Freeze-dried preparation, injection, and preparation method therefor

Abstract

A freeze-dried preparation of compound 1 (Olanzapine), an injection, and a preparation method therefor. The freeze-dried preparation comprises compound 1, an excipient, and an osmotic pressure regulator, wherein the excipient is at least one of lactose, sucrose, trehalose, or a corresponding hydrate thereof; the osmotic pressure regulator is a salt of sodium or potassium; and the freeze-dried preparation comprises 1 part by weight of compound 1 and 0.125-2.2 parts by weight of an osmotic pressure regulator. A combination of the excipient and osmotic pressure regulator in the formulation is utilized, which unexpectedly improves the stability of the freeze-dried preparation of compound 1, with storage stability being retained even during storage at 40°C, reduces the generation of impurities, and prolongs the storage period. Moreover, the content of impurities is also relatively low when the product is left to stand for 8 h after redissolution, such that the storage period of the freeze-dried preparation after redissolution can be prolonged.

Description

A freeze-dried preparation and injection and preparation method thereof Technical Field

[0001] The present invention belongs to the field of pharmaceutical preparations, and in particular relates to a freeze-dried preparation and an injection and a preparation method thereof. Background Art

[0002]

[0003] The structure of compound 1 is shown in formula I, which is a benzodiazepine The drug is a new atypical neuroleptic drug that can significantly improve the negative, positive and emotional symptoms of patients with schizophrenia because it has affinity with multiple receptors, including 5-HT 2A / 2C , 5-HT3, 5-HT6; dopamine D1, D2, D3, D4, D5; cholinergic muscarinic receptors M1-M5; α1 receptor; and histamine H1 receptor.

[0004] Neurotransmitters and their receptors such as 5-HT and 5-HT3 receptors, substance P and neurokinin 1 (NK1) receptors, dopamine and D2 receptors mediate the occurrence of chemotherapy-induced nausea and vomiting (CINV). 2c Compound 1 has strong affinities for 5-HT3, 5-HT3, and dopamine D2 receptors, whereas each CINV preventive drug typically blocks a specific receptor. Therefore, compared to setrons that target only 5-HT3 receptors or pitants that target NK1 receptors, compound 1 can act on multiple vomiting-related receptors, demonstrating a noteworthy antiemetic effect and a clear clinical advantage.

[0005] Currently, the marketed products of Compound 1 are mainly administered orally (PO), with few intramuscular injections (IM) and no injections such as subcutaneous injection (SC) and intravenous injection (IV).

[0006] In terms of speed of onset, for acute agitation, antiemetic prevention and emergency rescue of schizophrenia, the speed of onset of drugs via PO is generally significantly slower than that via injection.

[0007] In terms of efficacy and compliance, when used to treat nausea and vomiting, drugs administered PO may be excreted with vomiting before they are fully absorbed and effective, affecting clinical efficacy. Some formulations can even have a bitter or irritating taste, which can induce nausea and vomiting. For patients with dysphagia, such as the elderly and children, the parenteral route is recommended.

[0008] The currently marketed Compound 1 lyophilized powder for injection is administered intramuscularly, and the US instructions for storage specify a temperature of 20°C to 25°C. Improving product stability to allow for storage at higher temperatures (e.g., below 30°C) would facilitate quality assurance during shelf life and distribution.

[0009] Compound 1 is a poorly soluble and easily degraded drug, particularly prone to hydrolysis. Developing a liquid formulation for it is extremely challenging, so consideration was given to preparing it as a lyophilized powder for injection. CN 1028429C mentions a lyophilized powder injection product using mannitol as a diluent. However, after preparing the lyophilized powder injection according to the formulation provided by the applicant, the applicant discovered that Compound 1 in the powder still degraded rapidly during storage, resulting in instability.

[0010] During injection, excessively high or low osmotic pressure can cause adverse reactions such as hemolysis, irritation, and phlebitis. The marketed lyophilized powder injection of Compound 1 is not an isotonic solution after reconstitution according to the instructions, and its clinical use is limited to intramuscular injection. Due to the easy hydrolysis of Compound 1, the formulation design of the marketed lyophilized powder injection product is slightly flawed. Therefore, the reconstituted lyophilized powder must be used as soon as possible, placing a relatively stringent time limit on its use.

[0011] Therefore, there is a great clinical demand for developing an injectable formulation of Compound 1 with a simple formulation process, better storage stability and stability after reconstitution, and high safety, which can better meet the needs of multiple routes of administration such as intramuscular injection, subcutaneous injection, and intravenous injection, and meet various clinical treatment needs.

[0012] Summary of the Invention

[0013] The present invention aims to provide a lyophilized preparation and injection and a preparation method thereof. By selecting the types and ratios of excipients and osmotic pressure regulators, it is unexpectedly found that the storage stability and stability after reconstitution of the lyophilized preparation can be significantly improved, and the generation of impurities can be reduced. In addition, combined with the optimization of the lyophilization process, the moisture content of the lyophilized preparation (lyophilized powder) is reduced, making it less likely to shrink and collapse.

[0014] The object of the present invention is achieved through the following technical solutions:

[0015] A lyophilized preparation comprising compound 1, an excipient, and an osmotic pressure regulator;

[0016] The compound 1 has a structure as shown in Formula 1:

[0017] The excipient is at least one of lactose, sucrose, trehalose, or hydrates thereof; the hydrate is preferably lactose monohydrate or trehalose dihydrate.

[0018] The osmotic pressure regulator is a sodium or potassium salt.

[0019] The salt may be one or more of hydrochloride, tartrate, citrate, sulfate, carbonate or bicarbonate.

[0020] The osmotic pressure regulator is preferably sodium chloride or potassium chloride.

[0021] The freeze-dried preparation contains 1 part by weight of compound 1 and 0.125 to 2.2 parts by weight of an osmotic pressure regulator. The amount of the osmotic pressure regulator has a certain influence on the stability of the freeze-dried preparation.

[0022] The freeze-dried preparation contains 1 part by weight of compound 1 and 4 to 60 parts by weight of excipients. The amount of excipients used has little effect on the stabilizer of the freeze-dried preparation.

[0023] Preferably, the lyophilized preparation contains 1 part by weight of compound 1 and 4 to 20 parts by weight of excipients. The amount of excipients used has a significant impact on the accessibility of the lyophilization process and the lyophilization effect.

[0024] The freeze-dried preparation further contains a cosolvent.

[0025] The cosolvent is one or more of tartaric acid, hydrochloric acid, citric acid, acetic acid, malic acid, fumaric acid or phosphoric acid.

[0026] The freeze-dried preparation contains 1 part by weight of compound 1 and 0.2 to 1.0 parts by weight of a co-solvent.

[0027] The total moisture content of the freeze-dried preparation is less than 2.8% (W / W), preferably less than 1.5% (W / W), and particularly preferably less than 1.0% (W / W).

[0028] The freeze-dried preparation is prepared by freeze-drying a solution with a pH value of 4.0 to 6.5.

[0029] The freeze-dried preparation also contains other antiemetic active ingredients to enhance the antiemetic effect.

[0030] The other antiemetic active ingredients include one or more of 5-HT3 receptor antagonists, neurokinin-1 (NK1) receptor antagonists, glucocorticoids, benzodiazepines or dopamine receptor antagonists.

[0031] The 5-HT3 receptor antagonist includes one or more of ondansetron, granisetron, ramosetron, dolasetron, azasetron, palonosetron or tropisetron.

[0032] The neurokinin-1 (NK1) receptor antagonist includes one or more of aprepitant, rolapitant, netupitant, fosaprepitant or fornetupitant.

[0033] The glucocorticoid includes one or more of dexamethasone, prednisone or methylprednisolone.

[0034] The benzodiazepines include one or more of lorazepam and alprazolam.

[0035] The dopamine receptor antagonist includes one or more of prochlorperazine, promethazine, chlorpromazine, diphenhydramine, metoclopramide or haloperidol.

[0036] The active ingredients contained in the lyophilized preparation are Compound 1 and palonosetron.

[0037] The active ingredients contained in the lyophilized preparation are Compound 1, palonosetron and fornetupitant.

[0038] The freeze-dried preparation contains 1 to 30 mg, preferably 2 to 10 mg, of compound 1 per preparation unit (packaging unit, such as an ampoule).

[0039] When each preparation unit of the freeze-dried preparation contains other antiemetic active ingredients other than compound 1, the dosage of the 5-HT3 receptor antagonist is 0.1 to 150 mg, the dosage of the neurokinin-1 (NK1) receptor antagonist is 50 to 500 mg, the dosage of the glucocorticoid is 2.5 to 200 mg, the dosage of the benzodiazepine is 0.2 to 10 mg, and the dosage of the dopamine receptor antagonist is 0.25 to 50 mg.

[0040] In the lyophilized preparation, when each preparation unit contains more than one 5-HT3 receptor antagonist, the specific dosage can be: ondansetron 4-24 mg, azasetron 2.5-15 mg, dolasetron 50-150 mg, granisetron 1-6 mg, moresetron 0.1-0.9 mg, palonosetron 0.1-0.5 mg, and tropisetron 2.5-10 mg.

[0041] In the lyophilized preparation, when each preparation unit contains more than one neurokinin-1 (NK1) receptor antagonist, the specific dosage can be: aprepitant 50-250 mg, fosaprepitant 50-300 mg, netupitant 100-300 mg, fornetupitant 200-500 mg, and rolapitant 50-250 mg.

[0042] In the freeze-dried preparation, when each preparation unit contains more than one glucocorticoid, the specific dosage can be: dexamethasone 2.5-20 mg, prednisone 25-200 mg, and methylprednisolone 10-150 mg.

[0043] In the freeze-dried preparation, when each preparation unit contains more than one benzodiazepine drug, the specific dosage can be: lorazepam 0.2-10 mg, alprazolam 0.4-10 mg.

[0044] In the freeze-dried preparation, when each preparation unit contains more than one dopamine receptor antagonist, the specific dosage can be: prochlorperazine 5-20 mg, promethazine 5-30 mg, chlorpromazine 5-50 mg, metoclopramide 5-50 mg, haloperidol 0.25-5 mg, and diphenhydramine 5-25 mg.

[0045] The active ingredients contained in the lyophilized preparation are 2-20 mg of compound 1 and 0.1-0.5 mg of palonosetron.

[0046] The active ingredients contained in the lyophilized preparation are 2-20 mg of compound 1, 0.1-0.5 mg of palonosetron and 200-500 mg of fornetupitant.

[0047] An injection is obtained by reconstitution of the freeze-dried preparation.

[0048] The injection has a pH value of 4.0 to 6.5; the concentration of compound 1 is 1 to 20 mg / mL, preferably 2 to 5 mg / mL.

[0049] The re-dissolution is to add diluent for re-dissolution.

[0050] The diluent is water for injection, sodium chloride solution, glucose solution, or a solution containing glucose and sodium chloride.

[0051] By adjusting the type and amount of the diluent, the osmotic pressure of the obtained injection can be controlled to be 140-830 mOsm / kg, preferably 230-500 mOsm / kg, and more preferably 260-330 mOsm / kg.

[0052] The diluent is water for injection, with a constant volume of 2 to 8 mL, and the resulting injection has an osmotic pressure suitable for intravenous injection. A diluent other than water for injection is used, with a constant volume of 10 to 50 mL, and the resulting injection has an osmotic pressure suitable for intravenous injection. The osmotic pressure suitable for intravenous injection is preferably 230 to 340 mOsm / kg.

[0053] The concentration of the sodium chloride solution is below 0.9%.

[0054] The concentration of the glucose solution is preferably 5%.

[0055] The osmotic pressure of the solution containing glucose and sodium chloride is below 310mOsm / kg.

[0056] The injection can be used for intramuscular injection, subcutaneous injection and intravenous injection.

[0057] The lyophilized preparation and / or injection containing compound 1 can be used to prepare drugs for treating bipolar disorder, schizophrenia, mania, agitation, epilepsy, obsessive-compulsive disorder, generalized anxiety disorder, depression, nausea and vomiting caused by chemotherapy and radiotherapy, explosive vomiting, delayed vomiting, postoperative vomiting, and intractable vomiting.

[0058] The lyophilized preparation and / or injection containing compound 1 and other active antiemetic ingredients can be used to prepare drugs for nausea and vomiting, explosive vomiting, delayed vomiting, postoperative vomiting, and intractable vomiting caused by chemotherapy and radiotherapy.

[0059] The preparation method of the freeze-dried preparation comprises the following steps:

[0060] (1) Preparation of blank solution: Mix the excipient, osmotic pressure regulator and cosolvent, add part of the water for injection, and stir until completely dissolved to obtain solution A.

[0061] (2) Dissolving the API (Active Pharmaceutical Ingredient) and fixing the volume: Keep Solution A at 0-12°C, add the active ingredient to Solution A, stir until completely dissolved, adjust the pH value, and add the remaining amount of water for injection to fix the volume to obtain Solution B.

[0062] When the active ingredient is compound 1, the pH value is adjusted to 4.0 to 6.5, preferably 5.5 to 5.9.

[0063] When the active ingredients are Compound 1 and other antiemetic active ingredients, the pH value is determined according to the properties of the active ingredients, and is preferably adjusted to a pH of 3-7.

[0064] (3) Filtration and filling: Solution B is filtered through a microporous filter membrane and then filled into a container.

[0065] (4) Freeze-drying: After filling, the drug solution is freeze-dried within 24 hours. It is first pre-frozen at -5 to 7°C for more than 1 hour, then frozen below -35°C for more than 1 hour (called the primary freezing process), then dried at -25 to -2.5°C for more than 20 hours (called the primary drying process), and then dried at 30 to 50°C for more than 5 hours (called the secondary drying process) to obtain a freeze-dried preparation (freeze-dried powder).

[0066] In the method, after obtaining the freeze-dried preparation, the container containing the freeze-dried powder is preferably filled with nitrogen and sealed for storage to obtain the finished product.

[0067] The pH value is adjusted in step (2) by using hydrochloric acid solution or sodium hydroxide solution.

[0068] The solid content of the solution B in step (2) is 1.5% (w / v) or more, preferably 1.5 to 25% (w / v), and particularly preferably 1.5 to 10% (w / v).

[0069] The pore size of the microporous filtration membrane in step (3) is 0.22 to 0.45 μm.

[0070] In step (3), the filling volume is preferably 1 to 2 mL.

[0071] The container in step (3) is a packaging material such as a vial or an ampoule suitable for producing injection preparations.

[0072] In step (4), the primary drying temperature is preferably -14°C to -2.5°C.

[0073] In step (4), during the primary drying process and the secondary drying process, the vacuum degree of the freeze-drying device is 5 to 30 Pa.

[0074] Compared with the prior art, this application has the following advantages and beneficial effects:

[0075] 1. The present invention unexpectedly improves the stability of the lyophilized preparation of Compound 1 by using a combination of "excipients (lactose, sucrose, or trehalose) plus an osmotic pressure regulator" in the prescription. This improves storage stability even when stored at 40°C, reduces the generation of impurities, and prolongs the shelf life. Compared to the 20-25°C storage temperature requirement for general injectable lyophilized preparations, this product has improved tolerance at higher temperatures (40°C), which is more conducive to quality assurance of its storage and circulation during its shelf life. At the same time, the impurity content after 8 hours of storage after reconstitution is also low, which can extend the storage time of the lyophilized preparation after reconstitution, and has higher flexibility and safety in clinical use.

[0076] 2. The formulation of the present invention enables compound 1 to have good stability in a wider range of pH values ​​(4.0-6.5), reducing the stringent requirements for the preparation process.

[0077] 3. The freeze-dried preparation for injection of the present invention has good stability and can be directly injected after reconstitution, with a faster onset of effect, meeting the needs of clinical emergency situations.

[0078] 4. The formulation and process provided by the present invention have good tolerance, and the appearance of the freeze-dried preparation (freeze-dried powder) meets the requirements and is not prone to shrinkage and collapse. BRIEF DESCRIPTION OF THE DRAWINGS

[0079] Figures 1 to 27 are appearance pictures of the freeze-dried products obtained from the prescriptions in Tables 13 and 14. DETAILED DESCRIPTION

[0080] The present invention will be described in further detail below with reference to examples and drawings, but the embodiments of the present invention are not limited thereto.

[0081] The quantitative analysis method involved in the present invention is as follows:

[0082] Total moisture content: Refer to the Pharmacopoeia 2020 Edition Part IV General Rules, <0832 Determination of Water>, Method 1 (Fischer method) volumetric titration method.

[0083] Compound 1 content determination method: Take an appropriate amount of the lyophilized preparation (approximately equivalent to 10 mg of compound 1), reconstitute it with 2 mL of water for injection, and then quantitatively dilute it with diluent (acetonitrile and water, volume ratio 4:6) to produce a solution containing approximately 0.2 mg / mL of compound 1 per 1 mL, which serves as the sample solution. Chromatographic conditions: HPLC (Agilent); Column: C18; Flow rate: 1.0 mL / min; Detection wavelength: 250 nm; Injection volume: 10 μL; Mobile phase: 25 mmol / L sodium dihydrogen phosphate buffer (pH 6.8) and methanol, mixed in a volume ratio of 2:8.

[0084] Compound 1 impurity detection method: Take an appropriate amount of the lyophilized preparation (approximately equivalent to 10 mg of compound 1), reconstitute it with 2 mL of water for injection, and then quantitatively dilute it with diluent (acetonitrile and water, volume ratio 4:6) to produce a solution containing approximately 0.4 mg / mL of compound 1 per 1 mL, which serves as the sample solution. Chromatographic conditions: HPLC (Agilent); Column: C18; Flow rate: 1.0 mL / min; Detection wavelength: 250 nm; Injection volume: 10 μL; Mobile phase A: 25 mmol / L sodium dihydrogen phosphate buffer (pH 6.8), acetonitrile, and methanol, mixed in a volume ratio of 22:9:9; Mobile phase B: acetonitrile and methanol, mixed in a volume ratio of 1:1. Elution: Linear gradient elution of mobile phase A and mobile phase B.

[0085] Chromatographic conditions for ziprasidone impurity detection: high performance liquid chromatography; chromatographic column: C18; flow rate: 1.0 mL / min; detection wavelength: 229 nm; injection volume: 10 μL; mobile phase A: 0.05% phosphoric acid; mobile phase B: acetonitrile, elution: gradient elution of mobile phase A and mobile phase B.

[0086] Aripiprazole impurity detection method: Use the relevant substance analysis method in the United States Pharmacopoeia Aripiprazole Tablets monograph.

[0087] Nicergoline impurity detection method: high performance liquid chromatography, chromatographic column: CAPCELLPAK CR, 4.6 mm × 250 mm, 5 μm; flow rate: 1.0 mL / min; detection wavelength: 288 nm; injection volume: 10 μL; mobile phase: acetonitrile-phosphate buffer (60 mmol / L potassium dihydrogen phosphate solution containing 0.5% triethylamine, pH 2.1) (30:70).

[0088] Example 1

[0089] The formula of the lyophilized preparation of Compound 1 is shown in Table 1:

[0090] Table 1: Liquid formulation of compound 1

[0091] Additionally, all of the compound 1 in the comparative sample and formulations 1 to 3 in Table 1 were replaced with the same amount of ziprasidone, aripiprazole or nicergoline, and then the liquid formulations of each drug were lyophilized according to the following process.

[0092] Preparation process of freeze-dried preparations:

[0093] (1) Preparation of blank solution: Add excipients, osmotic pressure regulator and cosolvent into a 250 mL beaker, add about 80% water for injection, and stir until completely dissolved to obtain solution A.

[0094] (2) Dissolving the API: Solution A was maintained at 2-10°C, compound 1 was added to solution A, stirred until completely dissolved, and the pH was adjusted to 5.6±0.5.

[0095] (3) Volume adjustment: Transfer the solution obtained in step (2) into a 250 mL volumetric flask and add water for injection to adjust the volume to 250 mL to obtain solution B.

[0096] (4) Filtration and filling: After the volume is fixed, the liquid is sterile filtered. Filter twice using a PES microporous filter membrane with a pore size of 0.22 μm. Fill the filtered liquid into a vial with a filling volume of 2 mL.

[0097] (5) Freeze drying: A freezing process of the prior art is used, such as the freezing process disclosed in CN 1537007A, specifically: a vial containing a drug solution is frozen at -45°C for 3 h, and the frozen sample is then dried in a freeze drying apparatus at an air pressure of less than 125 mTorr for the first drying (also called primary drying) at -25°C for 20.5 h, and then dried at 40°C (heating rate 0.3°C / min) for 12 h to obtain a freeze-dried powder (freeze-dried preparation).

[0098] (6) Nitrogen filling, plugging and capping: The container containing the freeze-dried powder is filled with nitrogen, plugged and capped to obtain the finished product.

[0099] Stability study of the obtained freeze-dried preparation:

[0100] The lyophilized powder was placed at 40°C for 0 day, 3 months, and 6 months, and then 2 mL of water for injection was added to each vial for reconstitution (pH value after reconstitution was 5.6). After preparing the sample solution, the impurity content was tested. The results are shown in Tables 2 to 5:

[0101] Table 2: Impurity Content after Reconstitution of the Lyophilized Preparation of Compound 1 Note: ND means not detected; <RL means less than the reporting limit of 0.05%; the same applies hereinafter.

[0102] Table 3: Impurity Content after Reconstitution of the Lyophilized Preparation of Ziprasidone

[0103] Table 4: Impurity Content after Reconstitution of the Lyophilized Preparation of Aripiprazole

[0104] Table 5: Impurity Content after Reconstitution of the Lyophilized Preparation of Nicergoline

[0105] As can be seen from Table 2, for the lyophilized preparation of Compound 1, when reconstituted immediately after lyophilization, the impurity contents of the control sample and Formulations 1 - 3 are all at extremely low levels (<RL). After reconstitution after storage at 40°C for 3 months, the impurity content of the control sample without sodium chloride increased rapidly (reaching 0.28%), while the impurity contents of Formulations 1 - 3 were still at extremely low levels (0.11 - 0.17%). After reconstitution after storage at 40°C for 6 months, the total impurity content of the control sample increased to 0.35%, and the total impurity contents of Formulations 1 - 3 were only 0.23 - 0.26%, still lower than the impurity level of the control sample after storage at 40°C for 3 months. For Compound 1, the combination of sodium chloride and specific excipients improved the stability of the lyophilized preparation of Compound 1 and reduced the generation of impurities.

[0106] Replace Compound 1 in the control sample and Formulations 1 - 3 in Table 1 with ziprasidone, aripiprazole, or nicergoline respectively. As can be seen from Tables 3 - 5, for ziprasidone, aripiprazole, and nicergoline, after storage at 40°C for 3 months, the impurity contents of the control samples and each formulation of the three drugs increased rapidly compared to day 0; the addition of sodium chloride did not play a role in improving stability and reducing the generation of impurities.

[0107] It can be seen that the scheme of "excipient (lactose, sucrose or trehalose) + osmotic pressure regulator" in the present invention has certain drug selectivity. For Compound 1, it can greatly improve the stability of the API in the lyophilized preparation and reduce the amount of impurities generated; while for other tertiary amine drugs such as ziprasidone, aripiprazole, and nicergoline, it did not play a role in improving stability.

[0108] Replace tartaric acid in Formulations 1 - 3 in Table 1 with hydrochloric acid, citric acid, or acetic acid of the same amount to obtain Formulation 1' (cosolvent hydrochloric acid), Formulation 2' (cosolvent citric acid), and Formulation 3' (cosolvent acetic acid), and prepare the lyophilized powder by the same process. After the lyophilized powders obtained from Formulations 1' - 3 were stored at 40°C for 0 days, 3 months, and 6 months, 2 mL of injection water was added to each vial for reconstitution. After preparing the sample solution, the impurity situation was detected, and the results are shown in Table 6:

[0109] Table 6: Impurity content of compound 1 lyophilized formulation after reconstitution

[0110] Table 6 shows that even after 3 and 6 months at 40°C, the impurity levels of each formulation of Compound 1 were still significantly lower than those of the control. Furthermore, there was no significant difference in the total impurities between Formulations 1 through 3, and between Formulations 1' through 3', indicating that the cosolvent in this invention is not the primary factor in improving the stability of the Compound 1 formulation.

[0111] Other property parameters of the lyophilized formulation of Compound 1 are shown in Table 7 (in this application, data without clear storage temperature and time refer to the test after lyophilization):

[0112] Table 7: Property parameters of compound 1 lyophilized powder

[0113] As shown in Table 7, after being stored at 40°C for 3 months, the main drug content and moisture content of each prescription did not change significantly. This shows that the storage process did not have much effect on the main drug content and moisture content.

[0114] Take the comparative sample in Table 1 and one bottle of freeze-dried powder of prescriptions 1, 2, and 3, use a syringe to take 2 mL of water for injection to reconstitute, shake well, and observe the dissolution.

[0115] Take 1 bottle of the control sample in Table 1 and the lyophilized powder of prescriptions 1, 2, and 3, and use a syringe to take 2 mL of diluent (0.5% sodium lactate Ringer, 0.9% sodium chloride or 5% glucose) to reconstitute, shake well, and observe the dissolution.

[0116] The results were as follows: when 0.5% sodium lactate Ringer's was used as the diluent, solids precipitated from the control sample and prescriptions 1, 2, and 3; when water for injection, 0.9% sodium chloride, or 5% glucose was used as the diluent, the lyophilized powders of the control sample and prescriptions 1, 2, and 3 were completely dissolved in the diluent.

[0117] Take one bottle of the control sample and the freeze-dried powder of prescriptions 1, 2, and 3, and reconstitute them with water for injection, 0.9% sodium chloride, or 5% glucose as diluent (2 mL). After standing for 0, 2, 4, 8, and 24 hours, the impurity content was tested, as shown in Tables 8, 9, and 10:

[0118] Table 8: Impurity content of lyophilized powder after reconstitution with water for injection

[0119] Table 9: Impurity content of lyophilized powder after reconstitution with 0.9% sodium chloride diluent

[0120] Table 10: Impurity content of lyophilized powder after reconstitution with 5% glucose diluent

[0121] It can be seen from Tables 8, 9 and 10 that the total impurity content of the control sample is at a relatively low level (less than 0.2%) 4 hours after redissolution, but the impurity content increases significantly 8 hours after redissolution.

[0122] The impurity content after reconstitution was similar between Formulations 1, 2, and 3 in various dilutions; even 8 hours after reconstitution, the total impurity content remained at a relatively low level (less than 0.2%). Therefore, based on the comparative samples, the storage time requirement for Formulations 1, 2, and 3 after reconstitution can be relaxed.

[0123] In addition, using 20 mL of 0.9% sodium chloride or 5% glucose as the diluent, under the same conditions, the amount of impurities produced was almost the same as the results in Tables 9 and 10, and the volume of the diluent (or the concentration of the injection) had almost no effect on the amount of impurities produced.

[0124] Example 2

[0125] Based on the freeze-drying process in Table 1 and Example 1, the pH value of step (2) of the freeze-dried preparation preparation process was changed. The resulting freeze-dried preparation was placed at 40°C for 3 months and 6 months. 2 mL of water for injection was then added to each vial for reconstitution. The impurity content was tested. The results are shown in Table 11:

[0126] Table 11: Effect of pH value of the solution of prescription 1 to prescription 3 on impurities

[0127] In the stability study in Table 11, the 0-day impurity content of each formulation sample was less than the reporting limit.

[0128] As shown in Table 11, the stability of the lyophilized formulations of Compound 1 (Formulations 1 to 3) was excellent within the pH range of 4.0 to 6.5, with impurity levels significantly lower than those of the control. When the control formulations were adjusted to a pH below 5.0 and stored at 40°C for 6 months, the Impurity B content exceeded the acceptable limit (≤0.30%).

[0129] Example 3

[0130] Based on Table 1, the dosage of the osmotic pressure regulator and the dosage of the excipient were changed, and the freeze-drying process was the same as in Example 1.

[0131] Stability study of freeze-dried preparations:

[0132] The resulting lyophilized preparations were placed at 40°C for 3 months and 6 months, and then 2 mL of water for injection was added to each vial for reconstitution. The impurities were tested, and the results are shown in Tables 12 and 13:

[0133] Table 12: Changes in impurities in freeze-dried preparations with different osmotic pressure regulator dosages after storage at 40°C

[0134] In the stability study in Table 12, the 0-day impurity content of each formulation sample was less than the reporting limit.

[0135] When the dosage of the osmotic pressure regulator was 0.1 parts of compound 1 (formulation 1-1), the impurity B in the lyophilized preparation increased rapidly at 40° C., exceeding the acceptable standard (≤0.30%).

[0136] During the stability test, as the amount of osmotic pressure regulator increased (0.125 to 2.2 parts), the growth rate of impurity B content decreased.

[0137] Table 13: Impurity changes and appearance of freeze-dried preparations with different excipient dosages after storage at 40°C

[0138] In the stability study in Table 13, the 0-day impurity content of each formulation sample was less than the reporting limit.

[0139] As can be seen from Table 13, the amount of excipient used in an amount of 4 to 60 parts relative to 1 part of compound 1 has no effect on stability and the impurity content is low.

[0140] However, the freezing process conditions of the existing technology have a low temperature and a low drying rate. The drying time of 20.5 hours is not enough for the sample to complete the drying once, resulting in many samples with collapsed appearance. Moreover, a lower primary drying temperature and a longer drying time will increase energy consumption.

[0141] Example 4

[0142] The freeze-drying process of step (5) of Example 1 was adjusted to include the following steps:

[0143] After filling, pre-cooling (-5℃~5℃, 3 hours), and then freezing at -40℃ for 3 hours; primary drying is drying at -8.5℃~-6.5℃ for 20.5 hours, and the plate vacuum degree is 15~20Pa; secondary drying is drying at 40℃ (heating for 4 hours) for 10 hours, and the plate vacuum degree is 15Pa.

[0144] The freeze-drying process of this embodiment was used to freeze the formulations in Table 13, and the appearance and stability of the freeze-dried products were checked.

[0145] Table 14: Appearance of lyophilized formulations with different excipient amounts

[0146] After process adjustment, the appearance of most formulations did not shrink or collapse, and the stability results were basically consistent with Table 12.

[0147] When the ratio of compound 1 to excipient is low or the solid content is high (the amount of excipient exceeds 20 parts), the freezing effect of the samples (formulations 2-4, 2-6, 2-13, and 2-14) under the same pre-freezing conditions is poor, the primary drying rate is fast, and the bottle spray phenomenon is prone to occur, resulting in content loss and possibly affecting the sealing performance; extending the pre-freezing time, lowering the pre-freezing temperature, and reducing the primary drying rate can solve this problem, but it will increase energy consumption.

[0148] When the dosage of the osmotic pressure regulator is too high (e.g., in prescription 2-16, the dosage of sodium chloride is 2.5 parts relative to 1 part of compound 1), bubbling may appear on the sample surface when freeze-dried under the same conditions. This requires lowering the primary drying temperature and extending the primary drying time.

[0149] Therefore, in addition to stability, taking into account the accessibility of the freezing process and the appearance requirements of the freeze-dried product, the amount of excipient should be 4 to 20 parts, and the amount of osmotic pressure regulator should be 0.125 to 2.2 parts.

[0150] Example 5

[0151] A lyophilized preparation containing, in addition to Compound 1, other antiemetic active ingredients. The liquid formulation is shown in Table 15. The preparation process is based on Example 1, and the filling volume is adjusted as needed.

[0152] Table 15: Liquid formulation of compound preparation containing compound 1

[0153] The freeze-drying process is the same as in Example 1.

[0154] The obtained lyophilized preparation for injection was placed at 40°C for 0 day and 3 months, and then the corresponding filling volume (2 mL or 20 mL) of water for injection was added to each vial for reconstitution. The impurity situation of compound 1 was tested. The results are shown in Table 16.

[0155] Table 16: Changes in impurities of compound 1 after storage at 40°C in the compound lyophilized preparation

[0156] As shown in Table 16, after the compound preparation was stored at 40°C for 3 months, the impurity content of compound 1 remained at a very low level, indicating good storage stability.

[0157] The above embodiments are preferred implementation modes of the present invention, but the implementation modes of the present invention are not limited to the above embodiments. Any other changes, modifications, substitutions, combinations, and simplifications that do not deviate from the spirit and principles of the present invention should be considered as equivalent replacement methods and are included in the scope of protection of the present invention.

Claims

1. A freeze-dried preparation, characterized in that Containing compound 1, excipients and osmotic pressure regulators; The compound 1 has a structure as shown in Formula 1: The excipient is at least one of lactose, sucrose, trehalose, or hydrates thereof; The osmotic pressure regulator is a sodium or potassium salt; The freeze-dried preparation contains 1 part by weight of compound 1 and 0.125 to 2.2 parts by weight of an osmotic pressure regulator.

2. The freeze-dried preparation according to claim 1, characterized in that: The lyophilized preparation contains 1 part by weight of compound 1 and 4 to 60 parts by weight of excipients.

3. The freeze-dried preparation according to claim 1, characterized in that: Each unit of the lyophilized preparation contains 1 to 30 mg of Compound 1.

4. The freeze-dried preparation according to claim 1, characterized in that: The lyophilized preparation contains 1 part by weight of compound 1 and 4 to 20 parts by weight of excipients.

5. The freeze-dried preparation according to claim 1, characterized in that: The hydrates are lactose monohydrate and trehalose dihydrate.

6. The freeze-dried preparation according to claim 1, characterized in that: The salt is one or more of hydrochloride, tartrate, citrate, sulfate, carbonate or bicarbonate.

7. The freeze-dried preparation according to claim 1, characterized in that: The osmotic pressure regulator is sodium chloride or potassium chloride.

8. The freeze-dried preparation according to claim 1, characterized in that: The lyophilized preparation contains a cosolvent.

9. The freeze-dried preparation according to claim 8, characterized in that: The cosolvent is one or more of tartaric acid, hydrochloric acid, citric acid, acetic acid, malic acid, fumaric acid or phosphoric acid.

10. The freeze-dried preparation according to claim 8, characterized in that: The freeze-dried preparation contains 1 part by weight of compound 1 and 0.2 to 1.0 parts of a co-solvent.

11. The freeze-dried preparation according to claim 1, characterized in that: The freeze-dried preparation is prepared by freeze-drying a solution with a pH value of 4.0 to 6.

5.

12. The freeze-dried preparation according to claim 1, characterized in that: The freeze-dried preparation also contains other antiemetic active ingredients.

13. The freeze-dried preparation according to claim 12, characterized in that: The other antiemetic active ingredients include one or more of 5-HT3 receptor antagonists, neurokinin-1 (NK1) receptor antagonists, glucocorticoids, benzodiazepines or dopamine receptor antagonists.

14. The freeze-dried preparation according to claim 12, characterized in that: The lyophilized preparation contains Compound 1 and palonosetron.

15. The freeze-dried preparation according to claim 12, characterized in that: The lyophilized preparation contains compound 1, palonosetron and fornetupitant.

16. An injection, characterized in that: The freeze-dried preparation is obtained by reconstitution of the freeze-dried preparation according to any one of claims 1 to 11.

17. An injection, characterized in that: It is obtained by reconstitution of the freeze-dried preparation according to any one of claims 12 to 15.

18. The injection according to claim 16 or 17, characterized in that: The content of the compound 1 is 1-20 mg / mL.

19. The injection according to claim 16 or 17, characterized in that: The injection has a pH value of 4.0 to 6.

5.

20. The injection according to claim 16 or 17, characterized in that: The re-dissolving is to add a diluent for re-dissolving; The diluent is water for injection, sodium chloride solution, glucose solution, or a solution containing glucose and sodium chloride.

21. The injection according to claim 16 or 17, characterized in that: The injection is used for intramuscular injection, subcutaneous injection and intravenous injection.

22. The lyophilized preparation according to any one of claims 1 to 11 and / or the injection according to claim 16 is used in the preparation of a drug for treating bipolar disorder, schizophrenia, mania, agitation, epilepsy, obsessive-compulsive disorder, generalized anxiety disorder, depression, nausea and vomiting caused by chemotherapy and radiotherapy, explosive vomiting, delayed vomiting, postoperative vomiting, and intractable vomiting.

23. The freeze-dried preparation according to any one of claims 12 to 15 and / or the injection according to claim 17 for the preparation of drugs for nausea and vomiting, explosive vomiting, delayed vomiting, postoperative vomiting, and intractable vomiting caused by chemotherapy and radiotherapy.

24. The method for preparing the lyophilized preparation according to any one of claims 1 to 15, characterized in that The following steps are involved: (1) Preparation of blank solution: Mix the excipient, osmotic pressure regulator and cosolvent, add part of the water for injection, and stir until completely dissolved to obtain solution A; (2) Dissolving the API and making up the volume: Add the active ingredient to solution A at 0-12°C, stir until completely dissolved, adjust the pH value, and add the remaining amount of water for injection to make up the volume to obtain solution B; When the active ingredient is compound 1, the pH value is adjusted to 4.0-6.5; When the active ingredient is compound 1 and other antiemetic active ingredients, the pH value is adjusted to 3-7; (3) Filtration and filling: Solution B is filtered through a microporous filter membrane and then filled; (4) Freeze drying: After filling, the drug solution is freeze-dried within 24 hours. It is first pre-frozen at -5 to 7°C for more than 1 hour, and then frozen at below -35°C for more than 1 hour, which is called the primary freezing process; then dried at -25 to -2.5°C for more than 20 hours, which is called the primary drying process; and then dried at 30 to 50°C for more than 5 hours, which is called the secondary drying process, to obtain a freeze-dried preparation.

25. The preparation method according to claim 24, characterized in that: In step (4), during the primary drying process and the secondary drying process, the vacuum degree of the freeze-drying device is 5 to 30 Pa.

26. The preparation method according to claim 24, characterized in that: The solid content of solution B in step (2) is above 1.5% (w / v).

27. The freeze-dried preparation according to any one of claims 1 to 15, characterized in that: The stability of the compound 1 is maintained at 40° C. for at least six months, and the related impurity B does not exceed 0.3%.

28. The freeze-dried preparation according to any one of claims 1 to 15, characterized in that: After the freeze-dried preparation is prepared, the diluent is added for re-dissolution, and after being placed at 40° C. for 8 hours, the total impurities do not exceed 0.2%.

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