WO2023066251A1 - 偶联体药物制剂及其制备方法和用途 - Google Patents

偶联体药物制剂及其制备方法和用途 Download PDF

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WO2023066251A1
WO2023066251A1 PCT/CN2022/125935 CN2022125935W WO2023066251A1 WO 2023066251 A1 WO2023066251 A1 WO 2023066251A1 CN 2022125935 W CN2022125935 W CN 2022125935W WO 2023066251 A1 WO2023066251 A1 WO 2023066251A1
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preparation
pharmaceutical preparation
pharmaceutical
cancer
water
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English (en)
French (fr)
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范思祥
商培培
吴凡
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Coherent Biopharma Suzhou Ltd
Coherent Biopharma Suzhou Co Ltd
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Coherent Biopharma Suzhou Ltd
Coherent Biopharma Suzhou Co Ltd
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Priority to US18/703,208 priority Critical patent/US20240424106A1/en
Priority to CN202280070466.1A priority patent/CN118215503A/zh
Priority to JP2024523795A priority patent/JP7818858B2/ja
Priority to EP22882856.2A priority patent/EP4420681A4/en
Priority to AU2022371507A priority patent/AU2022371507A1/en
Priority to CA3235106A priority patent/CA3235106A1/en
Priority to KR1020247015273A priority patent/KR20240072273A/ko
Publication of WO2023066251A1 publication Critical patent/WO2023066251A1/zh
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/545—Heterocyclic compounds
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    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
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    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
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    • A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
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Definitions

  • the present invention relates to the field of biomedicine, in particular, the present invention relates to a conjugate pharmaceutical preparation, specifically a pharmaceutical preparation comprising a ligand-drug conjugate, and a preparation method and use thereof.
  • LDC ligand-drug conjugates
  • Ligand-drug conjugates have endocytosis-mediated functions, which can realize the combination of targeting and endocytic structures, and use dual-targeting ligands to enhance the affinity and targeting of drug conjugates to diseased cells.
  • highly efficient toxin drugs such as monomethyl auristatin E (MMAE) can be carried, and the linker makes it impossible for the conjugate to release drug molecules outside the cell (intercellular substance, blood circulation system, etc.), ensuring the stability of the drug when it circulates in the body. Stability, and reduce drug toxicity, will not produce toxic effects on normal cells.
  • the linker After entering the interior of the target cell, the linker is cleaved to release the therapeutic drug molecule, which can avoid multidrug resistance (MDR).
  • MDR multidrug resistance
  • LDC preparations need to ensure good stability during preparation, long-term storage and subsequent use.
  • the stability of LDC in the formulation depends on the pH regulator, stabilizer and surfactant used in the formulation. If the LDC is not properly formulated in the liquid, the LDC in the liquid solution tends to disintegrate, aggregate, or undergo undesired chemical modifications, etc.
  • There is a need in the art for novel pharmaceutical formulations containing LDCs that are sufficiently stable and suitable for administration to a subject and therefore, there is a need to prepare suitable formulations of LDCs for use in the treatment or prevention of disease.
  • the present invention intends to provide a conjugate pharmaceutical preparation, specifically a pharmaceutical preparation comprising a ligand-drug conjugate, and Its preparation method and use.
  • a conjugate pharmaceutical preparation specifically a pharmaceutical preparation comprising a ligand-drug conjugate
  • Its preparation method and use By limiting the pH value, the type and amount of pH regulators, lyophilized excipients, the dosing sequence and liquid formulation environment during drug preparation, and the parameters of the lyophilization process, the requirements for maintaining good stability during storage are met.
  • a pharmaceutical preparation comprising an active drug and optional pharmaceutically acceptable excipients.
  • the auxiliary materials include one or more of freeze-drying excipients, pH regulators and solvents.
  • the solvent is water; preferably, the solvent is purified water; more preferably, the purified water is sterile water, distilled water or Ionized water; more preferably, the sterile water is sterile water for injection, single distilled water or double distilled water.
  • the buffer salt contains one or more of acetate, phosphate, citrate or hydrates thereof; preferably, each One molecule of the hydrate contains 0.5, 1, 1.5, 2.0, 2.5 or 3 molecules of water; preferably, the buffer salt is sodium acetate, anhydrous sodium citrate, sodium citrate dihydrate or sodium dihydrogen phosphate one or more of.
  • the acidic substance contains acid; preferably, the acidic substance is one or more of hydrochloric acid, acetic acid or citric acid; the The alkaline substance includes alkali or salt; preferably, the alkaline substance is one or more of sodium hydroxide, sodium carbonate or sodium bicarbonate.
  • polyols such as one or more of mannitol and xylitol
  • the lyophilized excipient is mannitol
  • the preferred concentration is 20mg/mL-150m
  • the ligand-drug conjugate is a double ligand-drug conjugate; preferably, the The double ligand-drug conjugate is a drug conjugate targeting PSMA receptor and TRPV6 receptor; preferably, the double ligand-drug conjugate has the following structure:
  • the double ligand-drug conjugate has the following structure:
  • the preparation method according to [20] is characterized in that it comprises the following steps: taking the prescribed amount of the ligand-drug conjugate or its pharmaceutically acceptable salt, lyophilized excipients, pH Regulator and solvent, dissolve each component in the solvent at one time or in batches, optionally use the acidic substance or basic substance in the pH regulator to adjust the pH value to 5.0-8.0, mix well, and obtain; preferably , when dissolving the components in the solvent, the pH regulator is dissolved in the solvent simultaneously or preferentially to the ligand-drug conjugate or a pharmaceutically acceptable salt thereof.
  • the preparation method described in [20] or [21] it is characterized in that the preparation method is optionally carried out under the condition of avoiding light; preferably, the preparation method is carried out under the condition of avoiding light conduct.
  • preparation method according to any one of [20] to [23], characterized in that the preparation method is optionally carried out under nitrogen protection; preferably, the preparation method is not carried out under nitrogen under protected conditions.
  • a lyophilized preparation prepared by lyophilizing the pharmaceutical preparation according to any one of [1] to [19].
  • the pH is 5.0-8.0.
  • a drug-containing delivery device comprising one of the following formulations: the pharmaceutical formulation according to any one of [1] to [19], the lyophilized formulation according to [25], or the pharmaceutical formulation according to [25].
  • a prefilled syringe comprising one of the following formulations: the pharmaceutical formulation according to any one of [1] to [19], the lyophilized formulation according to [25], or the pharmaceutical formulation according to [25].
  • the liquid preparation described in [28] or [29] is preferably used for intravenous injection or intramuscular injection.
  • the pharmaceutical preparation according to any one of [1] to [19], the freeze-dried preparation according to [25] or the liquid preparation according to [28] or [29] are used in the preparation Use in a delivery device or prefilled syringe or medicament that enhances immune effector cell responses and/or reduces immunosuppression in a subject.
  • the pharmaceutical preparation according to any one of [1] to [19], the lyophilized preparation according to [25] or the liquid preparation according to [28] or [29] are used in the preparation Use in a delivery device or prefilled syringe or medicament for the treatment and/or prevention of cancer, immune diseases, cardiovascular diseases, metabolic diseases and neurological diseases in a subject.
  • the cancer includes breast cancer, lung cancer, prostate cancer, kidney cancer, leukemia, ovarian cancer, gastric cancer, uterine cancer, endometrial cancer, liver cancer, colon cancer Cancer, thyroid cancer, pancreatic cancer, colorectal cancer, esophageal cancer, testicular cancer, skin cancer, lymphoma, multiple myeloma;
  • the immune diseases include connective tissue disease, systemic sclerosis , rheumatoid arthritis and systemic lupus erythematosus;
  • the cardiovascular disease includes angina pectoris, myocardial infarction, stroke, heart attack, hypertensive heart disease, rheumatic heart disease, cardiomyopathy, One or more of cardiac arrhythmia and congenital heart disease;
  • said metabolic disease includes one or more of diabetes, gout, obesity, hypoglycemia, hyperglycemia, and dyslipidemia;
  • said neurological disease Includes one or more of Alzheimer's disease, Parkinson's disease, Huntington's disease
  • the present invention conducts pH screening on preparations containing ligand-drug conjugates, and limits the pH regulators and freeze-drying excipients used in them.
  • the drying process parameters finally achieve the effect that the properties, moisture content, impurity content, pH value, etc. of the preparation can be kept stable during storage.
  • Figure 1 is a DSC curve of a drug prescription solution containing CR19213.
  • the instruments, equipment, reagents, materials, etc. used in the present invention can be obtained through conventional commercial means.
  • references to "some specific/preferred implementations”, “other specific/preferred implementations”, “some specific/preferred technical solutions”, “other specific/preferred technical solutions”, etc. means that a particular element (eg, feature, structure, property, and/or characteristic) described in relation to that embodiment is included in at least one embodiment described herein, and may be present in other embodiments or may not present in other embodiments.
  • a particular element eg, feature, structure, property, and/or characteristic
  • numerical range represented by “numerical value A - numerical value B” or “numerical value A-numerical value B” means the range which includes numerical value A and B of an end point.
  • room temperature or "normal temperature” means an ambient temperature of about 25°C.
  • pharmaceutically acceptable means within the scope of reasonable medical judgment, it is suitable for use in contact with cells of humans and other animals without undue toxicity, irritation, allergic reactions, etc., and is in line with reasonable The benefit/risk ratios are proportionate.
  • pharmaceutically acceptable excipients refer to excipients and additives used in the production of medicines and prescriptions, such as pH regulators; Substances that are reasonably assessed and contained in pharmaceutical preparations.
  • pharmaceutical excipients In addition to shaping, adjusting pH, acting as a carrier, and improving stability, pharmaceutical excipients also have important functions such as solubilization, dissolution aid, and release regulation. They are important components that may affect the quality, safety, and effectiveness of drugs. .
  • “pharmaceutically acceptable salt” refers to relatively non-toxic, inorganic and organic acid addition salts and base addition salts of the conjugate compound of the present application.
  • Representative acid addition salts include hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, oxalate, valerate, oleate, palmitate, Stearate, Laurate, Borate, Benzoate, Lactate, Tosylate, Citrate, Maleate, Fumarate, Succinate, Tartrate, Naphthate salt, mesylate, glucoheptonate, lactobionate, sulfamate, malonate, salicylate, propionate, methylene-bis-b-hydroxynaphthoate, Gentisate, Isethionate, Di-p-toluoyl tartrate, Esylate, Benzenesulfonate, p-Toluenesulf
  • 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 that are sufficiently basic to form stable salts, and preferably include the following amines commonly used in medicinal chemistry because of their low toxicity and are acceptable for medical use: Ammonia, Ethanol Amine, N-Methylglucamine, Lysine, Arginine, Ornithine, Choline, N,N'-Dibenzylethylenediamine, Chloroprocaine, Diethanolamine, Procaine , N-benzylphenethylamine, diethylamine, piperazine, trishydroxymethylaminomethane, tetramethylammonium hydroxide, triethylamine, dibenzylamine, diphenylhydroxymethylamine, dehydroabietylamine, N -Ethylpiperidine, benzylamine, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, ethylamine, basic
  • ligand-drug conjugate or “ligand-drug conjugate” (LDC) is a chemical link that connects a biologically active drug to a ligand, and the ligand serves as a carrier to bind the small molecule Targeted delivery of drugs to target cells, where the ligand can be a polypeptide or a small molecule, and the drug with biological activity can be monomethyl auristatin E (MMAE).
  • MMAE monomethyl auristatin E
  • the ligand-drug conjugate is a double-ligand drug conjugate, preferably, the double-ligand drug conjugate is a drug conjugate targeting PSMA receptor and TRPV6 receptor.
  • the ligand-drug conjugate of the present invention is a double-ligand conjugate CR19213, the ligands target the PSMA receptor and the TRPV6 receptor respectively, and the drug is loaded with MMAE, and its structure is as follows:
  • the double ligand-drug conjugate has the following structure:
  • pH regulator is a reagent that can maintain the pH of the solution in an acceptable range, mainly acids, bases and salts with a buffering effect, such as commonly used hydrochloric acid, acetic acid, sodium hydroxide, dihydrogen phosphate Sodium, sodium acetate, etc.
  • the pH adjusting agents used in the formulations of the present invention can control the pH of the formulations of the present invention in the pH range of about 5.0 to 8.0.
  • formulations of the invention have a pH of about 5.0, 5.5, 6.0, 6.5, 7.0, 8.0.
  • polyol refers to a large class of alcohols containing two or more hydroxyl groups in the molecule, such as mannitol, inositol, ethylene glycol, polyethylene glycol, etc.
  • substitution refers to dissolving and/or suspending a solid preparation (such as a lyophilized preparation) in a physiologically acceptable solution.
  • lyophilized preparation refers to sterile solid for injection prepared by freeze-drying method.
  • freeze-drying excipient is also called freeze-drying protective agent, and refers to an additive added during the freeze-drying and storage of food, medicine and organisms. Stability and activity are maintained under the influence of freezing rate, freezing and dehydration stress, glass transition temperature, residual moisture in dry solid, temperature and humidity of storage environment, etc.).
  • the freeze-drying excipients can be polyols, sugars, amino acids, inorganic salts and proteins, such as mannitol, ethylene glycol, sucrose, sodium glutamate, sodium acetate, calcium carbonate and bovine serum albumin.
  • “stability” in “preparation stability” or “stable preparation” refers to basic properties such as moisture content, appearance, pH value, related substances, content, insoluble particles and reconstitution properties during product preparation and storage.
  • the preparation remains unchanged, does not change significantly or changes within a pharmaceutically acceptable range, and the quality of the preparation can be controlled within at least 24 months.
  • DSC differential scanning calorimetry
  • a thermal analysis method Under the program control temperature, measure the relationship between the power difference input to the sample and the reference object and the temperature.
  • the curve recorded by the differential scanning calorimeter is called the DSC curve. It takes the rate of heat absorption or heat release of the sample, that is, the heat flow rate as the ordinate, and the temperature T or time t as the abscissa, and can measure a variety of thermodynamics and kinetics. parameters, the method has a wide temperature range, high resolution, and less sample consumption. It is suitable for the analysis of inorganic substances, organic compounds and pharmaceuticals.
  • the present invention provides a pharmaceutical preparation, which may contain active drugs and optional pharmaceutically acceptable auxiliary materials.
  • the above pharmaceutical formulation may comprise a ligand-drug conjugate, a lyophilization excipient and a pH regulator.
  • the above-mentioned pharmaceutical preparation may comprise a ligand-drug conjugate, a lyophilization excipient, a pH regulator and a solvent.
  • the ligand-drug conjugate in the above pharmaceutical preparation may be a double ligand-drug conjugate targeting PSMA receptor and TRPV6 receptor.
  • the solvent in the above pharmaceutical formulation is water.
  • the solvent in the above pharmaceutical preparation is purified water.
  • the solvent in the above pharmaceutical preparation is sterile water, distilled water or deionized water.
  • the solvent in the above pharmaceutical preparation is sterile water for injection, single distilled water or double distilled water.
  • the active drug concentration in the above pharmaceutical preparation is 2mg/mL-8mg/mL, such as 2.0mg/mL, 2.2mg/mL, 2.4mg/mL, 2.6mg/mL, 2.8mg/mL, 3.0mg/mL, 3.2mg/mL, 3.4mg/mL, 3.6mg/mL, 3.8mg/mL, 4.0mg/mL, 4.2mg/mL, 4.4mg/mL, 4.6mg/mL, 4.8mg/mL, 5.0mg/mL, 5.2mg/mL, 5.4mg/mL, 5.6mg/mL, 5.8mg/mL, 6.0mg/mL, 6.2mg/mL, 6.4mg/mL, 6.6mg/mL, 6.8mg/mL, 7.0mg/mL, 7.2mg/mL, 7.4mg/mL, 7.6m
  • the pH adjuster in the above pharmaceutical formulation may comprise buffer salts.
  • the buffer salt contained in the pH regulator in the above pharmaceutical preparation may be selected from one or more of acetate, phosphate, citrate or hydrates thereof.
  • each molecule of the buffer salt hydrate in the above pharmaceutical preparation contains 0.5, 1, 1.5, 2.0, 2.5 or 3 molecules of water.
  • the pH regulator in the above pharmaceutical formulation may comprise sodium acetate.
  • the pH regulator in the above pharmaceutical preparation may comprise sodium dihydrogen phosphate.
  • the pH regulator in the above pharmaceutical formulation may comprise anhydrous sodium citrate.
  • the pH regulator in the above pharmaceutical formulation may comprise sodium citrate dihydrate.
  • the concentration of the buffer salt is 2.85 mg/mL ⁇ 11.4 mg/mL, such as 2.85mg/mL, 5.7mg/mL, 11.4mg/mL.
  • the pH adjuster in the above pharmaceutical formulation may comprise buffer salts and acidic substances and/or basic substances.
  • the buffer salt contained in the pH regulator in the above pharmaceutical preparation can be selected from one or more of acetate, phosphate, citrate or hydrate thereof;
  • the acidic substance can be selected from acid, such as hydrochloric acid One or more in , acetic acid or citric acid;
  • Alkaline substance can be selected from alkali or salt, for example one or more in sodium hydroxide, sodium carbonate or sodium bicarbonate.
  • the pH adjuster in the above pharmaceutical formulation may comprise sodium acetate and hydrochloric acid or sodium hydroxide.
  • the pH regulator in the above pharmaceutical preparation may comprise sodium dihydrogen phosphate and hydrochloric acid or sodium hydroxide.
  • the pH regulator in the above-mentioned pharmaceutical preparation may comprise anhydrous sodium citrate and hydrochloric acid or sodium hydroxide, and the concentration of the anhydrous sodium citrate is 2.85mg/mL ⁇ 11.4 mg/mL, such as 2.85mg/mL, 3.5mg/mL, 4.2mg/mL, 5.7mg/mL, 6.5mg/mL, 7.6mg/mL, 8.5mg/mL, 9.8mg/mL, 10.5mg/mL, 11.4 mg/mL.
  • the pH regulator in the above pharmaceutical preparation may comprise sodium citrate dihydrate and hydrochloric acid or sodium hydroxide, and the concentration of sodium citrate dihydrate is 2.85mg/mL ⁇ 11.4 mg/mL, such as 2.85mg/mL, 3.5mg/mL, 4.2mg/mL, 5.7mg/mL, 6.5mg/mL, 7.6mg/mL, 8.5mg/mL, 9.8mg/mL, 10.5mg/mL, 11.4 mg/mL.
  • the lyophilized excipients in the above pharmaceutical formulation may contain polyalcohols, such as one or more of mannitol and xylitol.
  • the lyophilized excipient in the above-mentioned pharmaceutical preparation comprises mannitol, preferably, the concentration of said mannitol is 20-150 mg/mL, such as 20 mg/mL, 30 mg/mL, 40 mg/mL. mL, 50mg/mL, 60mg/mL, 70mg/mL, 80mg/mL, 90mg/mL, 100mg/mL, 110mg/mL, 120mg/mL, 130mg/mL, 140mg/mL, 150mg/mL; more preferred concentrations are 40-60mg/mL.
  • the lyophilized excipients in the above-mentioned pharmaceutical preparations comprise polyols and saccharides, wherein the saccharides are one or more of monosaccharides, disaccharides, and polysaccharides, preferably, the saccharides are combined with
  • the mass ratio of the polyols 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, 1 :5;
  • the mass ratio of the saccharides to the polyols is 1:2 to 1:4.
  • the monosaccharide in the lyophilized excipient in the above pharmaceutical preparation includes one or more of glucose and fructose; the disaccharide includes one or more of sucrose, trehalose, and maltose; the polysaccharide includes cyclodextrose One or more of essence and dextran.
  • the lyophilized excipient in the above pharmaceutical preparation may contain mannitol and sucrose, preferably, the mass ratio of sucrose to mannitol is 1:4.
  • the pH value of the above-mentioned pharmaceutical preparation may be 5.0-8.0, such as 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, 8.0.
  • the pH value of the above pharmaceutical preparation may be 5.5-6.5, such as 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5.
  • the above-mentioned pharmaceutical preparation comprises a ligand-drug conjugate or a pharmaceutically acceptable salt thereof, a lyophilized excipient, a pH regulator and a solvent; wherein the pH of the pharmaceutical preparation is 5.0-8.0 .
  • each 1 mL of the above-mentioned pharmaceutical preparation comprises 5 mg of a double ligand-drug conjugate or a pharmaceutically acceptable salt thereof, 50 mg of mannitol, 5.7 mg of sodium citrate dihydrate, and optional acidic substances or alkaline substances and the rest of water; wherein the pH of the pharmaceutical preparation is 5.0-8.0.
  • every 1 mL of the above pharmaceutical preparation contains 5 mg of double ligand-drug conjugate or a pharmaceutically acceptable salt thereof, 40 mg of mannitol, 10 mg of sucrose, 4.5 mg of anhydrous sodium citrate and any Selected acidic substance or alkaline substance and the balance of water; wherein the pH of the pharmaceutical preparation is 5.0-8.0.
  • each 1 mL of the pharmaceutical preparation comprises 4 mg of the double ligand-drug conjugate or a pharmaceutically acceptable salt thereof, 50 mg of mannitol, an appropriate amount of sodium acetate, and an optional acidic substance or base sexual substances and the balance of water; wherein the pH of the pharmaceutical preparation is 5.0-8.0.
  • each 1 mL of the pharmaceutical preparation comprises 6 mg of a double ligand-drug conjugate or a pharmaceutically acceptable salt thereof, 50 mg of mannitol, an appropriate amount of sodium dihydrogen phosphate, and an optional acidic substance or alkaline substances and the remainder of water; wherein the pH of the pharmaceutical preparation is 5.0-8.0.
  • the pharmaceutical formulation described above is sterile.
  • the pharmaceutical formulation described above is stable when frozen and thawed.
  • the preparation method of the above-mentioned pharmaceutical preparation comprises the following steps: taking the prescribed amount of the active drug and optional pharmaceutically acceptable adjuvants, mixing them uniformly, and obtaining the preparation.
  • the preparation method of the above-mentioned pharmaceutical preparation comprises the steps of: taking the ligand-drug conjugate or its pharmaceutically acceptable salt, freeze-drying excipient, pH regulator and solvent in the prescribed amount , dissolve each component in the solvent at one time, mix well, and obtain; preferably, when dissolving the components in the solvent, the pH regulator is simultaneously or preferentially used in the ligand-drug conjugate or its pharmaceutically acceptable The salt is dissolved in the solvent.
  • the preparation method of the above-mentioned pharmaceutical preparation comprises the steps of: taking the ligand-drug conjugate or its pharmaceutically acceptable salt, freeze-drying excipient, pH regulator and solvent in the prescribed amount , dissolve each component in batches in a solvent, mix well, and obtain; The accepted salt is dissolved in a solvent.
  • the preparation method of the above-mentioned pharmaceutical preparation comprises the steps of: taking a prescribed amount of ligand-drug conjugate or a pharmaceutically acceptable salt thereof, a freeze-drying excipient, a pH regulator, and Solvent, dissolve each component in the solvent at one time, adjust the pH value to 5.0-8.0 with the acidic substance or basic substance in the pH regulator, mix well, and get it; preferably, when dissolving the components in the solvent, The pH adjuster is dissolved in the solvent simultaneously or preferentially to the ligand-drug conjugate or a pharmaceutically acceptable salt thereof.
  • the preparation method of the above-mentioned pharmaceutical preparation comprises the steps of: taking a prescribed amount of ligand-drug conjugate or a pharmaceutically acceptable salt thereof, a freeze-drying excipient, a pH regulator, and Solvent, dissolve each component in batches in the solvent, adjust the pH value to 5.0-8.0 with the acidic substance or basic substance in the pH regulator, mix well, and obtain; preferably, when dissolving the components in the solvent , dissolving the pH regulator in the solvent simultaneously or preferentially to the ligand-drug conjugate or a pharmaceutically acceptable salt thereof.
  • the preparation method of the above-mentioned pharmaceutical preparation is carried out under the condition of not protecting from light.
  • the preparation method of the above-mentioned pharmaceutical preparation is carried out under the condition of avoiding light.
  • the above-mentioned preparation method of the pharmaceutical preparation is carried out at a temperature of 15°C to 40°C, such as 15°C, 20°C, 25°C, 30°C, 35°C, 40°C.
  • the preparation method of the above-mentioned pharmaceutical preparation is carried out under the condition of nitrogen protection.
  • the preparation method of the above-mentioned pharmaceutical preparation is not carried out under the condition of nitrogen protection.
  • the preparation method of the above-mentioned pharmaceutical preparation is carried out under the condition of avoiding light, at a temperature of 15° C. to 40° C. and without nitrogen protection.
  • the invention provides a freeze-dried preparation, which is prepared by freeze-drying the pharmaceutical preparation of the invention.
  • the present invention also provides a preparation method of the above-mentioned freeze-dried preparation, which includes the following steps: freeze-dry the pharmaceutical preparation of the present invention, and obtain it.
  • the freeze-drying comprises the following steps: freezing the pharmaceutical preparation at -45°C; drying the pharmaceutical preparation once at -15°C to -5°C; The pharmaceutical preparation is subjected to secondary drying at 15° C. to 25° C.
  • the freeze-drying comprises the following steps: freezing the pharmaceutical preparation at -45°C; drying the pharmaceutical preparation once at -5°C; The pharmaceutical preparation is subjected to secondary drying.
  • the freeze-drying comprises the following steps: freezing the pharmaceutical preparation at -45°C; drying the pharmaceutical preparation once at -10°C; The pharmaceutical preparation is subjected to secondary drying at °C.
  • the freeze-drying comprises the following steps: freezing the pharmaceutical preparation at -45°C; drying the pharmaceutical preparation once at -15°C; The pharmaceutical preparation is subjected to secondary drying at °C.
  • the freeze-drying comprises the following steps: freezing the pharmaceutical preparation at -45°C for 120 minutes; drying the pharmaceutical preparation once at -15°C for 720 minutes; The pharmaceutical preparation was subjected to secondary drying at 25° C. for 720 min.
  • the lyophilized formulation described above is stable at room temperature.
  • the present invention provides a liquid preparation, which is prepared by reconstituting the freeze-dried preparation of the present invention with water.
  • the present invention also provides a method for preparing the above-mentioned liquid preparation, which includes the following steps: mixing the freeze-dried preparation of the present invention with water to obtain the finished product.
  • the reconstitution is accomplished with distilled water, pure water or sterile water.
  • the pH of the lyophilized formulation after reconstitution with water is 5.0-8.0.
  • the present invention provides a drug-containing delivery device, which contains one of the above-mentioned pharmaceutical preparation, the above-mentioned freeze-dried preparation or the above-mentioned liquid preparation.
  • the present invention also provides a prefilled syringe, which contains one of the above-mentioned pharmaceutical preparation, the above-mentioned freeze-dried preparation or the above-mentioned liquid preparation.
  • the present invention provides the use of the above-mentioned pharmaceutical formulation, the above-mentioned lyophilized formulation or the above-mentioned liquid formulation comprising an active drug in the manufacture of a delivery device or a pre-filled syringe or a medicament.
  • the delivery device or prefilled syringe or medicament for use above is used to enhance immune effector cell responses in a subject.
  • the delivery device or prefilled syringe or medicament for use above is for reducing immunosuppression in a subject.
  • the delivery device or prefilled syringe or medicament for use above is for treating and/or preventing cancer in a subject.
  • cancers mentioned above include 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, One or more of esophageal cancer, testicular cancer, skin cancer, lymphoma, multiple myeloma.
  • the delivery device or prefilled syringe or medicament for use above is for treating and/or preventing an immune disease in a subject.
  • the immune disease in the above use includes one or more of connective tissue disease, systemic sclerosis, rheumatoid arthritis and systemic lupus erythematosus.
  • the delivery device or prefilled syringe or medicament for use above is for treating and/or preventing cardiovascular disease in a subject.
  • cardiovascular diseases in the above use include one or more of angina pectoris, myocardial infarction, stroke, heart attack, hypertensive heart disease, rheumatic heart disease, cardiomyopathy, cardiac arrhythmia and congenital heart disease kind.
  • the delivery device or the prefilled syringe or the medicament for use above is for treating and/or preventing a metabolic disease in a subject.
  • the metabolic diseases in the above use include one or more of diabetes, gout, obesity, hypoglycemia, hyperglycemia and dyslipidemia.
  • the delivery device or prefilled syringe or medicament for use above is for treating and/or preventing a neurological disorder in a subject.
  • the neurological diseases in the above use include one or more of Alzheimer's disease, Parkinson's disease, Huntington's disease, head injury, multiple sclerosis, vertigo, coma and epilepsy.
  • CR19213 has poor solubility in water and is unstable to acid and alkali. Therefore, appropriate pH regulators should be added to the drug prescription containing CR19213 to ensure the preparation and stability of the product.
  • Injection-grade pH regulators are mainly buffer salts. Commonly used Tris, acetate, citrate and phosphate are selected, and the tentative concentration is 0.5%. Since CR19213 is sensitive to both acid and alkali, the pH of the buffer salt solution is temporarily It is set at 7.0 (adjusted with 1M hydrochloric acid or sodium hydroxide); the lyophilized excipient is tentatively set at 5% mannitol which is commonly used.
  • Table 1 The composition of prescriptions for screening pH regulators
  • stage Layer temperature (°C) Heating time (min) Hold time (min) Pressure control (mbar) pre-freeze -45 50 120 / pre-vacuum / / / 0.2 once dry -15 150 780 0.2 secondary drying 25 200 720 /
  • prescription 1 (pH7.0 0.5% Tris solution) CR19213 could not be dissolved, and other prescriptions could be dissolved.
  • high temperature 40°C
  • strong light 4500lx, near ultraviolet light 85 ⁇ w/cm 2
  • prescription 3 has the lowest impurity level, so sodium citrate is preferred as the pH regulator.
  • the pH value is of particular importance to drug stability. Therefore, in the process of preparing injection intermediates, the pH value must be controlled to ensure stable quality of the injection during freeze-drying and storage.
  • Prescription 13 Prescription 14
  • Prescription 15 Prescription 16
  • Prescription 17 Prescription 18
  • Prescription 19 CR19213 10.0mg 10.0mg 10.0mg 10.0mg 10.0mg 10.0mg 10.0mg sodium citrate 11.4mg 11.4mg 11.4mg 11.4mg 11.4mg 11.4mg 11.4mg 11.4mg Mannitol 100mg 100mg 100mg 100mg 100mg 100mg 100mg 100mg 100mg 100mg 100mg 100mg hydrochloric acid/sodium hydroxide Appropriate amount Appropriate amount Appropriate amount Appropriate amount Appropriate amount Appropriate amount Appropriate amount Appropriate amount Appropriate amount Appropriate amount Appropriate amount Appropriate amount Appropriate amount Appropriate amount Appropriate amount Appropriate amount Appropriate amount Appropriate amount Appropriate amount Appropriate amount Appropriate amount Appropri
  • formulation 13 precipitated insoluble matter during the preparation process.
  • the sample quality of the remaining formulations (intermediate pH 5.0-8.0) is equivalent, and the product quality has no significant change after 10 days at 40°C for 10 days. Since the pH value is about 6.0 (without adjusting by acid or alkali) after the addition of raw and auxiliary materials, the product quality under this acidity is stable. Therefore, the acidity target value of the intermediate is determined to be pH 6.0, and the acceptable range is 5.5-6.5.
  • the solubility of CR19213 is related to the pH value of the solution.
  • the amount of pH regulator reflected as the concentration of buffer salt directly affects the pH value of the solution. Therefore, the concentration of buffer salt needs to be screened. Because CR19213 is added to sodium citrate solution with pH 7.0, it becomes acidic after being completely dissolved. In order to make the finished product closer to neutrality, prepare 1.0% sodium citrate solution (11.4mg/mL) at pH 7.5 (adjusted by citric acid), and dilute with water to obtain concentrations of 0.1%, 0.25% and 0.5% Sodium citrate solution. The above-mentioned sodium citrate solutions with different concentrations were used to prepare intermediate solutions, and the dissolution conditions during the preparation of the intermediate solutions were investigated.
  • the pH value of the 0.5% sodium citrate solution was 8.42, and the pH value after adding mannitol and CR19213 for dissolution was 5.95. Since the bulk drug is acidic, in order to make the finished product closer to neutral, the pH value can be pre-adjusted without citric acid.
  • Prescription 9 Prescription 10
  • Prescription 11 Prescription 12
  • CR19213 10.0mg 10.0mg 10.0mg 10.0mg Sodium citrate (dihydrate) 11.4mg 11.4mg 11.4mg 11.4mg Mannitol 100mg 80mg / / sucrose / 20mg / / lactose / / 100mg / Sorbitol / / / 100mg hydrochloric acid/sodium hydroxide
  • Appropriate amount Appropriate amount
  • Appropriate amount Appropriate amount
  • Appropriate amount Appropriate amount
  • Appropriate amount Appropriate amount
  • Appropriate amount Appropriate amount
  • Appropriate amount Appropriate amount
  • Appropriate amount Appropriate amount
  • Appropriate amount Appropriate amount water for injection to 2mL 2mL 2mL 2mL
  • the formulation determined by the study was selected for process inspection to obtain a stable lyophilized preparation for injection.
  • the quality attributes of intermediates output by the feeding process are content, acidity, properties and related substances.
  • the dosing environment includes the oxygen content of the solution, the light environment to which the dosing solution is exposed, and the dosing temperature and time.
  • CR19213 is sensitive to 1% H 2 O 2 , and the solution state is easily oxidized. Therefore, it is necessary to investigate whether the product needs nitrogen protection during the preparation process to reduce the oxygen content.
  • the intermediate solutions were prepared by nitrogen protection process and non-nitrogen protection process respectively, and placed for 24 hours to investigate the stability of the intermediate solution. Mainly investigate whether there are significant differences in the properties, content, pH, and related substances of the intermediate solution.
  • the CR19213 raw material is sensitive to light. Considering that it will be exposed to indoor light during the actual dosing process, in order to investigate the influence of light during the preparation process, an experiment was designed to investigate the influence of indoor light on product stability during the dosing process.
  • CR19213 is sensitive to temperature.
  • the prepared intermediate solution was kept at 15°C, 25°C and 40°C respectively, and samples were taken at 0 hour, 8 hours, 20 hours and 24 hours. . Investigate the influence of temperature on the properties, pH, content and related substances of the intermediate solution.
  • the freeze-drying process parameters mainly inspect the primary drying and secondary drying temperatures.
  • the primary drying temperature is -15°C, -10°C, -5°C, respectively
  • the secondary drying temperature is 25°C, 15°C, 15°C, and the samples are prepared and the properties, acidity, moisture, reconstitution time, and Soluble properties, content and related substances.
  • Process 12 has relatively less moisture, and process 12 is selected as the freeze-drying parameter of CR19213 for injection.
  • stage Layer temperature (°C) Heating time (min) Hold time (min) Pressure control (mbar) pre-freeze -45 50 120 / once dry -15 150 720 0.2 secondary drying 25 200 720 /

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Abstract

生物医药领域的偶联体药物制剂及其制备方法和用途。该制剂中含有配体-药物偶联体、pH调节剂和冻干赋形剂。通过对上述包含配体-药物偶联体的制剂进行pH筛选，并限定其所使用的pH调节剂和冻干赋形剂，同时考察药物制备时的投药顺序和配液环境，并筛选冻干工艺参数，最终达到了使该制剂在储存期间性状、水分含量、杂质含量、pH值等均可以保持稳定的效果。

Description

偶联体药物制剂及其制备方法和用途
优先权和相关申请
本申请要求于2021年10月19日提交中国专利局、申请号为202111215700.9、发明名称为“偶联体药物制剂及其制备方法和用途”的中国专利申请的优先权，其全部内容通过引用结合在本申请中。
技术领域
本发明涉及生物医药领域，具体而言，本发明涉及一种偶联体药物制剂，具体为包含配体-药物偶联体的药物制剂，及其制备方法和用途。
背景技术
近年来，尽管肿瘤化疗取得了相当大的进步，但对危害人类生命健康最严重的，占恶性肿瘤90％以上的实体瘤的治疗未能达到满意的效果。行业内的药学家和肿瘤学家越来越深刻地意识到：要提高肿瘤治疗的疗效，必须从肿瘤发生发展的机制着手，才能取得突破性进展。
有关肿瘤发生发展的分子机制的研究表明，在肿瘤细胞中，细胞内的各种基本过程存在调节失控。因此研究者将注意力转向了癌症病理过程中起作用的特异的分子及生物靶点。在肿瘤细胞和发生病变的细胞表面存在着多种特异性或过表达受体。这些受体的配体可分为蛋白类，多肽类和小分子类。这些配体与受体结合具有特异性好、亲和力适中和生物效应明显的特性，与治疗性药物偶联形成配体-药物偶联体(LDC)可以明显提高药物的靶向性和药效，同时降低毒性。
配体-药物偶联体具有细胞内吞介导功能，其可以实现靶向和内吞结构的结合，利用双靶向配体增强药物偶联体对病变细胞的亲和性和靶向性，从而可以携带高效的毒素药物如一甲基澳瑞他汀E(MMAE)，连接子使偶联体在细胞外部(胞间质、血液循环系统等)无法释放药物分子，保证了药物在体内循环时的稳定性，并降低药物毒性，不会对正常细胞产生毒害作用。进入靶向细胞内部后，连接子裂解释放出具有治疗作用的药物分子，可避免产生多药耐药性(MDR)。
LDC制剂需要保证其在制备过程中、长期储存过程中以及后续使用期间维持良好的稳定性。LDC在制剂中的稳定性取决于制剂中所使用的pH调节剂、稳定剂和表面活性剂等。如果LDC没有适当地在液体中得以调配，则液体溶液中的LDC倾向于分解、聚集或发生不希望的化学修饰等。在本领域中对于含有足够稳定且适于施用给受试者的LDC的新颖药物制剂存在需要，因此，需要制备合适的LDC制剂，用来治疗或预防疾病。
发明内容
发明要解决的问题
针对上述本领域中对于稳定且适于施用给受试者的LDC新颖药物制剂的需求，本发明拟提供一种偶联体药物制剂，具体为包含配体-药物偶联体的药物制剂，及其制备方法和用途。通过限定pH值、pH调节剂种类及用量、冻干赋形剂、药物制备时的投药顺序和配液环境以及冻干工艺的参数，来满足其在储存期间保持良好稳定性的需求。
用于解决问题的方案
[1].一种药物制剂，其包含活性药物及任选的药学上可接受的辅料。
[2].根据[1]所述的药物制剂，其特征在于，所述活性药物包含配体-药物偶联体或其药物上可接受的盐；所述药学上可接受的辅料包含冻干赋形剂和pH调节剂中的一种或多种。
[3].根据[1]或[2]所述的药物制剂，其特征在于，所述活性药物包含配体-药物偶联体或其药物上可接受的盐；所述药学上可接受的辅料包含冻干赋形剂、pH调节剂和溶剂中的一种或多种。
[4].根据[3]所述的药物制剂，其特征在于，所述溶剂为水；优选地，所述溶剂为纯化水；更优选地，所述纯化水为无菌水、蒸馏水或去离子水；更优选地，所述无菌水为无菌注射用水、单蒸水或双蒸水。
[5].根据[3]所述的药物制剂，其特征在于，所述活性药物的浓度为2mg/mL-8mg/mL，例如2.0mg/mL、2.2mg/mL、2.4mg/mL、2.6mg/mL、2.8mg/mL、3.0mg/mL、3.2mg/mL、3.4mg/mL、3.6mg/mL、3.8mg/mL、4.0mg/mL、4.2mg/mL、4.4mg/mL、4.6mg/mL、4.8mg/mL、5.0mg/mL、5.2mg/mL、5.4mg/mL、5.6mg/mL、5.8mg/mL、6.0mg/mL、6.2mg/mL、6.4mg/mL、6.6mg/mL、6.8mg/mL、7.0mg/mL、7.2mg/mL、7.4mg/mL、7.6mg/mL、7.8mg/mL、8.0mg/mL。
[6].根据[2]或[3]所述的药物制剂，其特征在于，所述pH调节剂包含缓冲盐。
[7].根据[6]所述的药物制剂，其特征在于，所述pH调节剂还包含酸性物质和/或碱性物质。
[8].根据[6]所述的药物制剂，其特征在于，所述缓冲盐包含醋酸盐、磷酸盐、枸橼酸盐或其水合物中的一种或多种；优选地，每1分子所述水合物包含0.5、1、1.5、2.0、2.5或3分子水；优选地，所述缓冲盐为醋酸钠、无水枸橼酸钠、二水合枸橼酸钠或磷酸二氢钠中的一种或多种。
[9].根据[7]所述的药物制剂，其特征在于，所述酸性物质包含酸；优选地，所述酸性物质为盐酸、醋酸或枸橼酸中的一种或多种；所述碱性物质包含碱或盐；优选地，所述碱性物质为氢氧化钠、碳酸钠或碳酸氢钠中的一种或多种。
[10].根据[6]至[9]中任一项所述的药物制剂，其特征在于，当所述缓冲盐选自无水枸缘酸钠或二水合枸橼酸钠时，所述缓冲盐的浓度为2.85mg/mL～11.4mg/mL，例如2.85mg/mL、3.5mg/mL、4.2mg/mL、5.7mg/mL、6.5mg/mL、7.6mg/mL、8.5mg/mL、9.8mg/mL、10.5mg/mL、11.4mg/mL。
[11].根据[2]或[3]所述的药物制剂，其特征在于，所述冻干赋形剂包含多元醇，例如甘露醇、木糖醇中的一种或多种；优选地，所述冻干赋形剂为甘露醇，优选浓度为20mg/mL-150mg/mL，例如20mg/mL、30mg/mL、40mg/mL、50mg/mL、60mg/mL、70mg/mL、80mg/mL、90mg/mL、100mg/mL、110mg/mL、120mg/mL、130mg/mL、140mg/mL、150mg/mL；更优选浓度为40-60mg/mL。
[12].根据[11]所述的药物制剂，其特征在于，所述冻干赋形剂还包含糖类，例如单糖、二糖、多糖中的一种或多种；优选地，所述糖类与所述多元醇的质量比为1:1～1:5，例如1:1、1:1.5、1:2、1:2.5、1:3、1:3.5、1:4、1:4.5、1:5；更优选地，所述糖类与所述多元醇的质量比为1:2～1:4。
[13].根据[12]所述的药物制剂，其特征在于，所述单糖包含葡萄糖、果糖中的一种或多种；所述二糖包含蔗糖、海藻糖、麦芽糖中的一种或多种；所述多糖包含环糊精、右旋糖酐中的一种或多种。
[14].根据[11]至[13]中任一项所述的药物制剂，其特征在于，所述冻干赋形剂为甘露醇和蔗糖；优选地，所述蔗糖与甘露醇的质量比为1:4。
[15].根据[3]至[14]中任一项所述的药物制剂，其特征在于，所述药物制剂的pH值为5.0～8.0；例如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、8.0。
[16].根据[1]所述的药物制剂，其特征在于，所述药物制剂包含配体-药物偶联体或其药物上可接受的盐、冻干赋形剂、pH调节剂和溶剂；其中所述药物制剂的pH为5.0～8.0；优选地，每1mL所述药物制剂包含5mg双配体-药物偶联体或其药物上可接受的盐、50mg甘露醇、5.7mg二水合枸橼酸钠和任选的酸性物质或碱性物质以及余量的水；其中所述药物制剂的pH为5.0～8.0；优选地，每1mL所述药物制剂包含5mg双配体-药物偶联体或其药物上可接受的盐、40mg甘露醇、10mg蔗糖、4.5mg无水枸橼酸钠和任选的酸性物质或碱性物质以及余量的水；其中所述药物制剂的pH为5.0～8.0；优选地，每1mL所述药物制剂包含4mg双配体-药物偶联体或其药物上可接受的盐、50mg甘露醇、适量的醋酸钠和任选的酸性物质或碱性物质以及余量的水；其中所述药物制剂的pH为5.0～8.0；优选地，每1mL所述药物制剂包含6mg双配体-药物偶联体或其药物上可接受的盐、50mg甘露醇、适量的磷酸二氢钠和任选的酸性物质或碱性物质以及余量的水；其中所述药物制剂的pH为5.0～8.0。
[17].根据[2]至[16]中任一项所述的药物制剂，其特征在于，所述配体-药物偶联体为双配体-药物偶联体；优选地，所述双配体-药物偶联体为靶向PSMA受体和TRPV6受体的药物偶联体；优选地，所述双配体-药物偶联体具有如下结构：
Figure PCTCN2022125935-appb-000001
更优选地，所述双配体-药物偶联体具有如下结构：
Figure PCTCN2022125935-appb-000002
[18].根据[1]至[17]中任一项所述的药物制剂，其特征在于，所述药物制剂是无菌的。
[19].根据[1]至[17]中任一项所述的药物制剂，其特征在于，所述药物制剂在冷冻和解冻时是稳定的。
[20].根据[1]至[19]中任一项所述的药物制剂的制备方法，其包括如下步骤：取处方量的活性药物及任选的药学上可接受的辅料，混匀，即得。
[21].根据[20]所述的制备方法，其特征在于，其包括如下步骤：取处方量的配体-药物偶联体或其药物上可接受的盐、冻干赋形剂、pH调节剂和溶剂，在溶剂中一次性或分批地溶解各组分，任选地利用pH调节剂中的酸性物质或碱性物质调节pH值至5.0～8.0，混匀，即得；优选地，在溶剂中溶解各组分时，将pH调节剂同时或者优先于配体-药物偶联体或其药物上可接受的盐溶于溶剂中。
[22].根据[20]或[21]所述的制备方法，其特征在于，所述制备方法任选地在避光的条件下进行；优选地，所述制备方法在避光的条件下进行。
[23].根据[20]至[22]中任一项所述的制备方法，其特征在于，所述制备方法在温度为15℃～40℃的条件下进行。
[24].根据[20]至[23]中任一项所述的制备方法，其特征在于，所述制备方法任选地在氮气保护的条件下进行；优选地，所述制备方法不在氮气保护的条件下进行。
[25].一种冻干制剂，其特征在于，所述冻干制剂通过将根据[1]至[19]中任一项所述的药物制剂冻干来制备。
[26].根据[25]所述的冻干制剂的制备方法，其包括如下步骤：(i)-45℃对所述药物制剂进行冷冻；(ii)在-15℃～-5℃对所述药物制剂进行一次干燥；(iii)在15℃～25℃对所述药物制剂进行二次干燥；例如，所述一次干燥的温度为-15℃、-10℃或-5℃；所述二次干燥的温度为15℃或25℃；优选地，所述制备方法包括如下步骤：(i)-45℃对所述药物制剂进行冷冻；(ii)在-15℃对所述药物制剂进行一次干燥；(iii)在25℃对所述药物制剂进行二次干燥。
[27].根据[25]所述的冻干制剂，其特征在于，所述冻干制剂在室温条件下是稳定的。
[28].一种液体制剂，其由根据[25]所述的冻干制剂用水重构而成。
[29].根据[28]所述的液体制剂，其特征在于，所述水包括蒸馏水、纯水、无菌水中的一种或多种；优选地，所述冻干制剂用水重构后的pH为5.0～8.0。
[30].根据[28]或[29]所述的液体制剂的制备方法，其包括如下步骤：将所述冻干制剂与无菌水混 合，即得。
[31].一种含药递送装置，其包含下列制剂中的一种：根据[1]至[19]中任一项所述的药物制剂、根据[25]所述的冻干制剂或者根据[28]或[29]所述的液体制剂。
[32].一种预填装注射器，其包含下列制剂中的一种：根据[1]至[19]中任一项所述的药物制剂、根据[25]所述的冻干制剂或者根据[28]或[29]所述的液体制剂，优选用于静脉内注射或者肌内注射。
[33].根据[1]至[19]中任一项所述的药物制剂、根据[25]所述的冻干制剂或者根据[28]或[29]所述的液体制剂在制备用于在受试者中增强免疫效应细胞反应和/或减少免疫抑制的递送装置或预填装注射器或药物中的用途。
[34].根据[1]至[19]中任一项所述的药物制剂、根据[25]所述的冻干制剂或者根据[28]或[29]所述的液体制剂在制备用于在受试者中治疗和/或预防癌症、免疫性疾病、心血管疾病、代谢疾病和神经疾病的递送装置或预填装注射器或药物中的用途。
[35].根据[34]所述的用途，其特征在于，所述癌症包括乳腺癌、肺癌、前列腺癌、肾癌、白血病、卵巢癌、胃癌、子宫癌、子宫内膜癌、肝癌、结肠癌、甲状腺癌、胰腺癌、结直肠癌、食道癌、睾丸癌、皮肤癌、淋巴瘤、多发性骨髓瘤中的一种或多种；所述免疫性疾病包括结缔组织病、系统性硬化症、类风湿性关节炎和系统性红斑狼疮中的一种或多种；所述心血管疾病包括心绞痛、心肌梗死、中风、心脏病发作、高血压性心脏病、风湿性心脏病、心肌病、心脏心律失常和先天性心脏病中的一种或多种；所述代谢疾病包括糖尿病、痛风、肥胖症、低血糖症、高血糖症和血脂异常中的一种或多种；所述神经疾病包括阿尔茨海默病、帕金森病、亨廷顿病、头部损伤、多发性硬化症、眩晕、昏迷和癫痫中的一种或多种。
发明的效果
本发明通过对包含配体-药物偶联体的制剂进行pH筛选，并限定其所使用的pH调节剂和冻干赋形剂，同时考察药物制备时的投药顺序和配液环境，并筛选冻干工艺参数，最终达到了使该制剂在储存期间性状、水分含量、杂质含量、pH值等均可以保持稳定的效果。
附图说明
图1为含有CR19213的药物处方溶液的DSC曲线图。
具体实施方式
以下对本发明的实施方式进行说明，但本发明不限定于此。本发明不限于以下说明的各构成，在发明请求保护的范围内可以进行各种变更，而适当组合不同实施方式、实施例中各自公开的技术手段而得到的实施方式、实施例也包含在本发明的技术范围中。另外，本说明书中记载的文献全部作为参考文献在本说明书中进行援引。
除非另有说明，本发明中使用的仪器设备、试剂、材料等均可通过常规商业手段获得。
除非另有定义，本发明所用的技术和科学术语具有与本发明所属技术领域中的普通技术人员所通常理解的相同含义。
本说明书中，所提及的“一些具体/优选的实施方式”、“另一些具体/优选的实施方式”、“一些具体/优选的技术方案”、“另一些具体/优选的技术方案”等是指所描述的与该实施方式有关的特定要素(例如，特征、结构、性质和/或特性)包括在此处所述的至少一种实施方式中，并且可存在于其它实施方式中或者可不存在于其它实施方式中。另外，应理解，所述要素可以任何合适的方式组合在各种实施方式中。
本说明书中，使用“数值A～数值B”或“数值A-数值B”表示的数值范围是指包含端点数值A、B的范围。
本说明书中，出现“％”时，表示质量或重量百分含量，即“质量％”或“重量％”，除非有其他特殊说明。
本说明书中，使用“可以”表示的含义包括了进行某种处理以及不进行某种处理两方面的含义。 本说明书中，“任选的”或“任选地”是指接下来描述的事件或情况可发生或可不发生，并且该描述包括该事件发生的情况和该事件不发生的情况。
本说明书中，“室温”或“常温”表示约25℃的环境温度。
本发明的说明书和权利要求书及上述附图中的术语“包括”以及它们任何变形，意图在于覆盖不排他的包含。
本发明中，“药学上可接受的”指的是在合理的医学判断范围内，其适用于与人和其他动物的细胞接触而没有不适当的毒性、刺激性、过敏反应等，并且与合理的效益/风险比是相称的。
本发明中，“药学上可接受的辅料”是指生产药品和调配处方时使用的赋形剂和附加剂，例如pH调节剂；是除活性成分或前体以外，在安全性方面已进行了合理的评估，且包含在药物制剂中的物质。药用辅料除了赋形、调节pH值、充当载体、提高稳定性外，还具有增溶、助溶、调控释放等重要功能，是可能会影响到药品的质量、安全性和有效性的重要成分。
本发明中，“药物上可接受的盐”指的是本申请的偶联体化合物的相对无毒性的、无机和有机酸加成盐和碱加成盐。代表性的酸加成盐包括氢溴酸盐、盐酸盐、硫酸盐、硫酸氢盐、磷酸盐、硝酸盐、乙酸盐、草酸盐、戊酸盐、油酸盐、棕榈酸盐、硬脂酸盐、月桂酸盐、硼酸盐、苯甲酸盐、乳酸盐、甲苯磺酸盐、柠檬酸盐、马来酸盐、富马酸盐、琥珀酸盐、酒石酸盐、萘酸盐、甲磺酸盐、葡庚糖酸盐、乳糖酸盐、氨基磺酸盐、丙二酸盐、水杨酸盐、丙酸盐、亚甲基-双-b-羟基萘甲酸盐、龙胆酸盐、羟乙基磺酸盐、二对甲苯甲酰基酒石酸盐、乙磺酸盐、苯磺酸盐、对甲苯磺酸盐、环己基氨基磺酸盐和奎尼酸月桂基磺酸盐等。碱加成盐包括药学上可接受的金属和胺盐。适宜的金属盐包括钠、钾、钙、钡、锌、镁和铝盐。在一些实施方式中，钠盐和钾盐是优选的。适宜的无机碱加成盐由金属碱制备，所述金属碱包括例如氢化钠、氢氧化钠、氢氧化钾、氢氧化钙、氢氧化铝、氢氧化锂、氢氧化镁和氢氧化锌。适宜的胺碱加成盐由具有足够碱性的胺制备，以形成稳定的盐，并且优选包括以下常用于药物化学的胺，因为其毒性较低并且是医疗用途可接受的：氨、乙二胺、N-甲基葡糖胺、赖氨酸、精氨酸、鸟氨酸、胆碱、N,N'-二苄基乙二胺、氯普鲁卡因、二乙醇胺、普鲁卡因、N-苄基苯乙胺、二乙胺、哌嗪、三羟甲基氨基甲烷、四甲基氢氧化铵、三乙胺、二苄胺、二苯羟甲胺、脱氢枞胺、N-乙基哌啶、苄胺、四甲基铵、四乙基铵、甲胺、二甲胺、三甲胺、乙胺、碱性氨基酸(例如，赖氨酸和精氨酸)以及二环己胺等。
本发明中，“配体-药物偶联体”或“配体-药物偶联物”(LDC)是通过一个化学链接将具有生物活性的药物连接到配体上，配体作为载体将小分子药物靶向运输到目标细胞中，其中配体可以是多肽或小分子，具有生物活性的药物可以是一甲基澳瑞他汀E(Monomethyl auristatin E,MMAE)。优选地，所述配体-药物偶联体为双配体药物偶联体，优选地，所述双配体药物偶联体为靶向PSMA受体和TRPV6受体的药物偶联体。更优选地，本发明的配体-药物偶联体为双配体偶联物CR19213，配体分别靶向PSMA受体和TRPV6受体，载药为MMAE，其结构如下所示：
Figure PCTCN2022125935-appb-000003
进一步优选地，所述双配体-药物偶联体具有如下结构：
Figure PCTCN2022125935-appb-000004
本发明中，“pH调节剂”是可以将溶液的pH维持在可接受范围的试剂，主要为酸、碱以及具有缓冲作用的盐类，例如常用的盐酸、醋酸、氢氧化钠、磷酸二氢钠、醋酸钠等。在一些实施方案中，用于本发明制剂中的pH调节剂可以将本发明制剂的pH控制在大约5.0～8.0的pH范围。在一些具体的实施方案中，本发明的制剂具有约5.0、5.5、6.0、6.5、7.0、8.0的pH。
本发明中，“多元醇”是指分子中含有二个或二个以上羟基的一大类醇类，例如可以是甘露醇、肌醇、乙二醇、聚乙二醇等。
本发明中，“重构”是指将固体制剂(例如冻干制剂)溶解和/或悬浮于生理可接受的溶液中。
本发明中，“约”是指所限定的数值为大概的，在相关数据中某特定数值不需要非常精确。
本发明中，“冻干制剂”是指用冷冻干燥法制得的注射用无菌固体。
本发明中，“冻干赋形剂”又称冻干保护剂，是指在食品、药品以及生物体的冷冻干燥和储藏过程中添加的添加剂，目的为了使产品在很多因素(如化学成分、冻结速率、冻结和脱水应力、玻璃化转变温度、干燥固体中剩余水分、储藏环境的温度和湿度等)的影响下依然保持稳定性和活性。例如冻干赋形剂可以是多元醇、糖类、氨基酸类、无机盐类和蛋白质类等，如甘露醇、乙二醇、蔗糖、谷氨酸钠、乙酸钠、碳酸钙和牛血清蛋白等。
本发明中，“制剂的稳定”或“稳定的制剂”中的“稳定”是指在产品制备及储藏过程中水分含量、外观、pH值、有关物质、含量、不溶性微粒及复溶性状等基本保持不变、未明显变化或变化在药学上可接受的范围内，且该制剂可至少在24个月内质量可控。
本发明中，“DSC”是指差示扫描量热法(differential scanning calorimetry)，一种热分析法。在程序控制温度下，测量输入到试样和参比物的功率差与温度的关系。差示扫描量热仪记录到的曲线称DSC曲线，它以样品吸热或放热的速率，即热流率为纵坐标，以温度T或时间t为横坐标，可以测量多种热力学和动力学参数，该法使用温度范围宽、分辨率高、试样用量少。适用于无机物、有机化合物及药物分析。
[包含CR19213的药物制剂及其制备方法]
本发明提供了一种药物制剂，其可以包含活性药物和任选的药学上可接受的辅料。
在一项实施方案中，上述药物制剂可以包含配体-药物偶联体、冻干赋形剂和pH调节剂。
在一项实施方案中，上述药物制剂可以包含配体-药物偶联体、冻干赋形剂、pH调节剂和溶剂。
在一项实施方案中，上述药物制剂中的配体-药物偶联体可以是双配体-药物偶联体，靶向PSMA受体和TRPV6受体。
在一项实施方案中，上述药物制剂中的溶剂为水。
在一项优选的实施方案中，上述药物制剂中的溶剂为纯化水。
在另一项优选的实施方案中，上述药物制剂中的溶剂为无菌水、蒸馏水或去离子水。
在一项更优选的实施方案中，上述药物制剂中的溶剂为无菌注射用水、单蒸水或双蒸水。
在一项实施方案中，上述药物制剂中的活性药物浓度为2mg/mL-8mg/mL，例如2.0mg/mL、2.2mg/mL、2.4mg/mL、2.6mg/mL、2.8mg/mL、3.0mg/mL、3.2mg/mL、3.4mg/mL、3.6mg/mL、3.8mg/mL、4.0mg/mL、4.2mg/mL、4.4mg/mL、4.6mg/mL、4.8mg/mL、5.0mg/mL、5.2mg/mL、5.4mg/mL、5.6mg/mL、5.8mg/mL、6.0mg/mL、6.2mg/mL、6.4mg/mL、6.6mg/mL、6.8mg/mL、7.0mg/mL、 7.2mg/mL、7.4mg/mL、7.6mg/mL、7.8mg/mL、8.0mg/mL。
在一项实施方案中，上述药物制剂中的pH调节剂可以包含缓冲盐。
进一步地，上述药物制剂中的pH调节剂包含的缓冲盐可以选自醋酸盐、磷酸盐、枸橼酸盐或其水合物中的一种或多种。
进一步地，上述药物制剂中的每1分子所述缓冲盐水合物包含0.5、1、1.5、2.0、2.5或3分子水。
在一项优选的实施方案中，上述药物制剂中的pH调节剂可以包含醋酸钠。
在另一项优选的实施方案中，上述药物制剂中的pH调节剂可以包含磷酸二氢钠。
在又一项优选的实施方案中，上述药物制剂中的pH调节剂可以包含无水枸橼酸钠。
在又一项优选的实施方案中，上述药物制剂中的pH调节剂可以包含二水合枸橼酸钠。
在一项实施方案中，当上述药物制剂中的pH调节剂包含的缓冲盐选自无水枸缘酸钠或二水合枸橼酸钠时，所述缓冲盐的浓度为2.85mg/mL～11.4mg/mL，例如2.85mg/mL、5.7mg/mL、11.4mg/mL。
在一项实施方案中，上述药物制剂中的pH调节剂可以包含缓冲盐和酸性物质和/或碱性物质。
进一步地，上述药物制剂中的pH调节剂包含的缓冲盐可以选自醋酸盐、磷酸盐、枸橼酸盐或其水合物中的一种或多种；酸性物质可以选自酸，例如盐酸、醋酸或枸橼酸中的一种或多种；碱性物质可以选自碱或盐，例如氢氧化钠、碳酸钠、或碳酸氢钠中的一种或多种。
在一项优选的实施方案中，上述药物制剂中的pH调节剂可以包含醋酸钠和盐酸或氢氧化钠。
在另一项优选的实施方案中，上述药物制剂中的pH调节剂可以包含磷酸二氢钠和盐酸或氢氧化钠。
在又一项优选的实施方案中，上述药物制剂中的pH调节剂可以包含无水枸橼酸钠和盐酸或氢氧化钠，所述无水枸橼酸钠的浓度为2.85mg/mL～11.4mg/mL，例如2.85mg/mL、3.5mg/mL、4.2mg/mL、5.7mg/mL、6.5mg/mL、7.6mg/mL、8.5mg/mL、9.8mg/mL、10.5mg/mL、11.4mg/mL。
在又一项优选的实施方案中，上述药物制剂中的pH调节剂可以包含二水合枸橼酸钠和盐酸或氢氧化钠，所述二水合枸橼酸钠的浓度为2.85mg/mL～11.4mg/mL，例如2.85mg/mL、3.5mg/mL、4.2mg/mL、5.7mg/mL、6.5mg/mL、7.6mg/mL、8.5mg/mL、9.8mg/mL、10.5mg/mL、11.4mg/mL。
在一项实施方案中，上述药物制剂中的冻干赋形剂可以包含多元醇，例如甘露醇、木糖醇中的一种或多种。
在一项优选的实施方案中，上述药物制剂中的冻干赋形剂包含甘露醇，优选地，所述甘露醇的浓度为20-150mg/mL，例如20mg/mL、30mg/mL、40mg/mL、50mg/mL、60mg/mL、70mg/mL、80mg/mL、90mg/mL、100mg/mL、110mg/mL、120mg/mL、130mg/mL、140mg/mL、150mg/mL；更优选浓度为40-60mg/mL。
在一项实施方案中，上述药物制剂中的冻干赋形剂包含多元醇和糖类，其中糖类为单糖、二糖、多糖中的一种或多种，优选地，所述糖类与所述多元醇的质量比为1:1～1:5，例如1:1、1:1.5、1:2、1:2.5、1:3、1:3.5、1:4、1:4.5、1:5；优选地，所述糖类与所述多元醇的质量比为1:2～1:4。
进一步地，上述药物制剂中的冻干赋形剂中的单糖包括葡萄糖、果糖中的一种或多种；二糖包括蔗糖、海藻糖、麦芽糖中的一种或多种；多糖包括环糊精、右旋糖酐中的一种或多种。
在一项优选的实施方案中，上述药物制剂中的冻干赋形剂可以包含甘露醇和蔗糖，优选地，所述蔗糖与甘露醇的质量比为1:4。
在一项实施方案中，上述药物制剂的pH值可以为5.0～8.0，例如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、8.0。
在一项优选的实施方案中，上述药物制剂的pH值可以为5.5～6.5，例如5.5、5.6、5.7、5.8、5.9、6.0、6.1、6.2、6.3、6.4、6.5。
在一项实施方案中，上述药物制剂包含配体-药物偶联体或其药物上可接受的盐、冻干赋形剂、pH调节剂和溶剂；其中所述药物制剂的pH为5.0～8.0。
在一项优选的实施方案中，每1mL上述药物制剂包含5mg双配体-药物偶联体或其药物上可接受的盐、50mg甘露醇、5.7mg二水合枸橼酸钠和任选的酸性物质或碱性物质以及余量的水；其中所述药物 制剂的pH为5.0～8.0。
在一项优选的实施方案中，每1mL上述药物制剂包含5mg双配体-药物偶联体或其药物上可接受的盐、40mg甘露醇、10mg蔗糖、4.5mg无水枸橼酸钠和任选的酸性物质或碱性物质以及余量的水；其中所述药物制剂的pH为5.0～8.0。
在一项优选的实施方案中，每1mL所述药物制剂包含4mg双配体-药物偶联体或其药物上可接受的盐、50mg甘露醇、适量的醋酸钠和任选的酸性物质或碱性物质以及余量的水；其中所述药物制剂的pH为5.0～8.0。
在一项优选的实施方案中，每1mL所述药物制剂包含6mg双配体-药物偶联体或其药物上可接受的盐、50mg甘露醇、适量的磷酸二氢钠和任选的酸性物质或碱性物质以及余量的水；其中所述药物制剂的pH为5.0～8.0。
在一项实施方案中，上述药物制剂是无菌的。
在一项实施方案中，上述药物制剂在冷冻和解冻时是稳定的。
在一项实施方案中，上述药物制剂的制备方法包括下列步骤：取处方量的活性药物及任选的药学上可接受的辅料，混匀，即得。
在一项优选的实施方案中，上述药物制剂的制备方法包括如下步骤：取处方量的配体-药物偶联体或其药物上可接受的盐、冻干赋形剂、pH调节剂和溶剂，在溶剂中一次性溶解各组分，混匀，即得；优选地，在溶剂中溶解各组分时，将pH调节剂同时或者优先于配体-药物偶联体或其药物上可接受的盐溶于溶剂中。
在一项优选的实施方案中，上述药物制剂的制备方法包括如下步骤：取处方量的配体-药物偶联体或其药物上可接受的盐、冻干赋形剂、pH调节剂和溶剂，在溶剂中分批地溶解各组分，混匀，即得；优选地，在溶剂中溶解各组分时，将pH调节剂同时或者优先于配体-药物偶联体或其药物上可接受的盐溶于溶剂中。
在另一项优选的实施方案中，上述药物制剂的制备方法包括如下步骤：取处方量的配体-药物偶联体或其药物上可接受的盐、冻干赋形剂、pH调节剂和溶剂，在溶剂中一次性溶解各组分，利用pH调节剂中的酸性物质或碱性物质调节pH值至5.0～8.0，混匀，即得；优选地，在溶剂中溶解各组分时，将pH调节剂同时或者优先于配体-药物偶联体或其药物上可接受的盐溶于溶剂中。
在另一项优选的实施方案中，上述药物制剂的制备方法包括如下步骤：取处方量的配体-药物偶联体或其药物上可接受的盐、冻干赋形剂、pH调节剂和溶剂，在溶剂中分批地溶解各组分，利用pH调节剂中的酸性物质或碱性物质调节pH值至5.0～8.0，混匀，即得；优选地，在溶剂中溶解各组分时，将pH调节剂同时或者优先于配体-药物偶联体或其药物上可接受的盐溶于溶剂中。
在一项实施方案中，上述药物制剂的制备方法在不避光的条件下进行。
在一项实施方案中，上述药物制剂的制备方法在避光的条件下进行。
在一项实施方案中，上述药物制剂的制备方法在温度为15℃～40℃的条件下进行，例如15℃、20℃、25℃、30℃、35℃、40℃。
在一项实施方案中，上述药物制剂的制备方法在氮气保护的条件下进行。
在一项实施方案中，上述药物制剂的制备方法不在氮气保护的条件下进行。
在一项优选的实施方案中，上述药物制剂的制备方法在避光、温度为15℃～40℃且不在氮气保护的条件下进行。
[冻干制剂及其制备方法]
本发明提供了一种冻干制剂，其由本发明的药物制剂经冷冻干燥制得。
本发明还提供了上述冻干制剂的制备方法，其包括下列步骤：将本发明的药物制剂冷冻干燥，即得。
在一项实施方案中，在上述制备方法中，所述冷冻干燥包括下列步骤：-45℃对所述药物制剂进行冷冻；在-15℃～-5℃对所述药物制剂进行一次干燥；在15℃～25℃对所述药物制剂进行二次干燥。
在一项优选的实施方案中，在上述制备方法中，所述冷冻干燥包括下列步骤：-45℃对所述药物 制剂进行冷冻；在-5℃对所述药物制剂进行一次干燥；在15℃对所述药物制剂进行二次干燥。
在另一项优选的实施方案中，在上述制备方法中，所述冷冻干燥包括下列步骤：-45℃对所述药物制剂进行冷冻；在-10℃对所述药物制剂进行一次干燥；在15℃对所述药物制剂进行二次干燥。
在又一项优选的实施方案中，在上述制备方法中，所述冷冻干燥包括下列步骤：-45℃对所述药物制剂进行冷冻；在-15℃对所述药物制剂进行一次干燥；在25℃对所述药物制剂进行二次干燥。
在一项更优选的实施方案中，在上述制备方法中，所述冷冻干燥包括下列步骤：-45℃对所述药物制剂进行冷冻120min；在-15℃对所述药物制剂进行一次干燥720min；在25℃对所述药物制剂进行二次干燥720min。
在一项实施方案中，上述冻干制剂在室温条件下是稳定的。
[液体制剂及其制备方法]
本发明提供了一种液体制剂，其由本发明的冻干制剂用水重构制得。
本发明还提供了上述液体制剂的制备方法，其包括下列步骤：将本发明的冻干制剂与水混合，即得。
在一项实施方案中，在上述制备方法中，所述重构采用蒸馏水、纯水或无菌水来完成。
在一项实施方案中，所述冻干制剂用水重构后的pH为5.0～8.0。
[装置]
本发明提供了一种含药递送装置，其包含上述药物制剂、上述冻干制剂或上述液体制剂中的一种。
本发明还提供了一种预填装注射器，其包含上述药物制剂、上述冻干制剂或上述液体制剂中的一种。
[医药用途]
本发明提供了包含活性药物的上述药物制剂、上述冻干制剂或上述液体制剂在制备递送装置或预填装注射器或药物中的用途。
在一项实施方案中，上述用途中的递送装置或预填装注射器或药物用于在受试者中增强免疫效应细胞反应。
在一项实施方案中，上述用途中的递送装置或预填装注射器或药物用于在受试者中减少免疫抑制。
在一项实施方案中，上述用途中的递送装置或预填装注射器或药物用于在受试者中治疗和/或预防癌症。
进一步地，上述用途中的癌症包括乳腺癌、肺癌、前列腺癌、肾癌、白血病、卵巢癌、胃癌、子宫癌、子宫内膜癌、肝癌、结肠癌、甲状腺癌、胰腺癌、结直肠癌、食道癌、睾丸癌、皮肤癌、淋巴瘤、多发性骨髓瘤中的一种或多种。
在一项实施方案中，上述用途中的递送装置或预填装注射器或药物用于在受试者中治疗和/或预防免疫性疾病。
进一步地，上述用途中的免疫性疾病包括结缔组织病、系统性硬化症、类风湿性关节炎和系统性红斑狼疮中的一种或多种。
在一项实施方案中，上述用途中的递送装置或预填装注射器或药物用于在受试者中治疗和/或预防心血管疾病。
进一步地，上述用途中的心血管疾病包括心绞痛、心肌梗死、中风、心脏病发作、高血压性心脏病、风湿性心脏病、心肌病、心脏心律失常和先天性心脏病中的一种或多种。
在一项实施方案中，上述用途中的递送装置或预填装注射器或药物用于在受试者中治疗和/或预防代谢疾病。
进一步地，上述用途中的代谢疾病包括糖尿病、痛风、肥胖症、低血糖症、高血糖症和血脂异常中的一种或多种。
在一项实施方案中，上述用途中的递送装置或预填装注射器或药物用于在受试者中治疗和/或预防神经疾病。
进一步地，上述用途中的神经疾病包括阿尔茨海默病、帕金森病、亨廷顿病、头部损伤、多发性 硬化症、眩晕、昏迷和癫痫中的一种或多种。
以下将结合具体的实施例来进一步阐述本发明的技术方案。
实施例1
1.1 pH调节剂种类筛选
CR19213水中溶解性差，对酸、碱不稳定。因此在含有CR19213的药物处方中需添加合适的pH调节剂以保证产品的制备和稳定性。
注射级的pH调节剂主要为缓冲盐类，选择常用的Tris、醋酸盐、枸橼酸盐和磷酸盐，暂定浓度为0.5％；由于CR19213对酸和碱均敏感，缓冲盐溶液pH暂定为7.0(用1M盐酸或氢氧化钠调节)；冻干赋形剂暂定为常用的5％甘露醇。分别用上述缓冲盐溶液溶解CR19213制备样品，并进行高温(40℃)和强光(4500lx，近紫外光85μw/cm 2)10天影响因素试验，考察产品的性状、酸度、复溶时间、水分、复溶性状、含量和有关物质。
1.1.1处方
表1 pH调节剂种类筛选用处方组成
Figure PCTCN2022125935-appb-000005
1.1.2工艺
(1)分别配制pH7.0(用0.1M盐酸或氢氧化钠调节)的0.5％Tris溶液、0.5％醋酸钠溶液、0.5％枸橼酸钠、0.5％磷酸二氢钠溶液备用；
(2)分别称取处方量甘露醇，加入全量70％的相应缓冲盐溶液，搅拌溶解后加入处方量的原料CR19213，室温下避光搅拌溶解；
(3)分别补加相应量的缓冲盐溶液至全量；
(4)灌装，每瓶2mL，半压塞；
(5)冷冻干燥，真空条件下压塞；
(6)轧盖，既得。
表2冻干参数设置
阶段 板层温度(℃) 升温时间(min) 保持时间(min) 压力控制(mbar)
预冻 -45 50 120 /
预抽真空 / / / 0.2
一次干燥 -15 150 780 0.2
二次干燥 25 200 720 /
1.1.3检测结果
表3pH调节剂种类筛选结果
Figure PCTCN2022125935-appb-000006
结果显示：处方1(pH7.0 0.5％Tris溶液)CR19213不能溶解，其余处方均可溶解。成品经高温(40℃)和强光(4500lx，近紫外光85μw/cm 2)10天影响因素试验考察，高温条件有所降解，强光条件降解显著(高温，强光的降解主要与CR19213对温度和强光敏感有关)。其中，处方3(pH7.0 0.5％枸橼酸钠溶液)杂质水平最低，因此pH调节剂优选枸橼酸钠。
1.2 pH值筛选
pH值对药物稳定性有着特别重要的意义，因此，在配制注射剂中间体的过程中，必须对pH值进行必要的控制，以保证冻干过程中和贮藏过程中注射剂的质量稳定。
设计实验分别调节中间体溶液pH值至4.0、5.0、5.5、6.0、6.5、7.0和8.0，以成品pH值、含量、有关物质作为主要考察指标对比成品质量。
1.2.1处方
表4pH值筛选用处方组成
名称 处方13 处方14 处方15 处方16 处方17 处方18 处方19
CR19213 10.0mg 10.0mg 10.0mg 10.0mg 10.0mg 10.0mg 10.0mg
枸橼酸钠 11.4mg 11.4mg 11.4mg 11.4mg 11.4mg 11.4mg 11.4mg
甘露醇 100mg 100mg 100mg 100mg 100mg 100mg 100mg
盐酸/氢氧化钠 适量 适量 适量 适量 适量 适量 适量
水 2mL 2mL 2mL 2mL 2mL 2mL 2mL
pH值 4.0 5.0 5.5 6.0 6.5 7.0 8.0
1.2.2工艺
(1)在配制容器内加入处方量70％的注射用水，加入处方量的枸橼酸钠，搅拌使其溶解；
(2)称取处方量的甘露醇，加入配制容器内；搅拌溶解后加入处方量的CR19213，室温下避光搅拌溶解；
(3)用盐酸/氢氧化钠调节pH至选定值，加水至全量；
(4)灌装，每瓶2mL，半压塞；
(5)冷冻干燥，真空条件下压塞；冷冻干燥具体参数同表2；
(6)轧盖，既得。
1.2.3考察结果
表5 pH值筛选结果
Figure PCTCN2022125935-appb-000007
结果表明：处方13(pH4.0)在制备过程中析出不溶物。其余各处方(中间体pH5.0～8.0)样品质量相当，经40℃10天影响因素考察，产品质量无显著变化。由于原辅料加入后pH值约为6.0(不经过酸或碱调节)，此酸度下的产品质量稳定。因此，确定中间体酸度目标值为pH6.0，可接受范围为5.5～6.5。
1.3 pH调节剂用量筛选
CR19213的溶解性与溶液pH值有关，pH调节剂用量(体现为缓冲盐的浓度)直接影响溶液pH值，因此，需要对缓冲盐浓度进行筛选。因为CR19213加入至pH7.0的枸橼酸钠溶液，完全溶解后呈酸性。为使成品更接近中性，配制pH7.5(枸橼酸调节)的1.0％的枸橼酸钠溶液(11.4mg/mL)，并分别用水稀释获得浓度为0.1％、0.25％和0.5％的枸橼酸钠溶液。采用上述不同浓度的枸橼酸钠溶液，制备中间体溶液，考察中间体溶液配制过程中的溶解情况。
1.3.1处方
表6 pH调节剂用量筛选用处方组成
Figure PCTCN2022125935-appb-000008
1.3.2工艺
(1)配制pH7.5(枸橼酸调节)的1.0％的枸橼酸钠溶液，备用；
(2)用水分别稀释成0.1％、0.25％和0.5％的枸橼酸钠溶液；
(3)称取处方量甘露醇，加入全量70％的枸橼酸钠溶液，搅拌溶解后加入处方量的CR19213，室温下避光搅拌溶解；
(4)补加相应量的枸橼酸钠溶液至全量，既得。
1.3.3考察结果
表7 pH调节剂用量考察结果
批号 枸橼酸钠溶液浓度 溶解现象 溶液性状
处方5 0.1％ 有较多不溶物 呈混悬液
处方6 0.25％ 搅拌3小时后溶解 黄绿色澄明液体
处方7 0.5％ 搅拌20分钟后溶解 黄绿色澄明液体
处方8 1.0％ 搅拌12分钟后溶解 黄绿色澄明液体
溶解现象显示，0.1％浓度的枸橼酸钠溶液不能完全溶解CR19213，0.25％浓度的枸橼酸钠溶液(处方6)溶解CR19213需3小时，0.5％(处方7)和1.0％(处方8)浓度的枸橼酸钠溶液可在半小时内溶解CR19213。
经检测，0.5％枸橼酸钠溶液pH值为8.42，加入甘露醇、CR19213溶解后pH值为5.95。由于原料药显酸性，为使成品更接近中性，故可不用枸橼酸预调pH值。
实施例2
为获得美观、易于复溶、稳定性良好的冻干产品，需对保护剂进行筛选。选用常用的甘露醇、蔗糖、乳糖和山梨醇作为冻干赋形剂进行对比考察。
2.1处方
表8冻干赋形剂筛选用处方组成
名称 处方9 处方10 处方11 处方12
CR19213 10.0mg 10.0mg 10.0mg 10.0mg
枸橼酸钠(二水) 11.4mg 11.4mg 11.4mg 11.4mg
甘露醇 100mg 80mg / /
蔗糖 / 20mg / /
乳糖 / / 100mg /
山梨醇 / / / 100mg
盐酸/氢氧化钠 适量 适量 适量 适量
注射用水至 2mL 2mL 2mL 2mL
2.2工艺
(1)在配制容器内加入处方量70％的注射用水，加入处方量的枸橼酸钠(二水)，搅拌使其溶解；
(2)称取处方量的冻干赋形剂，加入配制容器内；搅拌溶解后加入处方量的CR19213，室温下避光搅拌溶解；
(3)如有必要用0.1M盐酸/氢氧化钠调节pH5～7，加水至全量；
(4)灌装，每瓶2mL，半压塞；
(5)冷冻干燥，真空条件下压塞；冷冻干燥具体参数同表2
(6)轧盖，既得。
2.3考察结果
表9冻干赋形剂筛选结果
Figure PCTCN2022125935-appb-000009
结果显示：乳糖(处方11)和山梨醇(处方12)作为本产品赋形剂使用时成品萎缩。处方9和处方10成品经40℃10天影响因素考察，产品质量相当。
实施例3
选择研究确定的处方进行工艺考察，以获得可稳定制备的注射用冻干制剂。
表10生产工艺考察用处方组成
名称 用量
CR19213 10.0mg
枸橼酸钠 11.4mg
甘露醇 100mg
盐酸/氢氧化钠 适量
注射用水至 2mL
3.1投料顺序考察
不同的辅料，酸碱性、稳定性的不同。原辅料的加入顺序可能对注射液质量产生影响。设计不同的原辅料投料顺序，考察原料与各辅料的加料顺序对产品质量的影响。
表11注射用CR19213不同投料顺序考察
Figure PCTCN2022125935-appb-000010
投料工艺输出的中间体质量属性为含量、酸度、性状和有关物质。
表12不同原辅料加入顺序考察结果
Figure PCTCN2022125935-appb-000011
结果显示，不同的投料顺序获得的中间体溶液性状、酸度和含量均相当。
3.2配液环境
配液环境包含溶液的含氧量、配液暴露的光环境、及配液温度和时间。
3.2.1溶液含氧量
CR19213对1％H 2O 2敏感，溶液状态容易被氧化。故需考察产品在制备过程中是否需要氮气保护以实现降低氧含量。
分别采用氮气保护工艺和不采用氮气保护工艺制备中间体溶液，并放置24小时，考察中间体溶液的稳定性。主要考察中间体溶液性状、含量、pH、有关物质是否有显著差异。
3.2.1.1工艺
表13溶液含氧量考察用工艺
Figure PCTCN2022125935-appb-000012
3.2.1.2考察结果
表14氮气保护工艺考察结果
Figure PCTCN2022125935-appb-000013
结果显示，药液中间体充氮气与否在24小时内性状、含量、pH、有关物质是均无显著差异，表明无需使用氮气保护工艺。
3.2.2光照对配液的影响考察
CR19213原料对光照敏感，考虑到实际配液过程中会接触室内灯光，为考察配制过程中光照的影响，设计实验考察配液过程中室内灯光对产品稳定性的影响。
配制中间体溶液，在避光条件和室内灯光照射条件下放置24小时，检测药液中间体的性状、pH、含量、有关物质。
表15配制过程中光照影响考察结果
Figure PCTCN2022125935-appb-000014
结果表明：24小时内室内灯光条件下中间体溶液的性状、pH、含量和有关物质与避光条件下中间体溶液无显著差异。
3.2.3配液温度控制
CR19213对温度敏感，为确定生产配制过程中的温度控制，将配制的中间体溶液分别于15℃、25℃和40℃条件下保温，并在0小时、8小时、20小时和24小时取样检测。考察温度对中间体溶液性状、pH、含量和有关物质的影响。
表16中间体溶液不同温度稳定性考察
Figure PCTCN2022125935-appb-000015
结果表明，中间体溶液在15℃、25℃、40℃条件下保温24小时后，中间体溶液性状、pH、含量和有关物质均未发生显著变化。
3.3冻干参数
为更好的优化冻干参数，我们对处方溶液进行DSC检测，结果见图1。
DSC检测结果显示，共晶点为-19.72℃，共熔点为-3.90℃，由此确定预冻温度为-45℃(低于共晶点约25℃)。
冻干工艺参数主要对一次干燥和二次干燥温度进行考察。一次干燥温度为分别选择-15℃、-10℃、-5℃，二次干燥温度分别选择25℃、15℃、15℃，制备样品并考察产品的性状、酸度、水分、复溶时间、复溶性状、含量和有关物质。
表17冻干参数设置
Figure PCTCN2022125935-appb-000016
表18冻干参数优化考察结果
Figure PCTCN2022125935-appb-000017
结果显示：采用冻干工艺12、13、14制备的样品性状、酸度、水分、复溶时间、复溶性状、含量和有关物质均无显著差异。工艺12水分相对略少，选择工艺12作为注射用CR19213的冻干参数。
表19确定的冻干参数
阶段 板层温度(℃) 升温时间(min) 保持时间(min) 压力控制(mbar)
预冻 -45 50 120 /
一次干燥 -15 150 720 0.2
二次干燥 25 200 720 /
实施例4
选择研究确定的处方组成，进行稳定性考察。
表20处方组成
名称 用量
CR19213 10.0mg
枸橼酸钠 11.4mg
甘露醇 100mg
注射用水至 2mL
2193015IB
按照上述处方和实施例1-3的工艺制备CR19213冻干制剂，放置在25℃条件下。稳定性检测结果如下：
表21确定处方和工艺的药物冻干制剂稳定性
Figure PCTCN2022125935-appb-000018
结果显示，性状、水分、pH值、有关物质、含量和不溶性微粒在25℃6个月内均未明显变化，说明确定的处方和工艺可获得在25℃至少稳定保存6个月的产品。

Claims (35)

  1. 一种药物制剂，其包含活性药物及任选的药学上可接受的辅料。
  2. 根据权利要求1所述的药物制剂，其特征在于，
    所述活性药物包含配体-药物偶联体或其药物上可接受的盐；
    所述药学上可接受的辅料包含冻干赋形剂和pH调节剂中的一种或多种。
  3. 根据权利要求1或2所述的药物制剂，其特征在于，
    所述活性药物包含配体-药物偶联体或其药物上可接受的盐；
    所述药学上可接受的辅料包含冻干赋形剂、pH调节剂和溶剂中的一种或多种。
  4. 根据权利要求3所述的药物制剂，其特征在于，所述溶剂为水；
    优选地，所述溶剂为纯化水；
    更优选地，所述纯化水为无菌水、蒸馏水或去离子水；
    更优选地，所述无菌水为无菌注射用水、单蒸水或双蒸水。
  5. 根据权利要求3所述的药物制剂，其特征在于，
    所述活性药物的浓度为2mg/mL-8mg/mL，例如2.0mg/mL、2.2mg/mL、2.4mg/mL、2.6mg/mL、2.8mg/mL、3.0mg/mL、3.2mg/mL、3.4mg/mL、3.6mg/mL、3.8mg/mL、4.0mg/mL、4.2mg/mL、4.4mg/mL、4.6mg/mL、4.8mg/mL、5.0mg/mL、5.2mg/mL、5.4mg/mL、5.6mg/mL、5.8mg/mL、6.0mg/mL、6.2mg/mL、6.4mg/mL、6.6mg/mL、6.8mg/mL、7.0mg/mL、7.2mg/mL、7.4mg/mL、7.6mg/mL、7.8mg/mL、8.0mg/mL。
  6. 根据权利要求2或3所述的药物制剂，其特征在于，
    所述pH调节剂包含缓冲盐。
  7. 根据权利要求6所述的药物制剂，其特征在于，
    所述pH调节剂还包含酸性物质和/或碱性物质。
  8. 根据权利要求6所述的药物制剂，其特征在于，
    所述缓冲盐包含醋酸盐、磷酸盐、枸橼酸盐或其水合物中的一种或多种；优选地，每1分子所述水合物包含0.5、1、1.5、2.0、2.5或3分子水；
    优选地，所述缓冲盐为醋酸钠、无水枸橼酸钠、二水合枸橼酸钠或磷酸二氢钠中的一种或多种。
  9. 根据权利要求7所述的药物制剂，其特征在于，
    所述酸性物质包含酸；优选地，所述酸性物质为盐酸、醋酸或枸橼酸中的一种或多种；
    所述碱性物质包含碱或盐；优选地，所述碱性物质为氢氧化钠、碳酸钠或碳酸氢钠中的一种或多种。
  10. 根据权利要求6至9中任一项所述的药物制剂，其特征在于，当所述缓冲盐选自无水枸缘酸钠或二水合枸橼酸钠时，所述缓冲盐的浓度为2.85mg/mL～11.4mg/mL，例如2.85mg/mL、3.5mg/mL、4.2mg/mL、5.7mg/mL、6.5mg/mL、7.6mg/mL、8.5mg/mL、9.8mg/mL、10.5mg/mL、11.4mg/mL。
  11. 根据权利要求2或3所述的药物制剂，其特征在于，
    所述冻干赋形剂包含多元醇，例如甘露醇、木糖醇中的一种或多种；
    优选地，所述冻干赋形剂为甘露醇，优选浓度为20mg/mL-150mg/mL，例如20mg/mL、30mg/mL、40mg/mL、50mg/mL、60mg/mL、70mg/mL、80mg/mL、90mg/mL、100mg/mL、110mg/mL、120mg/mL、130mg/mL、140mg/mL、150mg/mL；更优选浓度为40-60mg/mL。
  12. 根据权利要求11所述的药物制剂，其特征在于，
    所述冻干赋形剂还包含糖类，例如单糖、二糖、多糖中的一种或多种；
    优选地，所述糖类与所述多元醇的质量比为1:1～1:5，例如1:1、1:1.5、1:2、1:2.5、1:3、1:3.5、1:4、1:4.5、1:5；
    更优选地，所述糖类与所述多元醇的质量比为1:2～1:4。
  13. 根据权利要求12所述的药物制剂，其特征在于，
    所述单糖包含葡萄糖、果糖中的一种或多种；
    所述二糖包含蔗糖、海藻糖、麦芽糖中的一种或多种；
    所述多糖包含环糊精、右旋糖酐中的一种或多种。
  14. 根据权利要求11至13中任一项所述的药物制剂，其特征在于，
    所述冻干赋形剂为甘露醇和蔗糖；优选地，所述蔗糖与甘露醇的质量比为1:4。
  15. 根据权利要求3至14中任一项所述的药物制剂，其特征在于，
    所述药物制剂的pH值为5.0～8.0；例如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、8.0。
  16. 根据权利要求1所述的药物制剂，其特征在于，所述药物制剂包含配体-药物偶联体或其药物上可接受的盐、冻干赋形剂、pH调节剂和溶剂；其中所述药物制剂的pH为5.0～8.0；
    优选地，每1mL所述药物制剂包含5mg双配体-药物偶联体或其药物上可接受的盐、50mg甘露醇、5.7mg二水合枸橼酸钠和任选的酸性物质或碱性物质以及余量的水；其中所述药物制剂的pH为5.0～8.0；
    优选地，每1mL所述药物制剂包含5mg双配体-药物偶联体或其药物上可接受的盐、40mg甘露醇、10mg蔗糖、4.5mg无水枸橼酸钠和任选的酸性物质或碱性物质以及余量的水；其中所述药物制剂的pH为5.0～8.0；
    优选地，每1mL所述药物制剂包含4mg双配体-药物偶联体或其药物上可接受的盐、50mg甘露醇、适量的醋酸钠和任选的酸性物质或碱性物质以及余量的水；其中所述药物制剂的pH为5.0～8.0；
    优选地，每1mL所述药物制剂包含6mg双配体-药物偶联体或其药物上可接受的盐、50mg甘露醇、适量的磷酸二氢钠和任选的酸性物质或碱性物质以及余量的水；其中所述药物制剂的pH为5.0～8.0。
  17. 根据权利要求2至16中任一项所述的药物制剂，其特征在于，
    所述配体-药物偶联体为双配体-药物偶联体；
    优选地，所述双配体-药物偶联体为靶向PSMA受体和TRPV6受体的药物偶联体；
    优选地，所述双配体-药物偶联体具有如下结构：
    Figure PCTCN2022125935-appb-100001
    更优选地，所述双配体-药物偶联体具有如下结构：
    Figure PCTCN2022125935-appb-100002
  18. 根据权利要求1至17中任一项所述的药物制剂，其特征在于，所述药物制剂是无菌的。
  19. 根据权利要求1至17中任一项所述的药物制剂，其特征在于，所述药物制剂在冷冻和解冻时是稳定的。
  20. 根据权利要求1至19中任一项所述的药物制剂的制备方法，其包括如下步骤：
    取处方量的活性药物及任选的药学上可接受的辅料，混匀，即得。
  21. 根据权利要求20所述的制备方法，其特征在于，其包括如下步骤：取处方量的配体-药物偶联 体或其药物上可接受的盐、冻干赋形剂、pH调节剂和溶剂，在溶剂中一次性或分批地溶解各组分，任选地利用pH调节剂中的酸性物质或碱性物质调节pH值至5.0～8.0，混匀，即得；
    优选地，在溶剂中溶解各组分时，将pH调节剂同时或者优先于配体-药物偶联体或其药物上可接受的盐溶于溶剂中。
  22. 根据权利要求20或21所述的制备方法，其特征在于，
    所述制备方法任选地在避光的条件下进行；
    优选地，所述制备方法在避光的条件下进行。
  23. 根据权利要求20至22中任一项所述的制备方法，其特征在于，
    所述制备方法在温度为15℃～40℃的条件下进行。
  24. 根据权利要求20至23中任一项所述的制备方法，其特征在于，
    所述制备方法任选地在氮气保护的条件下进行；
    优选地，所述制备方法不在氮气保护的条件下进行。
  25. 一种冻干制剂，其特征在于，所述冻干制剂通过将根据权利要求1至19中任一项所述的药物制剂冻干来制备。
  26. 根据权利要求25所述的冻干制剂的制备方法，其包括如下步骤：(i)-45℃对所述药物制剂进行冷冻；(ii)在-15℃～-5℃对所述药物制剂进行一次干燥；(iii)在15℃～25℃对所述药物制剂进行二次干燥；例如，所述一次干燥的温度为-15℃、-10℃或-5℃；所述二次干燥的温度为15℃或25℃；
    优选地，所述制备方法包括如下步骤：(i)-45℃对所述药物制剂进行冷冻；(ii)在-15℃对所述药物制剂进行一次干燥；(iii)在25℃对所述药物制剂进行二次干燥。
  27. 根据权利要求25所述的冻干制剂，其特征在于，所述冻干制剂在室温条件下是稳定的。
  28. 一种液体制剂，其由根据权利要求25所述的冻干制剂用水重构而成。
  29. 根据权利要求28所述的液体制剂，其特征在于，所述水包括蒸馏水、纯水、无菌水中的一种或多种；优选地，所述冻干制剂用水重构后的pH为5.0～8.0。
  30. 根据权利要求28或29所述的液体制剂的制备方法，其包括如下步骤：
    将所述冻干制剂与无菌水混合，即得。
  31. 一种含药递送装置，其包含下列制剂中的一种：根据权利要求1至19中任一项所述的药物制剂、根据权利要求25所述的冻干制剂或者根据权利要求28或29所述的液体制剂。
  32. 一种预填装注射器，其包含下列制剂中的一种：根据权利要求1至19中任一项所述的药物制剂、根据权利要求25所述的冻干制剂或者根据权利要求28或29所述的液体制剂，优选用于静脉内注射或者肌内注射。
  33. 根据权利要求1至19中任一项所述的药物制剂、根据权利要求25所述的冻干制剂或者根据权利要求28或29所述的液体制剂在制备用于在受试者中增强免疫效应细胞反应和/或减少免疫抑制的递送装置或预填装注射器或药物中的用途。
  34. 根据权利要求1至19中任一项所述的药物制剂、根据权利要求25所述的冻干制剂或者根据权利要求28或29所述的液体制剂在制备用于在受试者中治疗和/或预防癌症、免疫性疾病、心血管疾病、代谢疾病和神经疾病的递送装置或预填装注射器或药物中的用途。
  35. 根据权利要求34所述的用途，其特征在于，
    所述癌症包括乳腺癌、肺癌、前列腺癌、肾癌、白血病、卵巢癌、胃癌、子宫癌、子宫内膜癌、肝癌、结肠癌、甲状腺癌、胰腺癌、结直肠癌、食道癌、睾丸癌、皮肤癌、淋巴瘤、多发性骨髓瘤中的一种或多种；
    所述免疫性疾病包括结缔组织病、系统性硬化症、类风湿性关节炎和系统性红斑狼疮中的一种或多种；
    所述心血管疾病包括心绞痛、心肌梗死、中风、心脏病发作、高血压性心脏病、风湿性心脏病、心肌病、心脏心律失常和先天性心脏病中的一种或多种；
    所述代谢疾病包括糖尿病、痛风、肥胖症、低血糖症、高血糖症和血脂异常中的一种或多种；
    所述神经疾病包括阿尔茨海默病、帕金森病、亨廷顿病、头部损伤、多发性硬化症、眩晕、昏迷和癫痫中的一种或多种。
PCT/CN2022/125935 2021-10-19 2022-10-18 偶联体药物制剂及其制备方法和用途 Ceased WO2023066251A1 (zh)

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