Injectable preparation and method for preparing the same, and suitable drug solution and method for preparing the same

Abstract

Injectable preparations and methods for their preparation, as well as suitable drug solutions and methods for their preparation. Tests have shown that the provided injectable preparations and suitable drug solutions meet the requirements for long-term clinical trials and commercial production and sale. The injectable preparation is a solution containing the compound of formula (I) below, and the solvent of the solution contains C2-C8 alcohols, and may also contain another co-solvent or solubilizer. A preferred injectable preparation is a mixed solution of DMA, ELP, and ethanol containing 10 mg / ml of the compound of formula (I). Here, DMA is the co-solvent and ELP is the solubilizer. For a ready-to-use injectable preparation of the compound of formula (I) below (suitable drug solution), the solvent is water, and the solute contains the compound of formula (I), DMA, ELP, ethanol, an isosmotic regulator, and a pH regulator, the concentration of compound A in the injectable preparation is 0.016-1.10 mg / ml, the pH of the injectable preparation is 7.4, and the injectable preparation is an isosmotic solution. Furthermore, the present invention discloses a method for preparing the above-mentioned injectable preparation and a method for preparing a suitable drug solution for the above-mentioned injectable preparation.

Description

[Technical Field]

[0001] The present invention relates to the research and development of an injectable preparation containing compound No. 16 disclosed in patent application PCT / CN2020 / 089692 (publication number: International Publication No. 2020228685), and belongs to the field of development of compound-based preparations for cancer treatment. [Background technology]

[0002] Compound No. 16 disclosed in patent application number PCT / CN2020 / 089692 (publication number: International Publication No. 2020228685) and compound A disclosed in patent application number PCT / CN2021 / 129077 (International Publication No. 2023077452) (both applications filed by the same applicant as this application) refer to the same compound (hereinafter referred to as compound A) having the structure of formula (I) below. Further research has revealed that the compound of formula (I) has no toxic side effects and possesses excellent anticancer efficacy, safety, and stability. In particular, it can specifically recognize aldo-keto reductase 1C3 (AKR1C3) overexpressed in tumor tissue or tumor cells, making it suitable for targeted therapy. Moreover, it can penetrate and exert its efficacy in the central nervous system (such as the brain). The compound of formula (I) (compound A) is called 1-(3-((2,4′-difluoro-1,1′-biphenyl]-4-yl)oxy)-4-nitrophenyl)-2,2,2-trifluoroethyl-bis(aziridine-1-yl)phosphate and has the structure shown in the following formula.

[0003] [ka]

[0004] For subsequent clinical trials, it is usually necessary to prepare a drug suitable for administration to patients via oral or injectable route. Therefore, it is necessary to develop a pharmaceutical preparation of compound A (or compound of formula (I), also referred to in this application as an active pharmaceutical ingredient or API) for the treatment of cancer patients who overexpress aldo ketoreductase 1C3 (AKR1C3).

[0005] The applicant of patent application number PCT / CN2020 / 101870 (publication number: International Publication No. 2021008520, corresponding to Chinese Patent Application No. 202080001484.5 of Chinese Patent Application Publication No. 112469394) discloses a formulation and method for preparing an injectable preparation of compound AST-3424 having a structure similar to that of compound A. Both of these compounds are nitrobenzyl derivatives and are conjugated to a DNA alkylating agent having an aziridine structure that can effectively kill tumor cells. By releasing a DNA alkylating agent having an aziridine structure in tumor tissue or tumor cells that overexpress the AKR1C3 enzyme, the DNA alkylating agent can specifically target and treat the tumor tissue or tumor cells that overexpress AKR1C3, thereby achieving the objective of killing the tumor tissue or tumor cells.

[0006] Therefore, based on the concept of developing preparations suitable for compound AST-3424, particularly injectable preparations, the inventors designed and selected injectable preparations for the study of formulations containing compound A. [Overview of the project]

[0007] The inventors found that compound A is poorly soluble in a mixed solvent of ethanol and propylene glycol, which is used as a solvent in formulations containing compound AST-3424. In other words, the concept of studying and selecting liquid preparations of compound A using a formulation similar to that of AST-3424 was impractical. To solve this problem, the inventors conducted further research and developed the following stable preparations and preparation methods applicable to compound A.

[0008] This invention provides injectable preparations containing compound A and methods for their preparation, as well as suitable drug solutions and methods for their preparation. Experiments have confirmed that the injectable preparations provided by the technical solutions of this invention can meet the requirements for long-term clinical trials and commercial production or sale. Specifically, this application discloses a series of technical solutions relating to injectable preparations containing compound A.

[0009] The present invention provides a compound A-containing injectable preparation, which is a solution containing the compound of formula (I).

[0010] [ka]

[0011] This solution is a storage-stable, concentrated injectable preparation containing compound A, which needs to be diluted before administration. At the time of use, medical staff, pharmacists, or staff at a pharmacy or manufacturing facility must dilute or prepare it as needed to obtain an injectable preparation ready for immediate use.

[0012] The concentrated injectable preparation of the present invention may be diluted with a solution formulated using any pharmaceutically acceptable isotonic modifier (as a solute) and sterile water for injection (as a solvent).

[0013] Suitable isotonic modifiers include, but are not limited to, anhydrous or hydrated sodium chloride, glucose, sucrose, fructose, xylitol, glycerol, sorbitol, mannitol, potassium chloride, mannose, calcium chloride, magnesium chloride, and other inorganic salts. Preferably, the isotonic modifier is glucose or sodium chloride.

[0014] In the compound A-containing injectable solution provided by the present invention, the solvent of the solution contains C2-C8 alcohols or liquid mixtures thereof.

[0015] C2-C8 alcohols include linear, branched, or cyclic aliphatic alcohols and aromatic alcohols, but exclude phenols and highly reactive benzyl alcohols.

[0016] Specifically, the C2-C8 alcohol is either a monohydric alcohol or a polyhydric alcohol. The polyhydric alcohol is a dihydric alcohol, a trihydric alcohol, or a hexahydric alcohol. Preferably, the C2-C8 alcohol is a monohydric alcohol, and more preferably ethanol.

[0017] Furthermore, C2-C8 alcohols include C2-C4 monohydric alcohols, C2-C6 dihydric alcohols, and C3-C6 trihydric alcohols. Therefore, the solvent of the above-mentioned injectable preparation solution may be a liquid mixture of C2-C4 monohydric alcohols and C2-C6 dihydric alcohols, or a liquid mixture of C2-C4 monohydric alcohols and C3-C6 trihydric alcohols.

[0018] Clearly, in this invention, a mixed solvent of a C2-C8 monohydric alcohol and a C2-C8 dihydric, trihydric, or hexahydric alcohol means that each of the above-mentioned monohydric alcohol and dihydric, trihydric, or hexahydric alcohol should be in a liquid state at room temperature and atmospheric pressure, or that the mixed solvent is a liquid.

[0019] Furthermore, the dihydric alcohols include ethylene glycol and propylene glycol, the trihydric alcohol includes glycerol, and the hexahydric alcohols include mannitol or sorbitol.

[0020] In the injectable preparation containing Compound A provided by the present invention, the monohydric alcohol contained in the solvent of the solution is preferably ethanol. As a vehicle or carrier for Compound A as the active pharmaceutical ingredient in the injection, ethanol is also one of the solvents for injections commonly used in pharmaceuticals. However, the inventors have found in experiments that Compound A as the active pharmaceutical ingredient has low solubility in ethanol alone or in a mixed solvent of ethanol and the aforementioned polyol. Therefore, in order to enhance the solubility of Compound A in the solvent system and further enhance its stability, it is necessary to use a specific surfactant in combination as a hydrotropic agent or solubilizer.

[0021] In the solution of the injectable preparation containing Compound A provided by the present invention, the solvent of the solution further contains at least one surfactant, particularly a nonionic surfactant, in addition to the C2-C8 alcohol or its liquid mixture. The above-mentioned surfactant has a solubilizing effect.

[0022] Preferably, the solvent of the solution further contains a nonionic surfactant as a solubilizer in addition to the C2-C8 alcohol or its liquid mixture.

[0023] The process of enhancing the solubility of a poorly soluble drug by adding a surfactant is called solubilization, and the added surfactant is a solubilizer.

[0024] A surfactant refers to a substance that can significantly reduce the surface tension of a target solution. Generally, a surfactant has a fixed hydrophilic group and a lipophilic group that can be arranged in one direction on the surface of its solution. The molecular structure of a surfactant has two parts, one part contains a hydrophilic group and the other part contains a hydrophobic group. The hydrophilic group is usually a polar group such as carboxylic acid, sulfonic acid, sulfuric acid, amino group or amine group, and their salts. As the polar hydrophilic group, a hydroxyl group, an amide group, and an ether bond can also be used. The hydrophobic group is usually a non-polar hydrocarbon chain such as a hydrocarbon chain having 8 or more carbon atoms. Surfactants are classified into non-ionic surfactants and ionic surfactants depending on whether the undissociated ether group, which is the main hydrophilic group, exists in an aqueous solution or not.

[0025] A non-ionic surfactant refers to a surfactant that does not dissociate in water, and examples thereof include, but are not limited to, ester surfactants, span surfactants, ether surfactants, peregale surfactants, amine surfactants, amide surfactants, tween surfactants, and ester-ether surfactants.

[0026] A non-ionic surfactant can be polyethylene glycol (PEG) containing -O-CH2-CH2- as a repeating unit. Examples include polyethylene glycol 200 (PEG200), polyethylene glycol 400 (PEG400), polyethylene glycol 600 (PEG600), polyethylene glycol 800 (PEG800), etc. Among them, PEG400 is a liquid with high compatibility with various solvents and is also a good solvent and solubilizer widely used in liquid preparations.

[0027] [[ID=ll]] Nonionic surfactants may also be surfactants having a polyethylene glycol (or polyoxyethylene) chain segment as the hydrophilic portion. Polyethylene glycol is low in toxicity and can be completely metabolized in the body. Because polyethylene glycol has a simple ethylene oxide repeating unit, it can have good solubility in both organic solvents and aqueous solutions. When segments of polyethylene glycol are bonded to different hydrophobic substances, different types of surfactants can be formed, and by changing the polyethylene glycol (PEG) chain (e.g., chain length, number of chains, bond position), the choice and diversity of nonionic surfactants can be further expanded.

[0028] Furthermore, the nonionic surfactant of the present invention can be selected from polyethylene glycol, hydroxystearic acid esters, polyoxyethylene alkyl ethers, tween, spun, or polyoxyethylene castor oil. Naturally, mixtures of two or more of the above-mentioned surfactants can also be selected and used, as long as the mixed surfactants can also significantly reduce the surface tension of the target solution. The nonionic surfactants provided by the present invention can solubilize poorly soluble substances and act as solubilizing agents.

[0029] Polyethylene glycol hydroxystearate esters, such as 15-hydroxystearate polyethylene glycol ester (HS15) and 12-hydroxystearate polyethylene glycol ester (HS12), are obtained by dehydrating and condensing polyethylene glycol single chains containing different ethylene oxide repeating units with hydroxystearic acid to form ester bonds. These are typically used in preparations as excipients for lipophilic drugs, primarily functioning as nonionic solubilizers.

[0030] By bonding polyethylene glycol single chains having different molecular weights to simple fatty alkyl long chains, polyoxyethylene alkyl ethers including lauryl ether alkyl, oleyl ether alkyl, stearyl alcohol alkyl, or hexadecyl can be obtained. These polyoxyethylene alkyl ethers can be used as solubilizers in the preparations. Any polyoxyethylene alkyl ether usable as a solubilizer may be a candidate for the nonionic surfactant of this application. The polyoxyethylene alkyl ether has the following general structural formulas B and C. Different polyoxyethylene alkyl ethers are obtained when n represents a different value and R represents a different group.

[0031] [ka] (Polyoxyethylene alkyl ether having general structural formula B), n=23, R=CH2(CH2) 10 CH 3、 n=20, R=CH2(CH2) 14 CH3; or n=20, R=CH2(CH2) 16 CH3;n=20, R={CH2(CH2)} 16 CH=CH(CH2)7CH3}.

[0032] [ka] (Polyoxyethylene alkyl ether having general structural formula C), n=8, R=CH2(CH2) 15 CH3; or n=40, R=CH2(CH2) 15 CH3.

[0033] As shown in the following formula D, anhydro sorbitol is present in the central structure, one end of each of the four polyethylene glycol (PEG) segments is bonded to the central unit, and the tail of one of these PEG segments is bonded to a long fatty chain, thus constituting the structure formula of Tween. General names of Tween include Tween 20, Tween 40, Tween 60, and Tween 80. In these surfactants, the total number of PEG repeating units is 20, that is, w + x + y + z = 20, and the long chains of fatty acids bonded to the tails of PEG can include lauric acid, palmitic acid, stearic acid, and oleic acid.

[0034] [Chemical formula] (w + x + y + z = 20) (Tween surfactant having general formula D), R = CH2(CH2)9CH3 (Tween 20); R = CH2(CH2) 13 CH3 (Tween 40); R = CH2(CH2) 15 CH3 (Tween 60); or, R = {CH2(CH2)6CH=CH(CH2)7CH3} (Tween 80).

[0035] By removing the PEG segments in the Tween structure or substituting them with long fatty chains, another type of surfactant, namely water-insoluble Span-based surfactants, can be obtained.

[0036] Castor oil, also known as glycerol ricinoleate, reacts with ethylene oxide in which a hydrophilic ethylene oxide structure is inserted between ricinoleic acid and glycerol to yield polyoxyethylene castor oil. Hydrogenating and saturating the double bond of castor oil, and then reacting it with ethylene oxide, yields polyoxyethylene hydrogenated castor oil. Those skilled in the art will understand that random reaction sites in ethylene oxide and castor oil are involved in the above reactions. Therefore, the resulting surfactant is a mixture containing unreacted castor oil and homopolymerized polyoxyethylene. The various types of polyoxyethylene castor oil or polyoxyethylene hydrogenated castor oil depend on the ratio of ethylene oxide to castor oil or hydrogenated castor oil involved in the reaction. For example, polyoxyethylene(35) castor oil (hereinafter referred to as ELP) is obtained by reacting 1 mole of castor oil with 35 moles of ethylene oxide.

[0037] In particular, in the technical solutions of the present invention that contain surfactants, examples of polyethylene glycol include PEG200, PEG400, PEG600, and PEG800; examples of hydroxystearate include HS12 and HS15; examples of alkyl groups of polyoxyethylene alkyl ether include lauryl ether alkyl, oleyl ether alkyl, stearyl alcohol alkyl, and hexadecyl; examples of twine-type surfactants include twine 20, twine 40, twine 60, and twine 80; examples of span-type surfactants include span 20, span 40, span 60, and span 80; and examples of polyoxyethylene castor oil include polyoxyethylene castor oil and polyoxyethylene hydrogenated castor oil.

[0038] Furthermore, the polyoxyethylene castor oil of the present invention may also be polyoxyethylene(35) castor oil. A pharmaceutically acceptable polyoxyethylene(35) castor oil is polyoxyethylene glycerol trilicinoleate, which may also contain small amounts of polyethylene glycol ricinoleate and free ethylene glycol, the ethylene glycol content of which should not exceed 620 ppm. The above polyoxyethylene(35) castor oil is obtained by reacting 1 mole of castor oil with 35 moles of ethylene oxide. According to the gel method for bacterial endotoxin testing described in General Rule 1143, Volume 4, Chinese Pharmacopoeia (2015 edition), the bacterial endotoxin content per 1 mg of polyoxyethylene(35) castor oil should not exceed 0.012 EU.

[0039] Preferably, in the compound A-containing injectable preparation solution provided by the present invention, the solvent of the solution further comprises one or more of polyoxyethylene (35) castor oil, polyethylene glycol 15-hydroxystearate, polyethylene glycol 400, and Tween 80, in addition to C2-C8 alcohols or liquid mixtures thereof.

[0040] In the above-mentioned injectable preparation solution containing a surfactant, the volume ratio of the surfactant to the C2-C8 alcohol is 1:(1-4), and in particular, the surfactant is selected from nonionic surfactants.

[0041] In particular, when the surfactant is ELP and the C2-C8 alcohol is ethanol, the volume ratio of ELP to ethanol is 1:3.

[0042] If the surfactant is HS15 and the C2-C8 alcohol is ethanol, the volume ratio of HS15 to ethanol is 1:4.

[0043] If the surfactant is PEG400 and the C2-C8 alcohol is ethanol, the volume ratio of PEG400 to ethanol is 1:1.

[0044] If the surfactant is Tween 80 and the C2-C8 alcohol is ethanol, the volume ratio of Tween 80 to ethanol is 1:1.

[0045] In another compound A-containing injectable preparation solution provided by the present invention, the solvent of the solution further comprises a C2-C8 alcohol or a liquid mixture thereof, in addition to an organic solvent having a hydrotropic effect.

[0046] This organic solvent is called a hydrotropic agent. A poorly soluble drug and an added third substance can form a soluble complex (conjugate, compound salt, or compound salt) in the solvent, thereby increasing the solubility of the drug. The added third substance is also called a hydrotropic agent. Examples of hydrotropic agents include (1) organic acids and their salts such as sodium benzoate, potassium iodide, sodium salicylate, and p-aminobenzoic acid; (2) amide or amine compounds such as ethylenediamine, urethane, urea, N,N-dimethylacetamide (DMA), and N,N-dimethylformamide; and (3) water-soluble polymer compounds such as polyvinylpyrrolidone.

[0047] Preferably, in the technical solution of the present invention, which contains a hydrotropic agent, the hydrotropic agent is selected from ethylenediamine, N,N-dimethylacetamide, N,N-dimethylformamide, or polyvinylpyrrolidone, and more preferably N,N-dimethylacetamide.

[0048] Medicinally acceptable N,N-dimethylacetamide (DMA) should be injectable grade with a purity of 99.8% or higher. The bacterial endotoxin content per 1 ml of N,N-dimethylacetamide should be as specified in the General Chapter of the United States Pharmacopeia (USP). <85> Therefore, when determined by the gel method, it should not exceed 2.0 EU.

[0049] In the above-mentioned injectable preparation solution containing a hydrotropic agent, the mass ratio of the hydrotropic organic solvent to compound A in the solvent of the solution is (10-50):1.

[0050] In the compound A-containing injectable preparation solution provided by the present invention, the solvent of the solution further comprises a C2-C8 alcohol or a liquid mixture thereof, a nonionic surfactant as a solubilizer, and an organic solvent having a hydrotropic effect.

[0051] Preferably, the nonionic surfactant is selected from polyoxyethylene (35) castor oil, and the organic solvent having a hydrotropic effect is selected from N,N-dimethylacetamide.

[0052] In particular, the mass ratio of the nonionic surfactant to compound A in the solvent of the solution is (0-90):1, preferably (5-50):1, more preferably (15-40):1, even more preferably (20-40):1, and still more preferably (25-40):1.

[0053] The mass ratio of the hydrotropic organic solvent in the solvent of the above solution to compound A is (0-100):1, preferably (1-50):1, more preferably (5-25):1, and even more preferably (5-10):1.

[0054] Examples of injectable preparations containing compound A provided by the present invention include injectable preparations in the various solvents described above, the solvent being selected from the following. (1) C2-C8 alcohols, (2) Combinations of C2-C8 alcohols and nonionic surfactants as solubilizers, (3) A combination of C2-C8 alcohols and an organic solvent that has a hydrotropic effect, (4) A combination of C2-C8 alcohols, a nonionic surfactant as a solubilizer, and an organic solvent having a hydrotropic effect.

[0055] Preferably, in the injectable preparation provided by the present invention, the content of compound A is 0.1 to 200 mg / ml, preferably 1 to 100 mg / ml, and more preferably 10 to 20 mg / ml.

[0056] The compound A-containing injectable preparation provided by this invention is a solution containing compound A at a concentration of 10 mg / ml, which is the concentration value recommended by the research and development team, considering many factors such as stability and ease of use, and can achieve better properties in comparative experiments.

[0057] The present invention provides an injectable preparation comprising compound A, N,N-dimethylacetamide, polyoxyethylene (35) castor oil, and ethanol.

[0058] The present invention provides an injectable preparation comprising a compound of the following formula (I), N,N-dimethylacetamide, polyoxyethylene (35) castor oil, and ethanol.

[0059] [ka]

[0060] In a preferred embodiment of the present invention, the content of the compound of formula (I) is 0.1 to 200 mg / ml, preferably 1 to 100 mg / ml, more preferably 10 to 20 mg / ml, and even more preferably 10 mg / ml.

[0061] In a preferred embodiment of the present invention, the mass ratio of the compound of formula (I) to N,N-dimethylacetamide is in the range of 1:(0 to 100), preferably 1:(1 to 50), more preferably 1:(5 to 25), even more preferably 1:(5 to 10), and even more preferably 1:5.

[0062] In a preferred embodiment of the present invention, the mass ratio of the compound of formula (I) to polyoxyethylene (35) castor oil is 1:(0-90), preferably 1:(5-50), more preferably 1:(15-40), even more preferably 1:(20-40), even more preferably 1:(25-40), and even more preferably 1:40.

[0063] The present invention provides an injectable preparation which is a 2 ml ethanol solution containing 20 mg of compound A (formula (I)), 100 mg of N,N-dimethylacetamide, and 800 mg of polyoxyethylene (35) castor oil.

[0064] The present invention provides a unit injection preparation which is a concentrated ethanol solution labeled as having a volume of 2 ml and containing 20 mg of compound A, 100 mg of N,N-dimethylacetamide, and 800 mg of polyoxyethylene (35) castor oil.

[0065] A unit injection preparation refers to a unit-packaged preparation that is ultimately sold in packaging containers such as vials or ampoules. This is a concentrated ethanol solution containing drug compound A, as well as excipient solvents such as ethanol, the hydrotropic agent DMA, and the solubilizing agent ELP. The specification shown on the label of the unit preparation is 2ml:20mg, meaning that 2ml of the unit injection preparation (i.e., concentrated ethanol solution) contains 20mg of drug compound A, 100mg of N,N-dimethylacetamide, and 800mg of polyoxyethylene(35) castor oil (the remainder being solvent ethanol). Values ​​in expressions such as 2ml:20mg of drug compound A, 100mg of N,N-dimethylacetamide, and 800mg of polyoxyethylene(35) castor oil refer here to the specified values ​​and also to the values ​​calculated at the time of loading for formulation. There may be some degree of deviation in measured values.

[0066] To further enhance the thermal stability of the injectable preparation over time, other non-toxic substances that do not react with compound A may be added. Examples of non-toxic substances include the following:

[0067] Protective gas: The injectable preparation is evacuated to significantly reduce the amount of active gases such as O2 and CO2 contained in the injectable preparation. Then, an inert gas that does not react with the active pharmaceutical ingredient, monohydric alcohol, dihydric alcohol, trihydric alcohol, hexahydric alcohol, N,N-dimethylacetamide, N,N-dimethylformamide, or surfactants (such as polyoxyethylene (35) castor oil, HS15, and Tween 80), such as N2 or other inert gases, is loaded. The protective gas(s)

[0068] Antioxidants: To further improve stability, appropriate amounts of antioxidants (such as butylated hydroxyanisole (BHA), 2,6-di-tert-butylated hydroxytoluene (BHT), vitamin E (tocopherol), vitamin C, or glutathione) are added to the injectable preparation.

[0069] To improve patient adherence to medication, drugs having anesthetic or analgesic effects may be added in appropriate amounts, as permitted by the pharmacopoeia or prescription collection.

[0070] The injectable preparations disclosed in this invention may also contain additional therapeutic agents to form formulations that can exhibit synergistic effects that enhance the therapeutic effect. In particular, it is recommended that these drugs be drugs that allow for the adjustment of the AKR1C3 enzyme content or the expression level of the corresponding gene.

[0071] In some cases, an antibacterial or antifungal agent may be added to the injectable agent disclosed in this invention to address specific environmental conditions.

[0072] In addition, substances such as electrolytes (e.g., salts of NaCl and KCl), glucose, and amino acids, which are commonly used in injectable preparations to regulate acid-base balance and osmotic pressure, may be added as needed.

[0073] Clearly, the aforementioned protective gases, antioxidants, anesthetic or analgesic drugs, antibacterial agents, antifungal agents, etc., may be added in very small amounts and may not affect the properties of compound A, such as its solubility, or may improve its stability. Additional therapeutic agents, as well as substances to regulate acid-base balance and osmotic pressure, may be added depending on the actual circumstances, such as the purpose, prescribed amount, and instructions in the pharmacopoeia and prescription collection.

[0074] The compound A-containing injectable preparation provided by the present invention does not contain water, and has a water content of 1.0% or less by mass, preferably 0.5% or less.

[0075] Clearly, the absence of water in the preparation process means that no water is added during the preparation process, and other reagents and solvents used are anhydrous reagents such as anhydrous ethanol, anhydrous propylene glycol, anhydrous polyoxyethylene (35) castor oil, and anhydrous N,N-dimethylacetamide. In other words, the water content needs to be controlled during the preparation process of the injectable preparation of the present invention. Theoretically, the lower the water content of the injectable preparation, the better its stability. Considering the technical issues and the realities of industrial mass production, the research and development team concluded that the water content (determined by the Karl Fischer method) should be within 1.0% by mass, preferably 0.5% by mass or less.

[0076] Through research, the inventors have found that the solubility of compound A increases stepwise with ethanol, polyoxyethylene (35) castor oil, and N,N-dimethylacetamide, respectively. Specifically, compound A has the lowest solubility in ethanol and the highest solubility in N,N-dimethylacetamide. Therefore, the present invention also provides technical solutions relating to the following injectable preparations. i) An injectable preparation comprising compound A and polyoxyethylene (35) castor oil, with or without ethanol. ii) An injectable preparation comprising compound A and N,N-dimethylacetamide, with or without ethanol. iii) An injectable preparation comprising compound A, polyoxyethylene (35) castor oil, and N,N-dimethylacetamide, but free of ethanol.

[0077] Naturally, if ethanol is not present, injectable preparation i) is considered to be a solution containing polyoxyethylene (35) castor oil as a solvent, injectable preparation ii) is considered to be a solution containing N,N-dimethylacetamide as a solvent, and injectable preparation iii) is considered to be a solution containing N,N-dimethylacetamide as a solvent. Those skilled in the art will understand that the above-mentioned injectable preparations i), ii), and iii) are liquid injectable solutions containing compound A as the active pharmaceutical ingredient.

[0078] Naturally, other substances that are non-reactive with compound A and non-toxic, such as protective gases, antioxidants, and drugs having the aforementioned anesthetic or analgesic effects, may be added to further enhance the thermal stability of the injectable preparations i), ii), and iii) over time, or to improve patient adherence to medication.

[0079] The injectable preparations i), ii), and iii) disclosed in this invention may also contain additional therapeutic agents to form formulations that can exert synergistic effects to enhance the therapeutic effect. In particular, it is recommended that these drugs be drugs that can adjust the content of the AKR1C3 enzyme or the expression level of the corresponding gene.

[0080] In some cases, to address specific environments, antibacterial or antifungal agents may also be added to the injectable agents i), ii), and iii) disclosed in this invention.

[0081] In addition, substances such as electrolytes (e.g., salts of NaCl and KCl), glucose, and amino acids, which are commonly used in injectable preparations to regulate acid-base balance and osmotic pressure, may be added as needed.

[0082] Clearly, the aforementioned protective gases, antioxidants, anesthetic or analgesic drugs, antibacterial agents, antifungal agents, etc., may be added in very small amounts and may not affect the properties of compound A, such as its solubility, or may improve its stability. Additional therapeutic agents, as well as substances to regulate acid-base balance and osmotic pressure, may be added depending on the actual circumstances, such as the purpose, prescribed amount, and instructions in the pharmacopoeia and prescription collection.

[0083] The injectable preparations i), ii), and iii) provided by the present invention do not contain water, and the mass content of water is 1.0% or less, preferably 0.5% or less.

[0084] The present invention provides an injectable preparation product comprising a packaging container and an injectable preparation contained in the container, wherein the injectable preparation is any one of the above-described injectable preparations, is filled in a light-shielding glass vial made of neutral borosilicate glass tube, and the content of the compound of formula (I) in the injectable preparation is 0.1 to 200 mg / ml, preferably 1 to 200 mg / ml, and more preferably 10 to 20 mg / ml.

[0085] The present invention provides an injectable preparation product comprising compound A, N,N-dimethylacetamide, polyoxyethylene (35) castor oil, and ethanol, the injectable preparation being filled in 2 ml, 5 ml, or 10 ml light-shielding glass vials made of neutral borosilicate glass tubes, wherein the compound A content in the injectable preparation is 10 mg / ml, the mass ratio of compound (I) to N,N-dimethylacetamide is 1:5, and the mass ratio of compound (I) to polyoxyethylene (35) castor oil is 1:40.

[0086] Specific examples of injectable preparations containing compound A are as described above. The injectable preparations can be filled into 2 ml, 5 ml, or 10 ml light-shielding glass vials made of neutral borosilicate glass tubing, then capped with rubber stoppers and sealed with aluminum-plastic composite caps for antibiotic vials. Naturally, the light-shielding glass vials and rubber stoppers are inner packaging materials that may come into direct contact with the injectable preparations.

[0087] In particular, the concentration of compound A as the active pharmaceutical ingredient in this example injection is adjusted to 10 mg / ml, or the concentration of N,N-dimethylacetamide is adjusted to 50 mg / ml, or the concentration of polyoxyethylene (35) castor oil is adjusted to 400 mg / ml. According to pharmaceutical standards, measured content may also vary, and as long as it falls within the corresponding range specified in the pharmacopoeia, prescription collection, or pharmaceutical standards, the concentration is considered acceptable. In other words, concentrations within the aforementioned corresponding range are technically equivalent to the adjusted concentrations.

[0088] Similarly, in the process of preparing or mixing solutions, the actual volume measured after mixing is often smaller than the sum of the individual volumes before mixing. Therefore, the reasonable volume changes resulting from the preparation or mixing of solutions in the technical solutions provided by the present invention are well known to those skilled in the art (researchers or medical staff in fields such as pharmaceutical research and development, organic chemical synthesis, and formulation research and development).

[0089] The present invention provides a method for preparing an injectable preparation, comprising the following steps: adding a specified amount of compound A to a specified amount of N,N-dimethylacetamide while stirring and dissolving it; then adding a specified amount of polyoxyethylene (35) castor oil while stirring and dissolving it; and finally adding ethanol until it reaches a specified volume, mixing and dissolving to obtain an injectable preparation.

[0090] Furthermore, the method for preparing the injectable preparation includes adding 20 mg of compound A to 100 mg of N,N-dimethylacetamide while stirring and dissolving it, then adding 800 mg of polyoxyethylene (35) castor oil while stirring and dissolving it, and finally adding ethanol and mixing and dissolving it until the volume becomes 2 ml.

[0091] The present invention further provides another method for preparing an injectable preparation, comprising the following steps: adding and dissolving a specified amount of compound A in a specified amount of N,N-dimethylacetamide with stirring to obtain a first solution; adding and dissolving a specified amount of polyoxyethylene (35) castor oil in a portion of ethanol with stirring to obtain a second solution; and adding the first solution to the second solution with stirring, stirring until the mixture becomes clear, then adding ethanol to a specified volume, mixing and dissolving to obtain an injectable preparation.

[0092] This procedure is carried out taking into account the fact that polyoxyethylene(35) castor oil is relatively viscous below 20°C. Therefore, the polyoxyethylene(35) castor oil and a portion of anhydrous ethanol are first mixed uniformly.

[0093] The present invention further provides a ready-to-use pharmaceutical composition injectable, an injectable for injecting compound A. This composition does not require dilution before administration. This composition is already ready for administration at the time of manufacture, and medical staff do not need to perform any dilution or preparation work before use.

[0094] Naturally, the injectable preparation for administering compound A may be a readily available injectable preparation suitable for administration via various routes, such as intradermal, subcutaneous, intramuscular, and intravenous injection.

[0095] The following is an example of an injectable preparation for immediate intravenous injection. Those skilled in the art can design other intradermal, subcutaneous, or intramuscular (intramuscular) injection preparations according to clinical needs.

[0096] The ready-to-use injectable preparations provided by the present invention for injecting compound A are prepared from water, an isotonic modifier, and one of the above-described injectable preparations, and the injectable preparations may or may not contain a pH modifier.

[0097] pH adjusters, or pH adjusting substances, include alkali metal salts or alkaline earth metal salts of weak acids such as carbonic acid, phosphoric acid, citric acid, and acetic acid, as well as inorganic bases such as hydroxides of alkali metals or alkaline earth metals such as Na and K, for example, sodium citrate, potassium citrate, sodium acetate, potassium acetate, potassium dihydrogen phosphate, sodium dihydrogen phosphate, dipotassium hydrogen phosphate, disodium hydrogen phosphate, potassium phosphate, sodium phosphate, sodium hydroxide, potassium hydroxide, sodium bicarbonate, potassium bicarbonate, sodium carbonate, and potassium carbonate.

[0098] The present invention provides an example of a ready-to-use injectable preparation for injecting compound A, comprising water, an isotonic modifier, compound A, N,N-dimethylacetamide, polyoxyethylene (35) castor oil, ethanol, and a pH adjuster.

[0099] Naturally, the aforementioned ready-to-use injectable solution is an isotonic solution with a pH value in the range of 6.8 to 10.5, and a concentration of compound A of 0.016 to 1.10 mg / ml.

[0100] A solution with a concentration of 308 mmol / L is generally considered isotonic for humans, with examples including 0.9% physiological saline and 5% glucose solution. Of course, in a less strict sense, solutions with concentrations between 280 and 320 mmol / L are also considered isotonic.

[0101] Naturally, if the target of treatment is another animal, such as a primate, the concentration of the isotonic solution should be adjusted accordingly.

[0102] In particular, the concentration of compound A is 0.02 to 1.00 mg / ml.

[0103] In particular, the pH value of injectable preparations ready for immediate use is 7.4 to 8.1, preferably 7.7. Injectable preparations with a pH within the above-mentioned pH range are more stable and can be guaranteed to be stored for a certain period of time (for example, after being prepared in the field, the patient may not be able to receive the injection on time temporarily, or in the case of intravenous infusion, the infusion process may take a certain amount of time until the infusion is completed).

[0104] The pH adjusters used in the injectable formulations provided by the present invention for injecting compound A, i.e., the pH adjusting substances described above, include alkali metal salts or alkaline earth metal salts of weak acids such as carbonic acid, phosphoric acid, citric acid, and acetic acid, as well as inorganic bases such as hydroxides of alkali metals or alkaline earth metals such as Na and K, for example, sodium citrate, potassium citrate, sodium acetate, potassium acetate, potassium dihydrogen phosphate, sodium dihydrogen phosphate, dipotassium hydrogen phosphate, disodium hydrogen phosphate, potassium phosphate, sodium phosphate, sodium hydroxide, potassium hydroxide, sodium bicarbonate, potassium bicarbonate, sodium carbonate, and potassium carbonate. Naturally, the pH adjusters contained in the ready-to-use injectable formulations of the present invention may be a single substance as described above, or a combination of multiple substances that may have a synergistic effect in adjusting the pH value.

[0105] The isotonic modifier contained in the ready-to-use injectable formulation provided by the present invention for injecting compound A may be any pharmaceutically acceptable osmotic modifier for the injectable formulation of the present invention. Suitable osmotic modifiers include, but are not limited to, anhydrous or aqueous sodium chloride, glucose, sucrose, fructose, xylitol, glycerol, sorbitol, mannitol, potassium chloride, mannose, calcium chloride, magnesium chloride, other inorganic salts, or mixtures thereof.

[0106] The present invention provides a ready-to-use injectable preparation for injecting compound A, comprising water, glucose as an isotonic modifier, compound A, N,N-dimethylacetamide, polyoxyethylene (35) castor oil, ethanol, and sodium bicarbonate as a pH modifier. This injectable preparation is an isotonic solution with a pH of 7.4, a compound A concentration of 0.016 to 1.10 mg / ml, and a glucose content of 4.5 to 5.0% by mass.

[0107] Preferably, the concentration of compound A is 0.02 to 1.00 mg / ml.

[0108] Preferably, the mass ratio of compound A to N,N-dimethylacetamide is 1:5.

[0109] Preferably, the mass ratio of compound A to polyoxyethylene (35) castor oil is 1:40.

[0110] The present invention further comprises the following steps for preparing a ready-to-use injectable preparation for intravenous injection of compound A: (a) A step of obtaining a mixed solution, wherein an appropriate amount of sodium bicarbonate solution is added to a 5% glucose injection as a pH adjuster so that the pH of the mixed solution is 7.7 to 8.1, (b) Next, add an injectable preparation contained in any one of the injectable preparations according to the present invention, or any one of the injectable preparation products according to the present invention, to the mixed solution obtained in step (a), mix, dissolve, and obtain an injectable preparation for immediate use for intravenous injection. The present invention provides a preparation method that includes the following:

[0111] Preferably, in step (a), the mixed solution is obtained by adding 1 volume of 5% sodium bicarbonate injection to 250 volumes of 5% glucose injection.

[0112] In specific examples, the amount and concentration of the sodium bicarbonate solution used as a pH adjuster, the amount of 5% glucose injection, and the amount of the compound A-containing injection preparation can be obtained by calculation. [Brief explanation of the drawing]

[0113] [Figure 1] This is a flowchart of the manufacturing process for an injectable preparation containing concentrated compound A. [Modes for carrying out the invention]

[0114] The present invention provides concentrated injectable preparations that are not ready for immediate use, packaged products thereof, and injectable preparations (ready-to-use pharmaceutical composition injectable preparations) that can satisfy the storage stability requirements of the compound of formula (I) (compound A).

[0115] In certain embodiments, the concentrated injectable preparation provided by the present invention may exhibit no significant changes under the conditions of a 6-month long-term stability experiment (-20°C ± 5°C), show a degree of stability in various parameters (characteristics, pH value, moisture, related substances, and content, etc.), and may meet the proposed quality standards.

[0116] In certain embodiments, the concentrated injectable formulations provided by the present invention may meet the criteria for single impurities and total impurities under accelerated stability testing conditions (5°C ± 3°C) for 6 months, exhibiting stable results to a certain extent without significant changes in various parameters (such as characteristics, pH value, moisture content, and content), and thus meeting the proposed quality standards.

[0117] In certain embodiments, the concentrated injectable preparation provided by the present invention remains a pale yellow, clear liquid with no apparent change in appearance after being placed under higher temperature (25°C ± 2°C) and light exposure conditions for 30 days, or after being placed under two freeze-thaw cycles for three times.

[0118] In certain embodiments, the concentrated injectable preparation provided by the present invention shows no significant change in pH value after being placed under higher temperature (25°C ± 2°C) and light exposure conditions for 30 days, or after being placed under two freeze-thaw conditions for three cycles, and the pH value is within the range of 4.5 to 7.0.

[0119] In certain embodiments, the concentrated injectable preparation provided by the present invention may meet the requirements of the standard after being placed for 30 days under higher temperature (25°C ± 2°C) and light exposure conditions, or after being placed for 3 cycles under two freeze-thaw conditions, with only minimal visible foreign matter.

[0120] In certain embodiments, the concentrated injectable preparations provided by the present invention have a total impurity content of less than 5% of the acceptable limit after being placed under higher temperature conditions (25°C ± 2°C) for 30 days, and also have a total impurity content of less than 5% of the acceptable limit after being placed under light exposure conditions (with outer packaging, illuminance level at 15°C as specified in the pharmacopoeia) or light exposure conditions (without outer packaging, illuminance level at 15°C as specified in the pharmacopoeia) for 30 days. The increased impurity content after light exposure with outer packaging is the same as the increased impurity content after light exposure without outer packaging, and both increased content levels are lower than the increased content under higher temperature conditions (25°C ± 2°C). All of these can meet the requirements of the quality standards.

[0121] In certain embodiments, the concentrated injectable preparation provided by the present invention may satisfy the requirements of the standard by having a water content of less than 0.3% after being placed under higher temperature (25°C ± 2°C) conditions and light exposure conditions for 30 days, or after being placed under two freeze-thaw conditions for three cycles.

[0122] In certain embodiments, the concentrated injectable formulation provided by the present invention may meet the requirements of the standard by not showing bacterial growth up to the third cycle during storage under two freeze-thaw conditions for three cycles.

[0123] In certain embodiments, the concentrated injectable formulation provided by the present invention may satisfy the requirements of the standard by having a bacterial endotoxin content of less than 1.2 EU / mg in the third cycle of storage under two freeze-thaw conditions for three cycles.

[0124] In certain embodiments, the content of the concentrated injectable preparation provided by the present invention decreases by 3.4% after being placed under higher temperature conditions (25°C ± 2°C) for 30 days, and can meet the requirements of quality standards. Furthermore, no significant change in content is observed after being placed under light exposure conditions (with outer packaging, illuminance level at 15°C as specified in the pharmacopoeia) and light exposure conditions (without outer packaging, illuminance level at 15°C as specified in the pharmacopoeia) for 30 days, or after being placed under freeze-thaw conditions 1 (2 days at -20°C ± 5°C → 2 days at 5°C ± 3°C) and freeze-thaw conditions 2 (2 days at -20°C ± 5°C → 2 days at 25°C ± 2°C) for 3 cycles. All of these can meet the requirements of quality standards.

[0125] In certain embodiments, the ready-to-use injectable formulations provided by the present invention maintain stability in appearance, solution color, solution clarity, pH value, osmotic pressure, related substances, and content for 6 hours or even 8 hours under indoor exposure to natural light and storage conditions at room temperature (25±3℃), and can meet the requirements of injectable formulations in clinical trials.

[0126] In certain embodiments, compound A in the concentrated injectable and compounded solutions provided by the present invention is chirally stable, and the two isomers are unlikely to undergo chiral transformation.

[0127] The pH value of the ready-to-use injectable formulation of the present invention may be adjusted using an appropriate amount of a pH adjusting agent containing an acidic or basic group. A suitable pH adjusting agent generally contains at least one acid or a salt thereof, or at least one base or a salt thereof. An acid or base is added to adjust the pH to the desired value. For example, if the pH value is lower than the desired pH value, a base (or several salts) is added to raise the pH to the desired value.

[0128] In some cases, the concentrated injectable preparation of the present invention is sterilized, for example, by a final sterilization method.

[0129] The composition injection of the present invention is packaged in a pharmaceutically acceptable packaging container. The packaging container may be a bag or bottle for intravenous injection. The bags and bottles for injection may be made of glass, suitable plastic, or polymer material. The entire packaging container or a large portion of the packaging container may contain the following materials, namely polyvinyl chloride, polyolefin, polyester, polypropylene, or a combination thereof. In other examples, only the surface material in contact with the pharmaceutical injection contains these materials. In the present invention, penicillin vials are preferred.

[0130] The concentrated injectable preparation of the present invention may further contain a certain amount of opioid analgesic.

[0131] Opioid analgesics include alfentanil, allyllotidine, alphaprozine, anilelysine, apomorphine, apocodeine, benzmorphine, vegitramide, brifentanil, buprenorphine, butorphanol, carfentanil, dextromoramide, codeine, cyclopolychlorinated biphenyl, cyprenorphine, desomorphine, dezosine, diampromide, dihydrocodeine, dimenoxadol, dimefeptanol, dimethylthiambutene, dioxophenylbutyrate, dipipanone, eptazocine, and ethylmethionine. Chiltiambuten, ethylmorphin, etonitazene, fentanyl, heroin, hydrocodone, hydroxymethylmorphin, hydromorphone, ketobemidone, isomethadone, levallorphan, levofenacylmorphan, levofenacilmorphan, lofentanyl, demerol, meptazinol, metazosine, methadone, methylmorphin, methopone, milfentanyl, morphin, morphin-6-glucuronic acid, mirofin, nalbuffine, papaverine, nicorandil, norlevorphanol, normethadone, nalolf Olphanin, Olphanin / Olfanin FQ (N / OFQ), Normorphine, Norpipanone, Omefentanil, Opium, Oxycodone, Oxydihydromorphinone, Papaveretam, Pentazocine, Phenadoxone, Phenomorphan, Phenazosin, Phenoperidine, Oxyhydromorphinone, Piminodin, Pyritramide, Proheptadine, Promedol, Profadol, Properidine, Propyram, Propoxyfen, Remifentanil, Sufentanil, Tapentadol, Tramadol, Trefentanil, Chili Din and nalbuffine; any opioid having agonist activity against opioid receptors and belonging to phenanthrene, morphinan, phenylmorphine, methadone, phenylpiperidine, propionanilide-4-anilinopiperidine, 4-arylpiperidine and 4-isoarylpiperidine; any opioid having agonist activity against opioid receptors and having the same five-membered ring skeleton as nalmefene, naltrexone, buprenorphine, levorphanol, meptazinol, pentazocine and dezosine;The drugs may be selected from any analogue, prodrug, derivative, or pharmaceutically acceptable salt thereof of fentanyl, or a mixture of its racemic or enantiomers, that are active against opioid receptors.

[0132] The following embodiments are provided to facilitate understanding of the present invention and should not be construed as limiting the invention. Those skilled in the art will know that specific embodiments and scopes may be modified according to the concept of the invention. The contents of this specification should not be construed as limiting the invention. Any modifications made in accordance with the spirit of the invention are protected within the scope of the invention.

[0133] The specific tests and examples of this application are described below.

[0134] The following tests reveal several physical and chemical properties of the compound of formula I (compound A) developed by the applicant, including its solubility, formulation properties, compatibility, and stability. The applicant hereby declares that the rights to the following experimental data belong to the applicant.

[0135] Compound I (compound A) has the following structure.

[0136] [ka]

[0137] I. Research on the solubility and solution stability of compound A (pharmaceutical active ingredient or API) 1.1 Investigation of the solubility of compound A in various solvents The solubility of compound A in single solvents (water, acidic and alkaline aqueous solutions, isopropanol, and methanol) was investigated. The test results are shown in Table 1.

[0138] [Table 1]

[0139] The results above indicate that compound A has extremely low solubility in water and acidic and alkaline aqueous solutions. Therefore, solubility studies in non-aqueous solvents were conducted to select the optimal solvent or hydrotropic agent.

[0140] To increase the concentration of the active ingredient in this injectable drug, the solubility of the active ingredient in a single adjuvant was investigated, and the optimal solvent, hydrotropic agent, or solubilizer was selected. The solubility test of compound A in a single solvent was performed as follows.

[0141] Each single solvent was sampled, and a fixed amount of API (compound of formula I) was added at 25°C, stirred, and the solubility of the API in the solvent system was observed. Once dissolution was complete, additional API was continuously added until a supersaturated solution was obtained. Samples were collected and filtered every two hours, and the content was analyzed. Table 2 shows the solubility of all single solvents at 25°C.

[0142] [Table 2]

[0143] The data above shows that compound A has the highest solubility in N,N-dimethylacetamide (over 200 mg / ml), approximately 20 mg / ml in polyoxyethylene (35) castor oil, and slightly higher solubility in polyethylene glycol 400 than in anhydrous ethanol.

[0144] When designing an injectable formulation, it is necessary to add an appropriate adjuvant. These adjuvants should not affect the therapeutic efficacy of the drug, must avoid interference with the test, and should be used at concentrations that do not cause toxicity or obvious irritation. To select the optimal solvent, hydrotropic agent, or solubilizer, the solubility of compound A with various adjuvants was examined individually.

[0145] Compound A and compound AST-3424 are structurally similar (both are nitrobenzyl derivatives bound to a DNA alkylating agent having an aziridine structure that can effectively kill tumor cells). Furthermore, both compounds can target and treat either tumor tissue or tumor cells that overexpress aldehyde ketoreductase 1C3 (AKR1C3) by releasing the aziridine-containing DNA alkylating agent in tumor tissue or tumor cells that overexpress the AKR1C3 enzyme, thereby achieving the objective of killing tumor tissue or tumor cells. Therefore, based on the same formulation development strategy, the inventors designed and selected an injectable formulation similar to the injectable formulation of compound AST-3424 (optimal formulation of AST-3424: 10 mg / ml compound AST-3424 + 75% ethanol + 25% propylene glycol) for use in formulation studies of compound A.

[0146] In addition to the solvent used in the reference formulation of compound AST-3424, anhydrous ethanol was adopted as a relatively safe non-aqueous solvent adjuvant commonly used in injectable formulations. During the development of the product formulation, the addition of N,N-dimethylacetamide (DMA) or polyoxyethylene (35) castor oil (ELP) was considered to improve solubility and enhance manufacturing convenience. Table 3 shows the formulation compositions using various adjuvants and the results of the solubility investigation of compound A.

[0147] [Table 3]

[0148] [Table 4]

[0149] Note: F1 refers to the group to which only anhydrous ethanol is added. The other groups include additional adjuvants / solvents as well as anhydrous ethanol; group F2 includes propylene glycol, group F3 includes glycerin, and group F4 includes DMA.

[0150] A 30 ml formulation solution containing 300 mg of compound A was prepared according to the formulation design of compound AST-3424 (volume ratio of ethanol to propylene glycol: 3:1). Here, the amount of propylene glycol (approximately 7.8 g) is between the amounts of propylene glycol used in formulations F2-1 and F2-2. However, the above experimental observations indicate that compound A cannot be completely dissolved in the formulation prepared based on the formulation design of compound AST-3424. Therefore, the method of preparing the formulation of compound I (compound A) based on the formulation of compound AST-3424 is not feasible. The inventors needed to develop an alternative formulation for compound A.

[0151] After processing the aforementioned formulation, a processed formulation was obtained. Observations before and after processing revealed that the surfactant polyoxyethylene (35) castor oil (ELP) and the hydrotropic agent N,N-dimethylacetamide (DMA) contributed to the dissolution of the API. In subsequent studies, anhydrous ethanol and the hydrotropic agent DMA were continued to be used, and preliminary studies were conducted on various surfactants, as surfactants can improve the solubility of the API in anhydrous ethanol.

[0152] 1.2 Investigation of the stability of compound A in various solvent systems The specific prescription information for the aforementioned prescriptions F1 to F4 that were processed is as follows ("p": prescription obtained by adding ELP to the prescriptions in Table 3). F1p: 300 mg of API, 7.5 g of ELP, and anhydrous ethanol added up to 30 ml. F2-1p: 3g propylene glycol, 300mg API, 7.5g ELP, and anhydrous ethanol added up to 30ml. F2-2p: 9g propylene glycol, 300mg API, 7.5g ELP, and anhydrous ethanol added up to 30ml. F3-1p: 1.5g glycerin, 300mg API, 7.5g ELP, and anhydrous ethanol added up to 30ml. F3-2p: 4.5g glycerin, 300mg API, 7.5g ELP, and anhydrous ethanol added up to 30ml. F4-1: 3g of DMA, 300mg of API, and anhydrous ethanol to which up to 30ml has been added. F4-2: 9g of DMA, 300mg of API, and anhydrous ethanol to which up to 30ml has been added. F4-3: 15g of DMA, 300mg of API, and anhydrous ethanol to which up to 30ml has been added.

[0153] The stability of compound A in the aforementioned formulation was investigated. At predetermined time points (day 0, day 5, and day 10), 1 ml samples were taken for HPLC analysis, and the content, total impurity amount, and water content were detected, respectively. Various investigation conditions and experimental results are shown in Table 4.

[0154] [Table 5]

[0155] Note: NA indicates that the storage conditions do not apply to day 0.

[0156] The data above indicates that when stored at 2-8°C for 10 days, compound A remained relatively stable in terms of content, total impurity levels, and moisture content in all formulation solvent systems.

[0157] II. Formulation design, preparation, and stability testing of Compound A injectable formulation. Based on the properties of compound A revealed by the above-mentioned studies on solubility and solution stability, further studies were conducted on formulation design, preparation, and stability.

[0158] Compound A injection has extremely low solubility in aqueous solvents and is formulated using non-aqueous solvents. Compound A injection needs to be diluted with another suitable adjuvant before clinical use. Therefore, compatibility and stability studies were conducted simultaneously during the formulation development stage. The appearance and osmotic pressure of the diluted solution were examined to confirm a suitable formulation in advance.

[0159] 2.1 Research on various surfactants, formulations, and stability From the surfactant ELP used in the aforementioned experiment, it can be seen that surfactants with specific properties can increase the solubility of compound A in anhydrous ethanol. Below, we investigated formulations using various surfactants and their stability. The experimental process and results are shown in Table 5.

[0160] [Table 6]

[0161] [Table 7]

[0162] Note: HS15: Relative density (Chinese Pharmacopoeia (2015 Edition) Volume 4 General Rule 0601) is 1.06-1.09. ELP: Relative density (Chinese Pharmacopoeia (2015 Edition) Volume 4 General Rule 0601) is 1.05-1.06.

[0163] The data above indicates that formulation F5 is essentially identical to formulation F1, the API is completely soluble in both solvent systems, the solutions are clear, and the purity of the API remained stable under various temperature conditions. The solubility of the API in anhydrous ethanol can be increased by using various surfactants (Tween 80, HS15, ELP, and PEG400).

[0164] 2.2 Formulation design and preliminary fit and stability testing Various concentrated injectable formulations of compound A were prepared according to the various formulation compositions listed in Table 6 below. These were then prepared into various compatible drug solutions using various compatible media (0.9% sodium chloride injection, sterile water for injection, and 5% glucose injection). These compatible solutions were tested for their appearance, osmotic pressure, and pH. The results of the compatibility stability studies are shown in Table 7.

[0165] [Table 8]

[0166] [Table 9]

[0167] [Table 10]

[0168] [Table 11]

[0169] [Table 12]

[0170] Based on the results of the preliminary suitability study shown in the table above, the following conclusions can be drawn.

[0171] (1) As a result of reducing the proportion of ELP, the osmotic pressure increased.

[0172] (2) Almost all of the compatible solutions for the 20 mg / ml sample were cloudy, while most of the compatible solutions for the 10 mg / ml sample were clear.

[0173] (3) From the data for formulations F14, F15, F16, F17, and F18, it can be seen that the suitable solutions for these formulations did not show significant differences in appearance or osmotic pressure.

[0174] (4) When formulations F10 to F13 were diluted and dissolved using a 5% glucose injection as the compatible medium, a clear compatible solution was obtained.

[0175] 2.3 Selection and Optimization of Formulations Based on a comprehensive review of the results of suitability studies of injectable formulations using various adjuvants, and the results of solubility studies of compound A, as well as considering the safety of DMA in injectable formulations, the prevalence of adjuvants in injectable formulations, and the need to reduce preparation time during manufacturing, five groups of concentrated injectable formulations listed in Table 8 were selected for further investigation. The investigation mainly focused on the relevant substances, their content, and moisture content under various conditions (various temperatures, storage periods, and light exposure conditions, etc.). The results are shown in Table 9. Meanwhile, the suitability stability, relevant substances, and content of formulation F19 were investigated, and the results are shown in Tables 10, 11, and 12, respectively.

[0176] Furthermore, in the process of prescription research, docetaxel injection and paclitaxel injection are often selected as the standard for comparing the osmotic pressure of suitable diluents used clinically, and these are used as the standard for the clinical use of the aforementioned products. The comparative data is shown in Table 13.

[0177] [Table 13]

[0178] The stability data for various concentrated injectable formulations of compound A, as shown in Table 8, was investigated. The investigation was conducted under the following conditions: with or without exposure to light, at various temperatures (25±2℃, 5±3℃, -20±5℃), and for various storage periods (0 days, 15 days, 1 month, 2 months, 3 months). The investigation items are as follows and are recorded in Table 9.

[0179] [Table 14]

[0180] [Table 15]

[0181] Formula F19 (2 ml: 20 mg) was prepared into compatible drug solutions at concentrations of 0.04 mg / ml and 1 mg / ml using various compatible media (water for injection, 0.9% sodium chloride injection, and 5% glucose injection). Samples were taken at various time points (0 hours, 4 hours, 6 hours, and 8 hours), and their appearance, pH value, osmotic pressure, related substances, and content (before and after filtration) were determined. The results are shown in Tables 10, 11, and 12, respectively.

[0182] The test items, corresponding test methods, and filtration methods of the present invention are as follows.

[0183] (1) Appearance: Visual inspection (2) pH value: 1 ml of the sample was taken, diluted to 20 ml with 0.9% sodium chloride solution, and the pH was measured according to Method 1 of General Rule 0631, Volume 4 of the Chinese Pharmacopoeia (2020 edition). (3) Osmotic pressure: Dew point osmometer (4) Detection of related substances and their content: Detection was performed using HPLC, with detection conditions and parameters being the same as those for AST-3424 (see relevant sections of International Publication No. 2021 / 008520, corresponding to paragraphs 133-138 of Chinese Patent No. 112469394). Related substances were quantified by area normalization, and their content was quantified by external standardization.

[0184] [Table 16]

[0185] [Table 17]

[0186] [Table 18]

[0187] [Table 19]

[0188] Based on the above data for prescription optimization, we can draw the following conclusions.

[0189] (1) According to the stability data for various formulations in Table 9, the content and related substances of the five formulations F19-F23 showed similar trends in change. The samples were relatively stable when stored at -20±5℃.

[0190] (2) The osmotic pressure of the compatible solution prepared from Formula F19 using 0.9% sodium chloride injection or 5% glucose injection was close to that of the compatible solutions prepared from commercially available docetaxel injection and paclitaxel injection. The osmotic pressure of the compatible solution using sterile water for injection was relatively low. Therefore, in subsequent studies, sterile water for injection was not investigated as a compatible medium.

[0191] (3) Solutions formulated with 0.9% sodium chloride injection or 5% glucose injection exhibited emulsion. Measurement of the content of the samples before and after filtration revealed that the content of the solutions formulated with 0.9% sodium chloride injection or 5% glucose injection fluctuated by less than 2% before and after filtration. This indicates that the emulsion of the suitable solution prepared from compound A using 0.9% sodium chloride injection or 5% glucose injection is not due to incomplete dissolution of the product and does not affect its use.

[0192] 2.4 Study on conformity stability Based on the confirmed formulation F19, injectable formulations were prepared using raw materials and auxiliary materials of the same quality as those used in good manufacturing practice (GMP) manufacturing, and compatibility stability studies were conducted. These preliminary compatibility stability results showed that the relevant substances in the compatible solution rapidly increased at room temperature. Considering the physicochemical properties of the active pharmaceutical ingredients, the pH of the compatible solvent was investigated. First, the pH values ​​of 5% glucose injection and 0.9% sodium chloride injection were adjusted to 7.0 and 8.0, respectively, using 5% sodium bicarbonate injection, and then these solutions were used for compatibility stability testing.

[0193] The results of the conformity stability test are shown in Table 14.

[0194] [Table 20]

[0195] [Table 21]

[0196] As can be seen from the data in Table 14, the three groups of compatible solutions using 0.9% sodium chloride injection (pH 8.0), 5% glucose injection (pH 7.0), and 5% glucose injection (pH 8.0) all had a pH above 7.0. After being left at room temperature for 8 hours, the relevant substances in these solutions remained relatively stable, and the pH and osmotic pressure of the compatible solutions met the requirements for injections. The compatible stability of formulation F19 (20 mg of compound A + 0.1 g of DMA + 0.8 g of ELP + ethanol added up to 2 ml) met the requirements for injections.

[0197] III. Study of the Influencing Factors of Compound A Injectable 3.1 Testing of Influencing Factors Compound A injection (2 mL: 20 mg, formulation F19) was prepared, stored, and processed under the experimental conditions listed in Table 15 below. Tests were performed according to the sampling time and test items specified in Table 16 below. The results for all test items under high temperature (25°C ± 2°C) storage, light exposure (without outer packaging), and light exposure (with outer packaging) were recorded in Tables 17, 18, and 19. Here, the T0 data represents the results of testing samples stored at -20°C simultaneously on day 5.

[0198] [Table 22]

[0199] [Table 23]

[0200] A = Characteristics, moisture content, pH value, visible foreign matter, content, and related substances.

[0201] [Table 24]

[0202] [Table 25]

[0203] [Table 26]

[0204] The data in Tables 17, 18, and 19 above indicates the following:

[0205] (1) Appearance: After 30 days of storage under both high temperature (25°C ± 2°C) and light exposure conditions, the appearance of the injectable formulation F19 remained unchanged, maintaining a pale yellow, clear liquid state.

[0206] (2) pH: Under both high temperature (25°C ± 2°C) and light exposure conditions, the pH of the injectable formulation F19 remained within the range of 4.5 to 7.0 after 30 days of storage without significant change.

[0207] (3) Visible foreign matter: After 30 days of storage under both high temperature (25°C ± 2°C) conditions and light exposure conditions, the visible foreign matter in the injectable formulation F19 met the standards and regulations.

[0208] (4) Total impurity content: After 30 days of storage under high temperature (25°C ± 2°C) conditions, the percentage of total impurities in the injectable formulation F19 was less than 5.0% of the standard limit. Under both light exposure conditions (with outer packaging, illuminance as specified in the Chinese Pharmacopoeia, 15°C) and light exposure conditions (without outer packaging, illuminance as specified in the Chinese Pharmacopoeia, 15°C), the percentage of total impurities after 30 days of storage was less than 5.0% of the standard limit. The increase in impurities under light exposure conditions (with outer packaging) was consistent with the increase observed under light exposure conditions (without outer packaging), and under both light exposure conditions, the increase was smaller than the increase observed under high temperature (25°C ± 2°C) conditions. All results met the quality standards regulations.

[0209] (5) Moisture content: After 30 days of storage under both high temperature (25°C ± 2°C) conditions and light exposure conditions, the moisture content of injectable formulation F19 was 0.3% or less, meeting the regulations.

[0210] (6) Content: After storage for 30 days under high temperature conditions (25℃±2℃), the content of injectable formulation F19 decreased by 3.4%, but still met the quality standards regulations. Under both light exposure conditions (with outer packaging, illuminance as specified in the Chinese Pharmacopoeia, 15℃) and light exposure conditions (without outer packaging, illuminance as specified in the Chinese Pharmacopoeia, 15℃), the content of injectable formulation F19 did not show significant fluctuations after 30 days of storage, and met the quality standards requirements.

[0211] 3.2 Freeze-thaw test Compound A injection (2 mL: 20 mg, formulation F19) was prepared and subjected to freeze-thaw treatment under the test conditions listed in Table 20 below. Samples for the freeze-thaw test were collected according to the sampling time and test items listed in Table 21 below. The test results for all test items under the two freeze-thaw test conditions are shown in Tables 22 and 23, respectively. Here, the initial data from the influence factor test described in Section 3.1 was used as T0 data.

[0212] Experimental Procedure Freeze-thaw cycle 1: The prepared compound A injection (2 mL: 20 mg) was stored at -20°C for 2 days, then transferred to an environment of 2-8°C and stored for 2 days. This constituted one temperature cycle. Three such temperature cycles were performed, and the samples were analyzed after each cycle. The first prepared compound A injection was stored in a -20°C freezer as a control.

[0213] Freeze-thaw cycle 2: The above process was repeated with one temperature cycle set to -20°C to 25°C.

[0214] [Table 27]

[0215] [Table 28]

[0216] Note: A = characteristics, moisture content, pH value, visible foreign matter, content, related substances; M = sterility, bacterial endotoxins.

[0217] [Table 29]

[0218] [Table 30]

[0219] Note: NA means not applicable. T0 data from the influencing factor study was used as initial data.

[0220] [Table 31]

[0221] [Table 32]

[0222] Note: NA means not applicable. T0 data from the influencing factor study was used as initial data.

[0223] The data in Tables 22 and 23 above indicates the following:

[0224] (1) Appearance: Under both freeze-thaw conditions, after 3 cycles, the injectable formulation F19 showed no significant change in appearance and remained a pale yellow, clear liquid.

[0225] (2) pH: Under both freeze-thaw conditions, after 3 cycles, the pH of the injectable formulation F19 remained within the range of 4.5 to 7.0 without significant change.

[0226] (3) Visible foreign matter: Under both freeze-thaw conditions, visible foreign matter met the regulations after 3 cycles.

[0227] (4) Total impurity amount: After three freeze-thaw cycles under freeze-thaw condition 1 (2 days at -20°C ± 5°C → 2 days at 5°C ± 3°C), the total impurity amount in the injectable formulation F19 remained essentially unchanged. After three freeze-thaw cycles under freeze-thaw condition 2 (2 days at -20°C ± 5°C → 2 days at 25°C ± 2°C), a new, unknown single impurity was detected. In both cases, the level of the new impurity was 0.1% or less, meeting the quality standards regulations.

[0228] (5) Water content: Under both freezing and thawing conditions, after 3 cycles, the water content of the injection formulation F19 was 0.3% or less, meeting the regulations.

[0229] (6) Sterility: Under both freezing and thawing conditions, after the 3rd cycle, no bacterial growth was detected in the injection formulation F19, meeting the regulations.

[0230] (7) Bacterial endotoxin: Under both freezing and thawing conditions, after the 3rd cycle, the bacterial endotoxin of the injection formulation F19 was less than 1.2 EU / mg, meeting the regulations.

[0231] (8) Content: Under both freezing and thawing condition 1 (-20°C ± 5°C for 2 days → 5°C ± 3°C for 2 days) and freezing and thawing condition 2 (-20°C ± 5°C for 2 days → 25°C ± 2°C for 2 days), after 3 cycles of freezing and thawing, the content of the injection formulation F19 showed no significant variation and met the quality standard regulations.

[0232] [[ID=1。原文中“ ”“

[0232] ”“ ”处的标签似乎有误,推测应为“ ”“

[0232] ”“ ”,翻译时保留原文形式。其余标签同理。 5°C ± 3°C for 2 days → 25°C ± 2°C for 2 days), after 3 cycles of freezing and thawing, the content of the injection formulation F19 showed no significant variation and met the quality standard regulations. IV. Preparation process and specific examples of concentrated injection of Compound A The preparations of the concentrated injection of Compound A used in the above experiments can all be prepared by the following process. <00。原文中“ ”“

[0233] ”“ ”处的标签似乎有误,推测应为“<000…0913> ”“ ”,翻译时保留原文形式。 00913> (The cleaning and sterilization of the rubber stopper The rubber stopper was cleaned, sterilized, and dried before use (steam sterilization conditions: 121°C, 30 minutes).

[0234] (2) The cleaning and sterilization of the aluminum cap [[ID=…。原文中“ ”“ ”“

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[0235] ”,翻译时保留原文形式。 The aluminum cap was cleaned, sterilized, and dried before use (steam sterilization conditions: 121°C, 30 minutes).

[0235] (3) The cleaning and sterilization of the vial The vial was cleaned, dry heat sterilized, and cooled before use.

[0236] (4) Weighing The active ingredient and adjuvant were weighed according to the specified amounts.

[0237] (5) Preparation and filtration of the solution Examples include prescriptions F9-F14, F19, F20, and F23.

[0238] Compound A, which had been weighed in advance, was added to N,N-dimethylacetamide (DMA, for injection) which had also been weighed in advance, and the mixture was stirred until it dissolved. The mixture was then set aside for later use.

[0239] A portion of the anhydrous ethanol was added to a liquid preparation tank (temperature controlled to 15-20°C). Next, pre-weighed polyoxyethylene (35) castor oil (ELP) was added. The container was rinsed with an appropriate amount of anhydrous ethanol, and stirring was started and continued until the solution was visibly clear.

[0240] The prepared solution of compound A and N,N-dimethylacetamide (for injection) was slowly poured into a liquid preparation tank. The container was rinsed with an appropriate amount of anhydrous ethanol, and the mixture was stirred for at least 10 minutes until the solution was visibly clear. Additional anhydrous ethanol was added until the total weight of the formulation was reached, and the mixture was stirred for at least 20 minutes.

[0241] Intermediate samples were taken for testing. Test parameters included characteristics, pH value, moisture content, density, content, bacterial endotoxins, moisture, and microbial load.

[0242] Two 0.22 μm sterile-grade polytetrafluoroethylene capsule filters were connected in sequence, and compressed air was used to sterilize and filter the drug solution before supplying it to a mobile liquid receiving tank at the filling station.

[0243] (6) Filling and crimping capping The filling volume was calculated and adjusted using the weighing method. After the adjustment to achieve the correct filling volume, the filling and partial capping process was started. After filling and complete capping, the intermediate product was transferred to the capping chamber and capped.

[0244] (7) Lamp inspection and packaging After capping, a lamp inspection was carried out on the intermediate product. Labels were attached to the intermediate products that passed the lamp inspection, samples of the final product were taken for a shipping test, and then packaging was carried out.

[0245] Taking prescriptions F9 - F14, F19, F20, F23, etc. as examples, the manufacturing process flowchart of the concentrated compound A (compound of formula I) injection preparation is shown in Figure 1.

[0246] The present invention also provides another process for preparing an injection containing compound A, which is mainly for preparing a laboratory - scale batch of injection preparation. This process is different from the aforementioned process in the solution preparation process, more specifically, in the order of adding components. The specific methods and steps are as follows.

[0247] The concentration of the compound A injection product is 10 mg / ml, and its prescription contains one active ingredient and three adjuvants. Among the three adjuvants (DMA, ELP, and absolute ethanol), the solubility of the active ingredient compound A decreases in that order. Therefore, first, compound A of the pharmaceutical active ingredient (API) is added to a specified amount of DMA and stirred until dissolved. After compound A is completely dissolved in DMA, a specified amount of ELP is added and stirring continues. Finally, absolute ethanol is added to the final volume to reduce the risk of precipitation during the dissolution of the API. During the operation, it was observed that the continuously added ELP and absolute ethanol dissolved rapidly and the final solution was clear and transparent.

[0248] V. Study on the compatibility and stability of immediately - available intravenous injections Above, the prescription design of the concentrated injection, characteristics such as stability, and specific preparation examples were studied. Below, the preparation process and stability study of immediately - available injections will be described.

[0249] To provide compatibility information between the injectable compound of formula I (compound A, API) and a compatible solution, it is necessary to investigate the short-term stability of the injectable compound in a 5% glucose injectable solution, which is a commonly used intravenous diluent. Considering that API is unstable in an acidic environment, the pH of the 5% glucose injectable solution is first adjusted to 7.4 using a sodium bicarbonate solution.

[0250] 5.1 Experimental Methods and Procedures pH adjustment of compatible media 1.0 ml of 5% sodium bicarbonate injection was added to 250 ml of 5% glucose injection to adjust the pH, and the mixture was thoroughly mixed. At this point, the pH of the mixed solution was approximately 8.0.

[0251] Preparation of a compatible solution for compound A Using a pH-adjusted 5% glucose injection solution, compound A injection (2 ml: 20 mg) was prepared into a suitable solution with a concentration of 0.02 mg / ml and a suitable solution with a concentration of 1.00 mg / ml.

[0252] Preparation of a suitable 0.02 mg / ml solution 0.501 ml of Compound A injection (2 ml:20 mg) was added to a mixing bag containing 250 ml of 5% glucose injection (which had been pre-adjusted to pH using 5% sodium bicarbonate injection). Before storage and sampling, the mixing bag was repeatedly inverted to ensure that the mixture was uniformly mixed.

[0253] Preparation of a suitable 1.00 mg / ml solution 27.8 ml of Compound A injection (2 ml:20 mg) was added to a mixing bag containing 250 ml of 5% glucose injection (which had been pre-adjusted to pH using 5% sodium bicarbonate injection). Before storage and sampling, the mixing bag was repeatedly inverted to ensure that the mixture was uniformly mixed.

[0254] Temperature and light conditions All compatible solution samples were stored under indoor lighting conditions at room temperature (25±3℃).

[0255] Sampling time and test items 0 hours (before and after filtration), 2 hours, 4 hours, and 8 hours. Appearance, solution color, solution clarity, pH value, osmotic pressure, related substances, and content.

[0256] 5.2 Experimental Results All experimental data are listed in Tables 24 and 25 below, which summarize the stability data for compatible solutions at different concentrations.

[0257] [Table 33]

[0258] [Table 34]

[0259] Note: *: Because the drug content of the 1.0 mg / ml compatible solution decreased by more than 5% at 8 hours compared to 0 hours, an additional test was performed at 6 hours using the injectable sample from the same batch used to prepare the compatible solution (see Table 26).

[0260] [Table 35]

[0261] The experimental data in Tables 24, 25, and 26 show the following:

[0262] The 0.02 mg / ml suitable solution showed no changes in characteristics, clarity, or content before and after filtration using a microfiltration infusion set. After filtration, the suitable solution showed no significant changes in characteristics, solution color and clarity, osmotic pressure, pH value, compound A content, or related substances within 8 hours.

[0263] The 1.00 mg / ml suitable solution showed no changes in characteristics, clarity, or content before and after filtration using a microfiltration infusion set. After filtration, the suitable solution showed no significant changes in characteristics, solution color and clarity, osmotic pressure, pH value, or compound A content within 6 hours.

[0264] The injectable preparation of prescription F19 must be diluted with pH-adjusted 5% glucose injection before administration (the pH of the 5% glucose injection is pre-adjusted by adding 1.0 ml of 5% sodium bicarbonate injection to 250 ml of 5% glucose injection). When diluted to a concentration in the range of 0.02 mg / ml to 1 mg / ml, the solution remains stable for 6 hours at room temperature under indoor lighting. The diluted solution may exhibit emulsion, which is caused by the adjuvant in the injectable preparation. After filtration with a disposable microfiltration infusion set, it has been confirmed that the content remains unchanged for up to 6 hours.

[0265] VI. Study on the chiral stability of Compound A in injection and in compatible drug solutions of Compound A injection. Compound A is a racemic mixture containing one chiral center. Separation of compound A yields two isomers, named A-P1 and A-P2. In formulation and suitability studies, interconversion between chiral isomers can affect drug safety. Therefore, the chiral stability of compound A needs to be studied, both in its injectable formulation and in suitable drug solutions.

[0266] Solution preparation (a) A concentrated injectable formulation of compound A (2 ml: 20 mg) was prepared according to the previously confirmed formulation F19 and its preparation method.

[0267] (b) A suitable drug solution with a concentration of 1.00 mg / ml was prepared according to the preparation process for suitable solutions described in Section 5.1.

[0268] Experimental methods and control conditions The injectable formulation (concentrated injectable) of compound A was stored at -20±5°C under light-shielded, sealed conditions. Samples were taken at various time points (0 months, 1 month, 3 months), and the content of A-P1 and A-P2 was determined using the HPLC method described above to evaluate stability. The results are shown in Table 27.

[0269] A 1.00 mg / ml compatible drug solution (ready-to-use injectable) was stored at room temperature (25°C ± 2°C) under indoor lighting. Samples were taken at various time points (0 hours, 2 hours, 4 hours, 8 hours, and 24 hours), and the content of A-P1 and A-P2 was determined using the HPLC method described above to evaluate chiral stability. The results are shown in Table 28.

[0270] [Table 36]

[0271] [Table 37]

[0272] The experimental data above indicates that compound A exhibits stable chirality in both the injectable formulation and its compatible solution, and that chiral interconversion between the two isomers is minimal.

Claims

1. An injectable preparation comprising a solution containing a compound of the following formula (I), wherein the solvent of the solution contains a C2-C8 alcohol or a liquid mixture thereof. 【Chemistry 1】

2. The injectable preparation according to claim 1, wherein the C2-C8 alcohol is a monohydric alcohol or a polyhydric alcohol, preferably a monohydric alcohol, and more preferably ethanol.

3. The injectable preparation according to claim 1, wherein the solvent of the solution further comprises a nonionic surfactant as a solubilizing agent.

4. The nonionic surfactant is selected from polyethylene glycol, hydroxystearic acid ester, polyoxyethylene alkyl ether, tween, span, or polyoxyethylene castor oil. Examples of polyethylene glycol include polyethylene glycol 200, polyethylene glycol 400, polyethylene glycol 600, and polyethylene glycol 800. Examples of the hydroxystearate esters include polyethylene glycol 15-hydroxystearate and polyethylene glycol 12-hydroxystearate. Examples of alkyl groups in the polyoxyethylene alkyl ether include lauryl ether alkyl, oleyl ether alkyl, stearyl alcohol alkyl, and hexadecyl. Examples of the aforementioned twins include twin 20, twin 40, twin 60, and twin 80. Examples of the spans include span 20, span 40, span 60, and span 80. Examples of the polyoxyethylene castor oil include polyoxyethylene castor oil and polyoxyethylene hydrogenated castor oil. The injectable preparation according to claim 3.

5. The injectable preparation according to claim 1, wherein the solvent further comprises one or more of polyoxyethylene (35) castor oil, polyethylene glycol 15-hydroxystearate, polyethylene glycol 400, and Tween 80.

6. The injectable preparation according to claim 3, wherein the volume ratio of the nonionic surfactant to the C2-C8 alcohol in the solvent of the solution is 1:(1-4).

7. The injectable preparation according to claim 1, wherein the solvent of the solution further comprises an organic solvent having a hydrotropic effect.

8. The injectable preparation according to claim 7, wherein the organic solvent having a hydrotropic effect is selected from ethylenediamine, N,N-dimethylacetamide, N,N-dimethylformamide, or polyvinylpyrrolidone, and is preferably N,N-dimethylacetamide.

9. The injectable preparation according to claim 7, wherein the mass ratio of the organic solvent having a hydrotropic effect in the solvent of the solution to the compound of formula (I) according to claim 1 is (10 to 50):

1.

10. The injectable preparation according to claim 1, wherein the solvent of the solution further comprises a nonionic surfactant as a solubilizer and an organic solvent having a hydrotropic effect.

11. The injectable preparation according to claim 10, wherein the nonionic surfactant is selected from polyoxyethylene (35) castor oil, and the organic solvent having a hydrotropic effect is selected from N,N-dimethylacetamide.

12. The mass ratio of the nonionic surfactant in the solvent of the solution to the compound of formula (I) described in claim 1 is (0-90):1, preferably (5-50):1, more preferably (15-40):1, more preferably (20-40):1, and even more preferably (25-40):1, or The mass ratio of the organic solvent having a hydrotropic effect in the solvent of the solution to the compound of formula (I) described in claim 1 is (0 to 100):1, preferably (1 to 50):1, more preferably (5 to 25):1, and even more preferably (5 to 10):

1. The injectable preparation according to claim 10.

13. The injectable preparation according to any one of claims 1 to 12, wherein the content of the compound of formula (I) is 0.1 to 200 mg / ml, preferably 1 to 100 mg / ml, and more preferably 10 to 20 mg / ml.

14. An injectable preparation comprising the compound of formula (I) described in claim 1, N,N-dimethylacetamide, polyoxyethylene (35) castor oil, and ethanol.

15. An injectable preparation comprising the compound of the following formula (I), N,N-dimethylacetamide, polyoxyethylene (35) castor oil, and ethanol. 【Chemistry 2】

16. The content of the compound of formula (I) is 0.1 to 200 mg / ml, preferably 1 to 100 mg / ml, more preferably 10 to 20 mg / ml. The mass ratio of the compound of formula (I) to N,N-dimethylacetamide is 1:(0 to 100), preferably 1:(1 to 50), more preferably 1:(5 to 25), and even more preferably 1:(5 to 10). The mass ratio of the compound of formula (I) to polyoxyethylene (35) castor oil is 1:(0-90), preferably 1:(5-50), more preferably 1:(15-40), even more preferably 1:(20-40), and even more preferably 1:(25-40). The injectable preparation according to claim 14 or 15.

17. The injectable preparation according to claim 15, wherein the compound of formula (I) is present in an amount of 10 mg / ml.

18. The injectable preparation according to claim 17, wherein the compound of formula (I) is 20 mg, N,N-dimethylacetamide is 100 mg, and polyoxyethylene (35) castor oil is 800 mg.

19. A unit injection preparation, labeled as having a volume of 2 ml, is a concentrated ethanol solution containing 20 mg of the compound of formula (I), 100 mg of N,N-dimethylacetamide, and 800 mg of polyoxyethylene (35) castor oil.

20. An injectable preparation comprising the compound of formula (I) described in claim 1 and polyoxyethylene (35) castor oil.

21. An injectable preparation comprising the compound of formula (I) described in claim 1 and N,N-dimethylacetamide.

22. An injectable preparation comprising the compound of formula (I) described in claim 1, N,N-dimethylacetamide, and polyoxyethylene (35) castor oil.

23. An injectable preparation according to any one of claims 1 to 22, wherein no water is added, and the mass percentage of water is 1.0% or less, preferably 0.5% or less.

24. An injectable preparation product comprising a packaging container and an injectable preparation contained in the container, wherein the injectable preparation is the injectable preparation according to any one of claims 1 to 23, is filled in a light-shielding glass vial made of neutral borosilicate glass tube, and the content of the compound of formula (I) in the injectable preparation is 0.1 to 200 mg / ml, preferably 1 to 200 mg / ml, and more preferably 10 to 20 mg / ml.

25. An injectable preparation product comprising essentially the compound of formula (I) described in claim 1, N,N-dimethylacetamide, polyoxyethylene (35) castor oil, and ethanol, and filled in a 2 ml, 5 ml, or 10 ml light-shielding glass vial made of neutral borosilicate glass tube, characterized in that the content of the compound of formula (I) in the injectable preparation is 10 mg / ml, the mass ratio of the compound of formula (I) to N,N-dimethylacetamide is 1:5, and the mass ratio of the compound of formula (I) to polyoxyethylene (35) castor oil is 1:

40.

26. A method for preparing an injectable preparation, comprising the following steps: adding a specified amount of the compound of formula (I) described in claim 1 to a specified amount of N,N-dimethylacetamide while stirring and dissolving it; then adding a specified amount of polyoxyethylene (35) castor oil while stirring and dissolving it; and finally adding ethanol to a specified volume, mixing and dissolving it.

27. A method for preparing an injectable preparation according to claim 26, characterized by adding 20 mg of the compound of formula (I) described in claim 1 to 100 mg of N,N-dimethylacetamide and stirring until dissolved, then adding 800 mg of polyoxyethylene (35) castor oil and stirring until dissolved, and finally adding ethanol until the volume is 2 ml and mixing and dissolving.

28. A method for preparing an injectable preparation, comprising the following steps: adding a specified amount of the compound of formula (I) to a specified amount of N,N-dimethylacetamide with stirring to obtain a first solution; adding a specified amount of polyoxyethylene (35) castor oil to a portion of ethanol with stirring to obtain a second solution; and adding the first solution to the second solution with stirring, stirring until the mixture becomes clear, and then adding ethanol to a specified volume, mixing, and dissolving.

29. A ready-to-use injectable preparation for injection, prepared from water, an isotonic adjusting agent, and an injectable preparation according to any one of claims 1 to 23, characterized in that a pH adjusting agent is added to the injectable preparation or not.

30. A ready-to-use injectable preparation comprising water, an isotonic adjusting agent, a compound of formula (I) according to claim 1, N,N-dimethylacetamide, polyoxyethylene (35) castor oil, ethanol, and a pH adjusting agent, wherein the injectable preparation is an isotonic solution with a pH of 6.8 to 10.5 and the concentration of the compound of formula (I) is 0.016 to 1.10 mg / ml, and the preparation is ready-to-use injectable preparation.

31. The ready-to-use injectable preparation according to claim 30, wherein the concentration of the compound of formula (I) is 0.020 to 1.00 mg / ml.

32. The ready-to-use injectable preparation according to claim 30, wherein the pH value of the injectable preparation is 7.4 to 8.1, preferably 7.

7.

33. A ready-to-use injectable preparation for injection according to claim 29 or 30, wherein the pH adjusting agent is selected from one or more of sodium citrate, potassium citrate, sodium acetate, potassium acetate, potassium dihydrogen phosphate, sodium dihydrogen phosphate, dipotassium hydrogen phosphate, disodium hydrogen phosphate, potassium phosphate, sodium phosphate, sodium hydroxide, potassium hydroxide, sodium bicarbonate, potassium bicarbonate, sodium carbonate, and potassium carbonate.

34. The ready-to-use injectable preparation according to claim 29 or 30, wherein the isotonic adjusting agent is selected from anhydrous or aqueous sodium chloride, glucose, sucrose, fructose, xylitol, glycerol, sorbitol, mannitol, potassium chloride, mannose, calcium chloride, magnesium chloride, or a mixture thereof.

35. An injectable preparation comprising water, glucose as an isotonic adjusting agent, the compound of formula (I) described in claim 1, N,N-dimethylacetamide, polyoxyethylene (35) castor oil, ethanol, and sodium bicarbonate as a pH adjusting agent, wherein the injectable preparation is an isotonic solution with a pH of 7.4, the concentration of the compound of formula (I) is 0.016 to 1.10 mg / ml, preferably 0.020 to 1.00 mg / ml, and the mass percentage of the glucose content is 4.5 to 5.0%.

36. The injectable preparation for injection according to claim 35, wherein the mass ratio of the compound of formula (I) to N,N-dimethylacetamide is 1:5, and the mass ratio of the compound of formula (I) to polyoxyethylene (35) castor oil is 1:

40.

37. A method for preparing an injectable preparation ready for immediate use, comprising the steps of: obtaining a mixed solution by adding an appropriate amount of sodium bicarbonate solution as a pH adjuster to a 5% glucose injectable preparation so that the pH of the mixed solution is 7.7 to 8.1; and then adding an injectable preparation according to any one of claims 1 to 23, or an injectable preparation product according to claim 24 or 25, to the mixed solution, mixing and dissolving to obtain the injectable preparation ready for immediate use.

38. The method for preparing a ready-to-use injectable preparation according to claim 37, wherein the mixed solution is obtained by adding 1 volume of 5% sodium bicarbonate injection to 250 volumes of 5% glucose injection.

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