Y-3 formulation convenient for storage and transportation

Abstract

Disclosed is a Y-3 formulation convenient for storage and transportation. The present invention belongs to the field of pharmaceutical formulations. In the present invention, Y-3, a pharmaceutically acceptable excipient convenient for freeze-drying formation, and a surfactant are dissolved and then subjected to freeze-drying treatment to form a freeze-dried powder for injection. As water is removed, the possibility of a chemical reaction is reduced. Preparing the drug into a freeze-dried powder for injection can increase the stability of the drug. Moreover, the freeze-dried formulation is convenient for storage and transportation due to the small volume and light weight thereof. Furthermore, the formulation can be stored for a long time without losing activity; thus, the shelf life of the drug is extended. During use, the formulation can be quickly restored to the original state by means of a mere reconstitution process.

Description

Y-3 preparation facilitating storage and transportation

[0001] The present application claims priority to the Chinese patent application No. 202411059946.5, filed on August 5, 2024, and entitled "Y-3 preparation facilitating storage and transportation", the content of which is incorporated herein by reference in its entirety. TECHNICAL FIELD

[0002] The present application belongs to the technical field of pharmaceutical preparations, and specifically relates to a Y-3 preparation facilitating storage and transportation. BACKGROUND

[0003] Y-3 injection is a new small-molecule neuroprotective agent developed by Nanjing Ningdan New Drug Technology Co., Ltd., with independent intellectual property rights. Its active ingredient Y-3 has the dual-target activity of dissociating PSD-95 and nNOS coupling and agonizing α2-GABAAR. In cerebral ischemic injury, Y-3 simultaneously intervenes in the dual-target of PSD95-nNOS and α2-GABAAR, which is more conducive to exerting brain protection; at the same time, as a positive allosteric modulator of α2-GABAAR, it eliminates the GABA disinhibition of the NMDAR-PSD-95-nNOS signaling pathway, which is conducive to maintaining drug efficacy.

[0004] Y-3 can selectively act on the pathological NMDAR downstream target, i.e., only inhibits the PSD-95-nNOS coupling induced by cerebral ischemia, without affecting the coupling of the two proteins under physiological conditions and other related protein-protein interactions and protein expression downstream of NMDA receptors. In addition, since Y-3 selectively agonizes α2-GABAAR without affecting the α1 subtype, it can reduce various adverse central nervous system effects mediated by the α1 subtype of GABAAR, including sedation, ataxia, amnesia, tolerance, and addiction, etc.

[0005] The structural formula of Y-3 is as follows:

[0006] WO2013064031A1 discloses a class of N-benzyl aniline derivatives, which have the most prominent feature of having the protective effect of cerebral ischemia-reperfusion injury and analgesic effect on chronic pathological pain, and can be used for preparing drugs for treating stroke, neuropathic pain, and inflammatory pathological pain.

[0007] CN116407530A discloses a composition, Y-3 micellar injection and a preparation method thereof, which comprises Y-3, propylene glycol and 15-hydroxystearic acid polyethylene glycol ester, and provides a preparation method of Y-3 micellar injection and its application.

[0008] Due to the physicochemical properties of Y-3 drug substance, the conventional injection formulation requires low temperature storage and cold chain transportation. In order to meet the follow-up supply demand and reduce the cost of the product, a new Y-3 formulation is needed to improve the existing product storage and transportation conditions, while meeting the safety of clinical medication.

[0009] Lyophilized formulation, also known as lyophilized powder injection, is a special form of drug preparation, mainly used for drugs that are unstable or easily degraded under normal conditions, such as protein drugs (such as interferon), enzymes (such as coenzyme A) and some blood products. The process mainly realizes the transformation of the drug from a solution state to a solid state through low-temperature pre-freezing, primary drying (sublimation), and secondary drying (desorption drying). Since this process does not involve high-temperature conditions, it is particularly suitable for temperature-sensitive drugs. Since the water is removed, the possibility of chemical reactions is reduced, and the stability of the drug can be improved after the drug is prepared into a lyophilized powder; at the same time, it is convenient for storage and transportation because the volume of the lyophilized preparation is small and the weight is light; and it can be stored for a long time without losing activity, prolonging the effective period of the drug. When used, only an appropriate amount of solvent (such as sterile water) is needed to quickly restore it to its original state.

[0010] Whether the Y-3 micellar injection disclosed in CN116407530A can be prepared into a lyophilized powder injection to improve the storage and transportation conditions of the drug; whether the lyophilized product still has the same quality attributes as the Y-3 micellar injection after reconstitution is a problem that needs to be explored and researched by the present invention, and the creativity and novelty of the present invention are also generated around solving the above core problems. SUMMARY

[0011] The technical problem solved by the present application is to provide a Y-3 formulation that is convenient to store and transport, to solve the existing storage and transportation conditions of Y-3, and as a nanometer preparation, the product after lyophilization and reconstitution has the same key nanometer quality attributes as Y-3 micellar injection.

[0012] Technical solution: A Y-3 formulation convenient for storage and transportation, the formulation is a lyophilized formulation, comprising: Y-3, a pharmaceutical excipient convenient for lyophilization molding, and a surfactant.

[0013] Further, preferably, comprising: Y-3, a pharmaceutical excipient convenient for lyophilization molding, a surfactant, and a low-molecular alcohol for further increasing solubility.

[0014] Further, preferably, comprising: Y-3, a pharmaceutical excipient convenient for lyophilization molding, a surfactant for increasing the solubility of Y-3, a low-molecular alcohol for further increasing solubility, and a solvent for reconstitution required for clinical administration.

[0015] Further, preferably, the proportion of Y-3 in the preparation is 0.1-12% (w / v), the proportion of the surfactant is 0.1-50% (w / v), and the proportion of the pharmaceutical excipient facilitating lyophilization is 1-30% (w / v).

[0016] Further, optionally, the proportion of Y-3 in the preparation is 0.1% (w / v), 0.2% (w / v), 0.5% (w / v), 0.8% (w / v), 1% (w / v), 1.5% (w / v), 2% (w / v), 2.5% (w / v), 3% (w / v), 3.5% (w / v), 4% (w / v), 4.5% (w / v), 5% (w / v), 5.5% (w / v), 6% (w / v), 6.5% (w / v), 7% (w / v), 7.5% (w / v), 8% (w / v), 8.5% (w / v), 9% (w / v), 9.5% (w / v), 10% (w / v), 10.5% (w / v), 11% (w / v), 11.5% (w / v), 12% (w / v), or a range between any two of the above values.

[0017] Further, optionally, the proportion of the surfactant in the preparation is 0.1% (w / v), 0.5% (w / v), 1% (w / v), 5% (w / v), 8% (w / v), 10% (w / v), 12% (w / v), 15% (w / v), 18% (w / v), 20% (w / v), 22% (w / v), 25% (w / v), 28% (w / v), 30% (w / v), 32% (w / v), 35% (w / v), 38% (w / v), 40% (w / v), 42% (w / v), 45% (w / v), 48% (w / v), 50% (w / v), or a range between any two of the above values.

[0018] Further, optionally, the proportion of the pharmaceutical excipient facilitating lyophilization in the preparation is 1% (w / v), 5% (w / v), 8% (w / v), 10% (w / v), 12% (w / v), 15% (w / v), 18% (w / v), 20% (w / v), 22% (w / v), 25% (w / v), 28% (w / v), 30% (w / v), or a range between any two of the above values.

[0019] In the present application, the w / v refers to the mass / volume percentage concentration of the solute in the solvent, with the unit of g / ml.

[0020] In the present application, unless otherwise specified, the proportion of each component in the preparation is the proportion of the raw material required for the preparation of the preparation.

[0021] Further, preferably, the reconstitution solvent comprises a low molecular alcohol to further increase the solubility and a reconstitution solvent required for clinical administration, wherein the proportion of the low molecular alcohol is 0-50% (w / v) and the balance is the reconstitution solvent required for clinical administration.

[0022] Further, optionally, the proportion of the low molecular alcohol in the reconstitution solvent is 0% (w / v), 1% (w / v), 5% (w / v), 8% (w / v), 10% (w / v), 12% (w / v), 15% (w / v), 18% (w / v), 20% (w / v), 22% (w / v), 25% (w / v), 28% (w / v), 30% (w / v), 32% (w / v), 35% (w / v), 38% (w / v), 40% (w / v), 42% (w / v), 45% (w / v), 48% (w / v), 50% (w / v), or a range between any two of the above values.

[0023] Further, preferably, the reconstitution solvent required for clinical administration and the low molecular alcohol to increase the solubility are jointly comprised in the reconstitution solvent of the reconstitution lyophilized preparation in the preparation, wherein the proportion of the low molecular alcohol is 0-50% (w / v) and the balance is the reconstitution solvent commonly used in the art. Optionally, the proportion of the low molecular alcohol is 0% (w / v), 1% (w / v), 5% (w / v), 8% (w / v), 10% (w / v), 12% (w / v), 15% (w / v), 18% (w / v), 20% (w / v), 22% (w / v), 25% (w / v), 28% (w / v), 30% (w / v), 32% (w / v), 35% (w / v), 38% (w / v), 40% (w / v), 42% (w / v), 45% (w / v), 48% (w / v), 50% (w / v), or a range between any two of the above values.

[0024] Furthermore, preferably, the formulation package further includes a solvent required for clinical application, i.e., the formulation is a composition comprising a lyophilized formulation and a solvent required for clinical application; the solvent required for clinical application comprises a low alcohol to increase solubility and a reconstitution solvent required for clinical application, wherein the proportion of the low alcohol is 0-50% (w / v) and the balance is the reconstitution solvent. Optionally, the proportion of low alcohol is 0% (w / v), 1% (w / v), 5% (w / v), 8% (w / v), 10% (w / v), 12% (w / v), 15% (w / v), 18% (w / v), 20% (w / v), 22% (w / v), 25% (w / v), 28% (w / v), 30% (w / v), 32% (w / v), 35% (w / v), 38% (w / v), 40% (w / v), 42% (w / v), 45% (w / v), 48% (w / v), 50% (w / v), or any two of the above values.

[0025] Furthermore, preferably, the pharmaceutical excipients that facilitate freeze-drying are selected from carbohydrate compounds and / or sugar alcohols;

[0026] And / or, the surfactant is selected from one or more of polyethylene glycol surfactants, polyoxyethylene surfactants, alkyl sulfate surfactants, cyclodextrin compounds and phospholipid compounds.

[0027] Further, preferably, the carbohydrate compound is selected from sucrose and / or trehalose;

[0028] And / or, the sugar alcohol compound is selected from mannitol;

[0029] And / or, the polyethylene glycol surfactant is selected from polyethylene glycol 15-hydroxystearate, PEG 3000-5000 -PLA 2000-5000 PEG 3000-5000 -PLA 2000-5000 -PEG 3000-5000 With PEG 3000-5000 -PCL 2000-5000 One or more of the following;

[0030] And / or, the polyoxyethylene surfactant is selected from one or more of polyoxyethylene (35) castor oil, polyoxyethylene 40 hydrogenated castor oil, polysorbate 80, polysorbate 20, poloxamer 188 and poloxamer 407;

[0031] And / or, the alkyl sulfate surfactant is selected from sodium dodecyl sulfate;

[0032] And / or, the cyclodextrin compounds are selected from hydroxypropyl beta-cyclodextrin and / or sulfobutyl beta-cyclodextrin;

[0033] and / or, the phospholipid compound is selected from one or more of hydrogenated soybean lecithin, soybean phospholipid, lecithin, dioleoylphosphatidylcholine, dipalmitoyl lecithin, distearoylphosphatidylcholine, distearoylphosphatidylethanolamine and dioleoylphosphatidylethanolamine.

[0034] Further, preferably, the surface active agent comprises one or two and more combinations of 15-hydroxystearic acid polyethylene glycol ester, polyoxyethylene (35) castor oil, polyoxyethylene 40 hydrogenated castor oil, polysorbate 80, polysorbate 20, sodium dodecyl sulfate, hydroxypropyl betadex, sulfobutyl betadex, hydrogenated soybean lecithin, soybean phospholipid, lecithin, dioleoylphosphatidylcholine, dipalmitoyl lecithin, distearoylphosphatidylcholine, distearoylphosphatidylethanolamine, dioleoylphosphatidylethanolamine, PEG 3000-5000 -PLA 2000-5000 , PEG 3000-5000 -PLA 2000-5000 -PEG 3000-5000 , poloxamer 188, poloxamer 407, PEG 3000-5000 -PCL 2000-5000 and two and more combinations thereof.

[0035] Further, preferably, the freeze-drying molding facilitating pharmaceutical excipient comprises one or two and more combinations of mannitol, sucrose and trehalose.

[0036] Further, preferably, the low molecular alcohol comprises one or two and more combinations of ethanol, propylene glycol, glycerol, tert-butyl alcohol, diethylene glycol monoethyl ether.

[0037] Further, preferably, the buffer that can be used in the preparation process to avoid pH fluctuation comprises one or two and more combinations of citric acid-sodium citrate, acetic acid-sodium acetate buffer, phosphate buffer, Tris-hydrochloric acid buffer.

[0038] Further, preferably, the reconstitution solvent is one or two and more combinations of phosphate buffer, Hanks balanced salt solution, Tris hydrochloric acid buffer, ethanol, propylene glycol, DMSO, water for injection, normal saline, glucose injection, fructose injection.

[0039] Further, preferably, the preparation process of the freeze-dried powder injection comprises dissolving, mixing, filtering sterilization, sub-packaging, freeze-drying and capping; wherein:

[0040] The dissolving step in the preparation process is carried out in the dark, and the pH value of the solution after dissolving is adjusted to 5-10 by buffer solution;

[0041] The solvent used in the dissolving step in the preparation process preferably includes a low molecular alcohol to increase the solubility and a common dissolving solvent; the common dissolving solvent is the same as the kind of the reconstitution solvent required in the clinical application, i.e. preferably one or a combination of two or more of phosphate buffer, Hanks balanced salt solution, Tris hydrochloride buffer, ethanol, propylene glycol, DMSO, water for injection, normal saline, glucose injection, fructose injection;

[0042] The mixing step in the preparation process uses an emulsifying tank or microfluidic mixing;

[0043] The sterilization step in the preparation process uses an online or offline method, and uses a filter level of 0.45 microns / 0.22 microns / 0.22 microns or 0.45 microns / 0.22 microns x 2, and the filtered drug solution needs to meet the sterile requirements;

[0044] The dispensing step in the preparation process has a dispensing amount of 5mg-80mg of Y-3 per bottle;

[0045] The freeze-drying step in the preparation process has a low-temperature pre-freezing temperature of -80 to -40 degrees Celsius, a primary drying temperature of -30 to -10 degrees Celsius, a secondary drying temperature of 0 to 30 degrees Celsius, and a freeze-drying process time of 30 to 52 hours.

[0046] Further, optionally, the dispensing step in the preparation process has a dispensing amount of 5mg, 10mg, 15mg, 20mg, 25mg, 30mg, 35mg, 40mg, 45mg, 50mg, 55mg, 60mg, 65mg, 70mg, 75mg, 80mg of Y-3 per bottle or a range between any two of the above values.

[0047] Further, optionally, the low-temperature pre-freezing temperature is -80 degrees Celsius, -70 degrees Celsius, -60 degrees Celsius, -50 degrees Celsius, -40 degrees Celsius, or a range between any two of the above values.

[0048] Further, optionally, the primary drying temperature is -30 degrees Celsius, -20 degrees Celsius, -10 degrees Celsius, or a range between any two of the above values.

[0049] Further, optionally, the secondary drying temperature is 0 degrees Celsius, 10 degrees Celsius, 20 degrees Celsius, 30 degrees Celsius, or a range between any two of the above values.

[0050] Further, optionally, the freeze-drying process time is 30 hours, 35 hours, 40 hours, 45 hours, 50 hours, 52 hours, or a range between any two of the above values.

[0051] Further, preferably, the freeze-dried powder injection is any one of the following forms: a combination vial, a single vial, a pre-filled syringe, a pre-filled syringe and a single vial, a single vial, an ampoule, a double-chamber vial, and a double-chamber pre-filled syringe.

[0052] Further, preferably, the Y-3 preparation is administered in the following process: the Y-3 freeze-dried powder is reconstituted with a reconstitution solvent to obtain a Y-3 concentrated solution, and then the Y-3 concentrated solution is diluted into a compatible solvent to obtain a desired concentration for administration.

[0053] Further, preferably, the Y-3 preparation is administered in the following process: the Y-3 freeze-dried powder is reconstituted with a reconstitution solvent to obtain a Y-3 concentrated solution, and then the Y-3 concentrated solution is diluted into a compatible solvent to obtain a desired concentration for administration. Beneficial effects:

[0054] Y-3 is reconstituted with pharmaceutical excipients, surfactants, and low-molecular alcohols, and then freeze-dried after adjusting the pH of the solution with a buffer. After freeze-drying, the freeze-dried powder is obtained. Since water is removed, the possibility of chemical reactions is reduced. The stability of the drug can be improved after the drug is prepared into a freeze-dried powder. At the same time, storage and transportation are convenient because the volume and weight of the freeze-dried preparation are small. The freeze-dried preparation can be stored for a long time without losing activity, thereby prolonging the shelf life of the drug. During use, the freeze-dried powder can be quickly restored to the original state by reconstitution with a reconstitution solvent. BRIEF DESCRIPTION OF DRAWINGS

[0055] FIG. 1 is a typical chromatogram obtained by using the related substance detection method of the present application. DETAILED DESCRIPTION

[0056] The technical solutions in the embodiments of the present application will be described below in conjunction with the embodiments of the present application. Obviously, the described embodiments are only a part of the embodiments of the present application, rather than all the embodiments. Based on the embodiments of the present application, all other embodiments obtained by those of ordinary skill in the art without creative labor fall within the scope of the present application.

[0057] Embodiment 1

[0058] In this embodiment, the reconstitution solvent for the Y-3 pharmaceutical composition for injection is preliminarily screened.

[0059] Table 1 Preliminary screening of reconstitution solvents (I)

[0060] Table 1 Preliminary screening of reconstitution solvents (II)

[0061] Note: The average particle size and polydispersity coefficient of Y-3 injection in the above table are the results of Y-3 micellar injection in the prior art, and the meanings in the following table are the same.

[0062] Table 1 Preliminary screening of solvents for reconstitution (three)

[0063] Table 1 Preliminary screening of solvents for reconstitution (four)

[0064] Table 1 Preliminary screening of solvents for reconstitution (five)

[0065] The preliminary research results suggest that ethanol, phosphate buffer, propylene glycol, Hanks balanced salt solution, Tris hydrochloride buffer, DMSO, water for injection, normal saline, glucose injection, fructose injection, or at least two compounds as reconstitution solvents for Y-3 injection have no significant effect on the key quality indicators of the product.

[0066] Example 2

[0067] The effects of low-alcohol: ethanol, tert-butyl alcohol, propylene glycol, glycerol, diethylene glycol monoethyl ether, alone or in combination, on the key quality indicators of the product were investigated, and the screened formulations and results are shown in Table 2.

[0068] Table 2. Investigation of low-alcohol-tert-butyl alcohol dosage screening formulations

[0069] Table 2. Investigation of low-alcohol-ethanol dosage screening formulations

[0070] Table 2. Investigation of low-alcohol-propylene glycol dosage screening formulations

[0071] Table 2. Investigation of low-alcohol-glycerol dosage screening formulations

[0072] Table 2. Investigation of low-alcohol-diethylene glycol monoethyl ether dosage screening formulations

[0073] Table 2. Investigation of low-alcohol formulation results (one)

[0074] Table 2. Investigation of low-alcohol formulation results (two)

[0075] Table 2. Investigation of low-alcohol formulation results (three)

[0076] Table 2. Results of investigating low-alcohol formula (four)

[0077] Table 2. Results of investigating low-alcohol formula (five)

[0078] The results of the study suggest that the use of at least one of ethanol, propylene glycol, glycerol, tert-butyl alcohol, and diethylene glycol monoethyl ether as a solvent for reconstitution of Y-3 for injection obtained by lyophilization of the composition meets the quality requirements.

[0079] Example 3

[0080] Screening of lyophilization protectants: the amounts of mannitol, sucrose, and trehalose in the formula, and the results are shown in Table 3.

[0081] Table 3. Formula for screening the amount of lyophilization protectant (mannitol)

[0082] Table 3. Formula for screening the amount of lyophilization protectant (trehalose)

[0083] Table 3. Formula for screening the amount of lyophilization protectant (sucrose)

[0084] Table 3. Results of screening the amount of lyophilization protectant (mannitol)

[0085] Table 3. Results of screening the amount of lyophilization protectant (trehalose)

[0086] Table 3. Results of screening the amount of lyophilization protectant (sucrose)

[0087] The results of the study suggest that the use of at least one of ethanol, propylene glycol, glycerol, tert-butyl alcohol, and diethylene glycol monoethyl ether as a solvent for reconstitution of Y-3 for injection obtained by lyophilization of the composition meets the quality requirements.

[0088] Example 4

[0089] Screening of the types and amounts of surfactants in the formula (wherein the solvent for reconstitution is 0.6 g of propylene glycol and 1.4 g of water):

[0090] Table 4. Formula for screening the types of surfactants and results (one)

[0091] Table 4. Formula for screening the types of surfactants and results (two) The results of the study suggest that the use of at least one of ethanol, propylene glycol, glycerol, tert-butyl alcohol, and diethylene glycol monoethyl ether as a solvent for reconstitution of Y-3 for injection obtained by lyophilization of the composition meets the quality requirements.

[0092] Table 4 Formulation and results of surfactant type screening (three)

[0093] Table 4 Formulation and results of surfactant type screening (four)

[0094] Example 5

[0095] The concentration of main drug Y-3 in the screening formulation:

[0096] Table 5. Y-3 concentration preliminary screening formulation (one)

[0097] Table 5. Y-3 concentration preliminary screening formulation (two)

[0098] Table 5. Y-3 concentration preliminary screening formulation (three)

[0099] The results show that the concentration of Y-3 in the freeze-drying formulation is 0.1-12% (w / v), which can obtain freeze-dried products with appearance meeting the requirements.

[0100] Example 6

[0101] Preparation process of Y-3 for injection:

[0102] Preparation method: (1) Solution preparation: 15-hydroxystearic acid polyethylene glycol ester / Y-3 / mannitol solution preparation 1: Put 15-hydroxystearic acid polyethylene glycol ester into the solution preparation tank and start stirring. Add the prescribed amount of Y-3 and mannitol, and stir until they are evenly dispersed and completely dissolved. Solution preparation 2 of prescribed amount of tert-butyl alcohol / PBS aqueous solution: Take the solution preparation barrel and add the prescribed amount of water for injection, start stirring, and then add the prescribed amount of potassium phosphate dibasic-potassium phosphate monobasic buffer salt and tert-butyl alcohol, and stir until they are completely dissolved.

[0103] (2) Mixing the solution and constant volume: Add solution preparation 2 to solution preparation 1 through a peristaltic pump or compressed gas, stir, and observe with the naked eye until the mixture is completely mixed. Then add the cooled water for injection to make up to the full amount.

[0104] (3) Intermediate detection.

[0105] (4) Filtration: After the intermediate detection is qualified, the solution is delivered to the storage tank through a 0.45 μm / 0.2 μm sterilization filter.

[0106] (5) Westlin bottle filling

[0107] (6) Freeze-drying: set the shelf temperature to -50 °C, maintain; vacuumize, raise the shelf temperature to -30 °C, maintain; raise the shelf temperature to 0 °C, maintain; raise the shelf temperature to 20 °C, maintain; raise the shelf temperature to 30 °C, maintain until freeze-drying is completed. Press the plug, and take out the box.

[0108] Example 7

[0109] Preparation process development of Y-3 for injection:

[0110] Preparation method: (1) Solution preparation: 15-hydroxystearic acid polyethylene glycol ester / Y-3 / trehalose solution preparation 1: add 15-hydroxystearic acid polyethylene glycol ester to the solution preparation tank and start stirring. Add the prescribed amount of Y-3 and trehalose, stir thoroughly to disperse uniformly, and stir until completely dissolved. Solution preparation 2 of the prescribed amount of ethanol / phosphate buffer solution: take the solution preparation barrel, add the prescribed amount of water for injection, start stirring, and then add the prescribed amount of sodium dihydrogen phosphate-disodium hydrogen phosphate and ethanol in sequence, and stir until completely dissolved.

[0111] (2) Mix the solutions and make up the volume: Pump solution 2 and solution 1 to the microfluidic chip through high-pressure pumps, mix them in the chip, and then add cooled water for injection to make up the full volume.

[0112] (3) Intermediate detection.

[0113] (4) Filtration: After the intermediate detection is qualified, the solution is transported to the storage tank through a 0.45 μm / 0.2 μm sterilization filter.

[0114] (5) Pre-flush needle filling

[0115] (6) Freeze-drying: set the shelf temperature to -80 °C, maintain; vacuumize, raise the shelf temperature to -30 °C, maintain; raise the shelf temperature to 0 °C, maintain; raise the shelf temperature to 15 °C, maintain; raise the shelf temperature to 30 °C, maintain until freeze-drying is completed. Press the plug, and take out the box.

[0116] Example 8

[0117] Preparation process development of Y-3 for injection:

[0118] Preparation method: (1) Solution preparation: 15-hydroxystearic acid polyethylene glycol ester / Y-3 / trehalose solution preparation 1: add 15-hydroxystearic acid polyethylene glycol ester to the solution preparation tank and start stirring. Add the prescribed amount of Y-3 and trehalose, stir thoroughly to disperse uniformly, and stir until completely dissolved. Solution preparation 2 of the prescribed amount of ethanol / phosphate buffer solution: take the solution preparation barrel, add the prescribed amount of water for injection, start stirring, and then add the prescribed amount of sodium dihydrogen phosphate-disodium hydrogen phosphate and ethanol in sequence, and stir until completely dissolved.

[0119] (2) Mixing and constant volume of the solution: liquid solution 2 and solution 1 are pumped into the Y-shaped microfluidic chip through high-pressure pumps, and then cooled water is added to constant volume.

[0120] (3) Intermediate detection.

[0121] (4) Filtration: after the intermediate detection is qualified, the solution is delivered to the storage tank through 0.45 μm / 0.22 μm / 0.22 μm sterilizing filter.

[0122] (5) Pre-needle filling

[0123] (6) Freeze-drying: set the plate layer temperature to -40°C and maintain; vacuumize, and then increase the plate layer temperature to -10°C and maintain; increase the plate layer temperature to 0°C and maintain; increase the plate layer temperature to 15°C and maintain; increase the plate layer temperature to 30°C and maintain until the freeze-drying is completed. Press the plug and take out the box.

[0124] Example 9

[0125] Preparation process of Y-3 for injection:

[0126] Preparation method: (1) Solution preparation: 15-hydroxypolyethylene glycol stearate / Y-3 / trehalose solution solution 1: add 15-hydroxypolyethylene glycol stearate into the solution tank and start stirring. Add the prescribed amount of Y-3 and trehalose, and stir until they are evenly dispersed and completely dissolved. Solution 2 of ethanol / phosphate buffer solution: take the solution tank and add the prescribed amount of water, start stirring, and then add the prescribed amount of sodium dihydrogen phosphate-disodium hydrogen phosphate and ethanol in sequence, and stir until they are completely dissolved.

[0127] (2) Mixing and constant volume of the solution: liquid solution 2 and solution 1 are pumped into the Y-shaped microfluidic chip through high-pressure pumps, and then cooled water is added to constant volume.

[0128] (3) Intermediate detection.

[0129] (4) Filtration: after the intermediate detection is qualified, the solution is delivered to the storage tank through 0.45 μm / 0.22 μm / 0.22 μm sterilizing filter.

[0130] (5) Pre-needle filling

[0131] (6) Freeze-drying: set the plate layer temperature to -40°C and maintain; vacuumize, and then increase the plate layer temperature to -10°C and maintain; increase the plate layer temperature to 0°C and maintain; increase the plate layer temperature to 15°C and maintain; increase the plate layer temperature to 30°C and maintain until the freeze-drying is completed. Press the plug and take out the box.

[0132] Example 10

[0133] Preparation process of Y-3 for injection:

[0134] Preparation method: (1) Liquid preparation: 15-hydroxystearic acid polyethylene glycol ester / Y-3 / trehalose solution preparation 1: 15-hydroxystearic acid polyethylene glycol ester is added to the liquid preparation tank, and stirring is started. Add the prescribed amount of Y-3, trehalose, and stir thoroughly to disperse uniformly. Stir until all are dissolved uniformly. Prescription amount of tert-butyl alcohol / phosphoric acid buffer solution preparation 2: Take the liquid preparation barrel and add the prescribed amount of water for injection. Start stirring, and add the prescribed amount of citric acid-sodium citrate, tert-butyl alcohol in turn, and stir until all are dissolved.

[0135] (2) Mix the liquid preparation and make up to volume: Pump the liquid preparation 2 and the liquid preparation 1 to the Y-shaped microfluidic chip through the high-pressure pump, and then add cooled water for injection to make up to the full volume after mixing in the chip.

[0136] (3) Intermediate detection.

[0137] (4) Filtration: After the intermediate detection is qualified, the liquid is transported to the storage tank through 0.45 μm / 0.22 μm*2 sterilization filter.

[0138] (5) Westlin bottle filling

[0139] (6) Freeze-drying: Set the plate layer temperature to -50°C and maintain; vacuumize, and raise the plate layer temperature to -15°C and maintain; raise the plate layer temperature to 5°C and maintain; raise the plate layer temperature to 15°C and maintain; raise the plate layer temperature to 30°C and maintain until the freeze-drying is completed. Press the plug and take out the box.

[0140] Example 11

[0141] Preparation process of Y-3 for injection:

[0142] Preparation method: (1) Liquid preparation: 15-hydroxystearic acid polyethylene glycol ester / Y-3 / tert-butyl alcohol solution preparation 1: 15-hydroxystearic acid polyethylene glycol ester is added to the liquid preparation tank, and stirring is started. Add the prescribed amount of Y-3, tert-butyl alcohol, and stir thoroughly to disperse uniformly. Stir until all are dissolved uniformly. Prescription amount of mannitol / phosphoric acid buffer solution preparation 2: Take the liquid preparation barrel and add the prescribed amount of water for injection. Start stirring, and add the prescribed amount of potassium phosphate dibasic-potassium phosphate monobasic buffer salt, mannitol in turn, and stir until all are dissolved.

[0143] (2) Mix the liquid preparation and make up to volume: Pump the liquid preparation 2 and the liquid preparation 1 to the Y-shaped microfluidic chip through the high-pressure pump, and then add cooled water for injection to make up to the full volume after mixing in the chip.

[0144] (3) Intermediate detection.

[0145] (4) Filtration: After the intermediate is qualified, the feed liquid is delivered to the storage tank through 0.45 μm / 0.22 μm*2 sterilization filter.

[0146] (5) Vial filling

[0147] (6) Freeze-drying: Set the plate temperature to -45°C, maintain; vacuumize, raise the plate temperature to -20°C, maintain; raise the plate temperature to 0°C, maintain; raise the plate temperature to 8°C, maintain; raise the plate temperature to 30°C, maintain until the freeze-drying is completed. Press the plug and take out the box.

[0148] Example 12

[0149] Preparation process development of Y-3 for injection:

[0150] Preparation method: (1) Solution preparation: 15-hydroxystearic acid polyethylene glycol ester / Y-3 / tert-butyl alcohol solution solution 1: add 15-hydroxystearic acid polyethylene glycol ester to the solution preparation tank and start stirring. Add the prescribed amount of Y-3 and tert-butyl alcohol, and fully stir to disperse uniformly. Stir until all are dissolved uniformly. Solution 2: Take the solution preparation barrel and add the prescribed amount of water for injection, start stirring, and add the prescribed amount of Tris-hydrochloric acid and trehalose in turn, and stir until all are dissolved.

[0151] (2) Mix the solution and set the volume: Pump solution 2 and solution 1 to the Y-shaped microfluidic chip through the high-pressure pump, mix after the chip, and add cold water for injection to set the volume to the full amount.

[0152] (3) Intermediate detection.

[0153] (4) Filtration: After the intermediate is qualified, the feed liquid is delivered to the storage tank through 0.45 μm / 0.22 μm*2 sterilization filter.

[0154] (5) Vial filling

[0155] (6) Freeze-drying: Set the plate temperature to -40°C, maintain; vacuumize, raise the plate temperature to -20°C, maintain; raise the plate temperature to -5°C, maintain; raise the plate temperature to 10°C, maintain; raise the plate temperature to 25°C, maintain until the freeze-drying is completed. Press the plug and take out the box.

[0156] Example 13

[0157] Preparation process development of Y-3 for injection:

[0158] Preparation method: (1) Liquid preparation: 15-hydroxystearic acid polyethylene glycol ester / Y-3 / tert-butyl alcohol solution liquid preparation 1: 15-hydroxystearic acid polyethylene glycol ester is added to the liquid preparation tank, and stirring is started. Add the prescribed amount of Y-3, tert-butyl alcohol, and stir well to disperse evenly. Stir until all are dissolved evenly. Prescription amount of trehalose / phosphoric acid buffer solution liquid preparation 2: Take the liquid preparation bucket and add the prescribed amount of water for injection. Start stirring, and add the prescribed amount of dipotassium phosphate-potassium dihydrogen phosphate buffer salt and trehalose in turn, and stir until all are dissolved.

[0159] (2) Mix the liquid preparation and make up to volume: Transfer liquid preparation 2 to liquid preparation 1, start stirring and mixing, and use bottom stirring to achieve mixing. Start the emulsification and dispersion device on the basis of mixing. To better emulsify, you can add a wall scraping function. After thorough mixing, add cooled water for injection to make up to the full amount.

[0160] (3) Intermediate detection.

[0161] (4) Filtration: After the intermediate detection is qualified, the liquid is transported to the storage tank through a 0.45 μm / 0.22 μm*2 sterilization filter.

[0162] (5) Westlin bottle filling

[0163] (6) Freeze-drying: Set the plate layer temperature to -40°C and maintain; vacuumize, raise the plate layer temperature to -20°C and maintain; raise the plate layer temperature to -5°C and maintain; raise the plate layer temperature to 10°C and maintain; raise the plate layer temperature to 25°C and maintain until freeze-drying is complete. Press the plug and remove the box.

[0164] Example 14

[0165] Preparation of Y-3 for injection:

[0166] Preparation method: (1) Liquid preparation: 15-hydroxystearic acid polyethylene glycol ester / Y-3 / tert-butyl alcohol solution liquid preparation 1: 15-hydroxystearic acid polyethylene glycol ester is added to the liquid preparation tank, and stirring is started. Add the prescribed amount of Y-3, tert-butyl alcohol, and stir well to disperse evenly. Stir until all are dissolved evenly. Prescription amount of trehalose / phosphoric acid buffer solution liquid preparation 2: Take the liquid preparation bucket and add the prescribed amount of water for injection. Start stirring, and add the prescribed amount of dipotassium phosphate-potassium dihydrogen phosphate buffer salt and trehalose in turn, and stir until all are dissolved.

[0167] (2) Mix the liquid preparation and make up to volume: Transfer liquid preparation 2 to liquid preparation 1, start stirring and mixing, and use bottom stirring to achieve mixing. Start the emulsification and dispersion device on the basis of mixing. To better emulsify, you can add a wall scraping function. After thorough mixing, add cooled water for injection to make up to the full amount.

[0168] (3) Intermediate detection.

[0169] (4) Filtration: After the intermediate is qualified, the feed liquid is delivered to the storage tank through 0.45 μm / 0.22 μm*2 sterilization filter.

[0170] (5) Vial filling

[0171] (6) Freeze-drying: Set the plate layer temperature to -40°C and maintain; vacuumize, raise the plate layer temperature to -20°C and maintain; raise the plate layer temperature to -5°C and maintain; raise the plate layer temperature to 10°C and maintain; raise the plate layer temperature to 25°C and maintain until the freeze-drying is completed. Press the plug and take out the box.

[0172] Example 15

[0173] Preparation process development of Y-3 for injection:

[0174] Preparation method: (1) Solution preparation: 15-hydroxystearic acid polyethylene glycol ester / Y-3 / tert-butyl alcohol solution solution 1: add 15-hydroxystearic acid polyethylene glycol ester to the solution preparation tank and start stirring. Add the prescribed amount of Y-3, tert-butyl alcohol, and polysorbate 80 and stir until they are evenly dispersed and completely dissolved. Solution preparation 2: take the solution preparation barrel, add the prescribed amount of water for injection, start stirring, and then add the prescribed amount of dipotassium hydrogen phosphate-potassium dihydrogen phosphate buffer salt and trehalose in sequence and stir until they are completely dissolved.

[0175] (2) Mix the solutions and make up the volume: Pump solution 2 and solution 1 to the Y-shaped microfluidic chip through high-pressure pumps, mix them in the chip, and then make up the volume with cooled water for injection.

[0176] (3) Intermediate detection.

[0177] (4) Filtration: After the intermediate is qualified, the feed liquid is delivered to the storage tank through 0.45 μm / 0.22 μm*2 sterilization filter.

[0178] (5) Vial filling

[0179] (6) Freeze-drying: Set the plate layer temperature to -40°C and maintain; vacuumize, raise the plate layer temperature to -20°C and maintain; raise the plate layer temperature to -5°C and maintain; raise the plate layer temperature to 10°C and maintain; raise the plate layer temperature to 25°C and maintain until the freeze-drying is completed. Press the plug and take out the box.

[0180] Example 16

[0181] Preparation process development of Y-3 for injection:

[0182] Preparation method: (1) Solution preparation: 15-hydroxystearic acid polyethylene glycol ester / Y-3 / tert-butanol solution preparation 1: Add 15-hydroxystearic acid polyethylene glycol ester to the preparation tank and start stirring. Add the prescribed amount of Y-3, polysorbate 80, and tert-butanol, and stir thoroughly to disperse evenly until completely dissolved. 2. Prescribed amount of trehalose / phosphate buffer solution preparation 2: Take the preparation tank and add the prescribed amount of water for injection, start stirring, and add the prescribed amount of dipotassium hydrogen phosphate-potassium dihydrogen phosphate buffer salt and trehalose in sequence, stirring until completely dissolved.

[0183] (2) Mixing and Volume Adjustment: Transfer solution 2 to solution 1 and start stirring to mix. Mixing is achieved by bottom stirring. After mixing, turn on the emulsification and dispersion device. For better emulsification, a wall scraping function can be added. After thorough mixing, add cooled water for injection to adjust the volume to the full volume.

[0184] (3) Intermediate detection.

[0185] (4) Filtration: After the intermediate is qualified, the liquid is transported to the storage tank through a 0.45μm / 0.22μm*2 sterilization filter.

[0186] (5) Vial filling

[0187] (6) Freeze-drying: Set the plate temperature to -50℃ and maintain it; evacuate and raise the plate temperature to -30℃ and maintain it; raise the plate temperature to -10℃ and maintain it; raise the plate temperature to 10℃ and maintain it; raise the plate temperature to 30℃ and maintain it until the freeze-drying is completed. Plug and remove from the box.

[0188] Example 17

[0189] Development of preparation process for injectable Y-3:

[0190] Preparation method: (1) Solution preparation: Hydroxypropyl beta-cyclodextrin / Y-3 / tert-butanol solution preparation 1: Add hydroxypropyl beta-cyclodextrin, the prescribed amount of Y-3, tert-butanol, and ethanol to the preparation tank, turn on the stirrer, and stir thoroughly to disperse evenly until completely dissolved. Prescribed amount of trehalose / phosphate buffer solution preparation 2: Take the preparation tank and add the prescribed amount of water for injection, turn on the stirrer, and add the prescribed amount of dipotassium hydrogen phosphate-potassium dihydrogen phosphate buffer salt and trehalose in sequence, stirring until completely dissolved.

[0191] (2) Mixing and Volume Adjustment: Transfer solution 2 to solution 1 and start stirring to mix. Mixing is achieved by bottom stirring. After mixing, turn on the emulsification and dispersion device. For better emulsification, a wall scraping function can be added. After thorough mixing, add cooled water for injection to adjust the volume to the full volume.

[0192] (3) Intermediate detection.

[0193] (4) Filtration: After the intermediate is qualified, the feed liquid is delivered to the storage tank through 0.45 μm / 0.22 μm*2 sterilization filter.

[0194] (5) Vial filling

[0195] (6) Freeze-drying: Set the plate temperature to -40°C, maintain; vacuumize, raise the plate temperature to -20°C, maintain; raise the plate temperature to -5°C, maintain; raise the plate temperature to 10°C, maintain; raise the plate temperature to 25°C, maintain until the freeze-drying is completed. Press the plug and take out the box.

[0196] Example 18

[0197] Preparation process development of Y-3 for injection:

[0198] Preparation method: (1) Solution preparation: hydroxypropyl betacyclodextrin / Y-3 / tert-butyl alcohol solution solution preparation 1: add hydroxypropyl betacyclodextrin, prescription amount of Y-3, tert-butyl alcohol, and ethanol into the solution preparation tank, start stirring, and fully stir to make the dispersion uniform until all are dissolved uniformly. Prescription amount of trehalose / phosphoric acid buffer solution solution preparation 2: take the solution preparation barrel, add the prescription amount of water for injection, start stirring, and then add the prescription amount of dipotassium hydrogen phosphate-potassium dihydrogen phosphate buffer salt and trehalose in sequence, and stir until all are dissolved.

[0199] (2) Mix the solution and constant volume: pump solution 2 and solution 1 to the Y-shaped microfluidic chip through the high-pressure pump, mix after the chip, and then add cold water for injection to constant volume.

[0200] (3) Intermediate detection.

[0201] (4) Filtration: After the intermediate is qualified, the feed liquid is delivered to the storage tank through 0.45 μm / 0.22 μm*2 sterilization filter.

[0202] (5) Vial filling

[0203] (6) Freeze-drying: Set the plate temperature to -40°C, maintain; vacuumize, raise the plate temperature to -20°C, maintain; raise the plate temperature to -5°C, maintain; raise the plate temperature to 10°C, maintain; raise the plate temperature to 25°C, maintain until the freeze-drying is completed. Press the plug and take out the box.

[0204] Example 19

[0205] Preparation process development of Y-3 for injection:

[0206] Preparation method: (1) liquid preparation: sulfobutyl betadex / Y-3 / tert-butyl alcohol solution liquid preparation 1: add the prescription amount of Y-3, tert-butyl alcohol, ethanol to the liquid preparation tank, start stirring, fully stir to disperse uniformly, and then dissolve uniformly. Prescription amount of trehalose / phosphoric acid buffer solution liquid preparation 2: take the liquid preparation barrel, add the prescription amount of water for injection, start stirring, and then add the prescription amount of dipotassium hydrogen phosphate-potassium dihydrogen phosphate buffer salt, trehalose, mannitol in turn, and stir until all are dissolved.

[0207] (2) Mix the liquid preparation and constant volume: pump liquid preparation 2 and liquid preparation 1 to the Y-shaped microfluidic chip through the high-pressure pump, add cooled water for injection after mixing in the chip, and then constant volume to the full amount.

[0208] (3) Intermediate detection.

[0209] (4) Filtration: after the intermediate detection is qualified, the liquid is transported to the storage tank through 0.45 μm / 0.22 μm*2 sterilization filter.

[0210] (5) Westlin bottle filling

[0211] (6) Freeze-drying: set the plate layer temperature to -40°C, maintain; vacuumize, raise the plate layer temperature to -20°C, maintain; raise the plate layer temperature to -5°C, maintain; raise the plate layer temperature to 10°C, maintain; raise the plate layer temperature to 25°C, maintain until freeze-drying is completed. Press the plug and take out the box.

[0212] Example 20

[0213] Preparation process development of Y-3 for injection:

[0214] Preparation method: (1) liquid preparation: sulfobutyl betadex / Y-3 / tert-butyl alcohol solution liquid preparation 1: add the prescription amount of Y-3, tert-butyl alcohol, ethanol to the liquid preparation tank, start stirring, fully stir to disperse uniformly, and then dissolve uniformly. Prescription amount of trehalose / phosphoric acid buffer solution liquid preparation 2: take the liquid preparation barrel, add the prescription amount of water for injection, start stirring, and then add the prescription amount of dipotassium hydrogen phosphate-potassium dihydrogen phosphate buffer salt, trehalose, mannitol in turn, and stir until all are dissolved.

[0215] (2) Mix the liquid preparation and constant volume: pump liquid preparation 2 and liquid preparation 1 to the Y-shaped microfluidic chip through the high-pressure pump, add cooled water for injection after mixing in the chip, and then constant volume to the full amount.

[0216] (3) Intermediate detection.

[0217] (4) Filtration: after the intermediate detection is qualified, the liquid is transported to the storage tank through 0.45 μm / 0.22 μm*2 sterilization filter.

[0218] (5) Westlin bottle filling.

[0219] (6) Freeze-drying: Set the shelf temperature to -40°C, hold; evacuate, raise the shelf temperature to -20°C, hold; raise the shelf temperature to -5°C, hold; raise the shelf temperature to 10°C, hold; raise the shelf temperature to 25°C, hold until freeze-drying is complete. Press, out of the chamber.

[0220] Example 21

[0221] Example 6-Example 20 Y-3 for injection preparation process development, results (reconstitution solvent is 0.6 g propylene glycol and 1.4 g water):

[0222] Example 22

[0223] Example 6-Example 20 Y-3 for injection preparation process development stability (accelerated 30°C ± 2°C, relative humidity RH 65% ± 5%) results:

[0224] The analytical method for related substances in the present application is as follows, unless otherwise specified:

[0225] Instrument: Agilent / Agilent liquid chromatography system; ultraviolet detector;

[0226] Chromatographic column: Agilent ZORBAX SB-C18, 4.6 mm x 150 mm, 3.5 μm;

[0227] Mobile phase A: 0.02 mol / L ammonium acetate solution (pH value is adjusted to 4.8 with glacial acetic acid);

[0228] Mobile phase B: Tetrahydrofuran-acetonitrile (40:60);

[0229] Detection wavelength: 311 nm;

[0230] Column temperature: 35°C;

[0231] Flow rate: 1.0 mL / min;

[0232] Injection volume: 10 μL;

[0233] Sample tray: 4°C;

[0234] Run time: 50 min (40.1-50 min for equilibrating the chromatographic column);

[0235] Gradient table: Inject according to the following table.

[0236] A typical chromatogram is shown in Figure 1, where A is impurity Y-3-A, B is impurity Y-3-IMPA, C is impurity Y-3-IMPB, D is Y-3, E is impurity Y-3-IMPD, and F is impurity Y-3-IMPK.

[0237] In Figure 1, 1 is a 1% self-control solution, 2 is a test sample solution, 3 is a system suitability solution, 4 is a sensitivity solution, 5 is a blank excipient solution, and 6 is a blank solvent.

[0238] It is apparent for a person skilled in the art that the present application is not limited to the details of the above-described exemplary embodiments, but can be implemented in other concrete forms without departing from the spirit or essential characteristics of the present application. Therefore, the embodiments should be considered in all respects as illustrative and not restrictive, the scope of the present application being defined by the appended claims rather than the above description, and it is intended to embrace all changes and modifications that fall within the meaning and scope of the equivalent elements of the claims. Any reference signs in the claims should not be construed as limiting the claims to the figures in which the reference signs are used.

Claims

1. A Y-3 formulation for ease of storage and transportation, the formulation being a lyophilized formulation, characterized in that, It comprises: Y-3, a pharmaceutical excipient for facilitating lyophilization molding and a surfactant.

2. The Y-3 formulation convenient for storage and transportation according to claim 1, characterized in that, The structural formula of Y-3 is as follows: The pharmaceutical excipient for facilitating lyophilization molding is selected from saccharide compounds and / or sugar alcohol compounds. And / or, the surfactant is selected from one or more of polyethylene glycol surfactants, polyoxyethylene surfactants, alkyl sulfate surfactants, cyclodextrin compounds and phospholipid compounds.

3. The Y-3 formulation convenient for storage and transportation according to claim 2, characterized in that, The saccharide compounds are selected from sucrose and / or trehalose. And / or, the sugar alcohol compounds are selected from mannitol. and / or the polyethylene glycol-based surfactant is selected from polyethylene glycol 15-hydroxystearate, PEG 3000-5000 -PLA 2000-5000 , PEG 3000-5000 -PLA 2000-5000 -PEG 3000-5000 with PEG 3000-5000 -PCL 2000-5000 one or more of: And / or, the polyoxyethylene surfactants are selected from one or more of polyoxyethylene (35) castor oil, polyoxyethylene 40 hydrogenated castor oil, polysorbate 80, polysorbate 20, poloxamer 188 and poloxamer 407. And / or, the alkyl sulfate surfactants are selected from sodium dodecyl sulfate. And / or, the cyclodextrin compounds are selected from hydroxypropyl betadex and / or sulfobutyl betadex. And / or, the phospholipid compounds are selected from one or more of hydrogenated soybean lecithin, soybean phospholipid, lecithin, dioleoyl phosphatidylcholine, dipalmitoyl lecithin, distearoyl phosphatidylcholine, distearoyl phosphatidyl ethanolamine and dioleoyl phosphatidyl ethanolamine.

4. The Y-3 formulation for ease of storage and transportation according to any one of claims 1 to 3, characterized in that: It comprises: Y-3, a pharmaceutical excipient for facilitating lyophilization molding, a surfactant and a low-molecular alcohol for further increasing solubility.

5. The Y-3 formulation for ease of storage and transportation according to any one of claims 1 to 3, characterized in that, It comprises: Y-3, a pharmaceutical excipient for facilitating lyophilization molding, a surfactant for increasing solubility of Y-3, a low-molecular alcohol for further increasing solubility and a solvent for reconstitution required in clinical administration.

6. The Y-3 formulation for ease of storage and transportation according to any one of claims 1 to 3, characterized in that, The proportion of Y-3 in the preparation is 0.1-12% (w / v), the proportion of the surfactant is 0.1-50% (w / v) and the proportion of the pharmaceutical excipient for facilitating lyophilization molding is 1-30% (w / v).

7. The Y-3 formulation convenient for storage and transportation as claimed in claim 5, wherein, The solvent for reconstitution required in clinical administration in the preparation comprises a low-molecular alcohol for increasing solubility, wherein the proportion of the low-molecular alcohol is 0-50% (w / v) and the rest is the solvent for reconstitution.

8. The Y-3 formulation convenient for storage and transportation as claimed in claim 1, wherein, The surfactant comprises one or a combination of 15-hydroxystearic acid polyethylene glycol ester, polyoxyethylene (35) castor oil, polyoxyethylene 40 hydrogenated castor oil, polysorbate 80, polysorbate 20, sodium dodecyl sulfate, hydroxypropyl betadex, sulfobutyl betadex, hydrogenated soybean lecithin, soybean phospholipid, lecithin, dioleoyl phosphatidylcholine, dipalmitoyl lecithin, distearoyl phosphatidylcholine, distearoyl phosphatidylethanolamine, dioleoyl phosphatidylethanolamine, PEG 3000-5000 -PLA 2000-5000 , PEG 3000-5000 -PLA 2000-5000 -PEG 3000-5000 , poloxamer 188, poloxamer 407, PEG 3000-5000 -PCL 2000-5000 one or a combination of two or more compositions.

9. The Y-3 formulation convenient for storage and transportation as claimed in claim 1, wherein, The pharmaceutical excipient for facilitating lyophilization molding comprises one or two or more combinations of mannitol, sucrose and trehalose.

10. The Y-3 formulation convenient for storage and transportation as claimed in claim 4, wherein, The low-molecular alcohol comprises one or two or more combinations of ethanol, propylene glycol, glycerol, tert-butyl alcohol and diethylene glycol monoethyl ether.

11. The Y-3 formulation convenient for storage and transportation as claimed in claim 5, wherein, The buffer used in the preparation process to avoid pH fluctuation comprises one or two or more combinations of citric acid-sodium citrate, acetic acid-sodium acetate buffer, phosphate buffer and Tris-hydrochloric acid buffer.

12. The Y-3 formulation convenient for storage and transportation as claimed in claim 5, wherein, The solvent for reconstitution is one or two or more combinations of phosphate buffer, Hanks balanced salt solution, Tris-hydrochloric acid buffer, ethanol, propylene glycol, DMSO, water for injection, normal saline, glucose injection and fructose injection.

13. The Y-3 formulation convenient for storage and transport according to any one of claims 1 to 12, wherein, The preparation process of the lyophilized powder comprises dissolving, mixing, filtering sterilization, sub-packaging, lyophilization and capping; wherein: The dissolving step in the preparation process is carried out in the dark and the pH value of the solution after dissolving is adjusted to 5-10 by a buffer solution; The mixing step in the preparation process is mixed by using an emulsifying tank or a microfluidic method; The filtration sterilization step in the preparation process is performed in-line or off-line, using 0.45 micron / 0.22 micron / 0.22 micron or 0.45 micron / 0.22 micron*2 filter levels, and the filtered drug solution needs to meet the sterile requirements; The split quantity in the split step in the preparation process is 5mg-80mg per bottle of Y-3; The freeze-drying step in the preparation process has a low-temperature pre-freezing temperature of -80 to -40 degrees Celsius, a first drying temperature of -30 to -10 degrees Celsius, a second drying temperature of 0 to 30 degrees Celsius, and a freeze-drying process time of 30 to 52 hours.

14. The Y-3 formulation convenient for storage and transport according to claim 13, wherein, The split process of the freeze-dried powder injection is any one of the following: combined vials, single vials, pre-charged needles, pre-charged needles and single vials, single vials, ampoules, double-chamber vials, and double-chamber pre-charged needles, which can be used as a clinical administration inner packaging form.

15. The Y-3 formulation convenient for storage and transport according to any one of claims 1 to 12, wherein, The clinical administration process of the Y-3 preparation is: first, reconstitute the Y-3 freeze-dried powder with a reconstitution solvent to obtain a Y-3 concentrated solution, and then dilute it to a clinically commonly used compatible solvent to obtain the required administration concentration.

16. The Y-3 formulation convenient for storage and transport according to any one of claims 1 to 12, wherein, The clinical administration process of the freeze-dried preparation is: reconstitute the Y-3 injection with a clinically commonly used compatible solvent to obtain the required administration concentration, and then intravenously infuse it into the patient; the compatible solvent is selected from one or more of the following: normal saline, water for injection, glucose injection, and fructose injection.

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