, and dyslipidemia. The pharmaceutical composition according to claim 29, characterized in that the neurological disease includes one or more of Alzheimer's disease, Parkinson's disease, Huntington's disease, head injury, multiple sclerosis, dizziness, coma, and epilepsy.

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