Freeze-dried preparation and injection and preparation method thereof

Abstract

The invention discloses a freeze-drying preparation, an injection and a preparation method of the freeze-drying preparation. The freeze-drying preparation contains a compound 1, an excipient and an osmotic pressure regulator, the excipient is one or more of lactose, cane sugar or trehalose, or a hydrate of lactose, cane sugar or trehalose; the osmotic pressure regulator is sodium or potassium salt; the freeze-drying preparation contains 1 part by weight of a compound 1 and 0.125-2.2 parts by weight of an osmotic pressure regulator. According to the present invention, the combination of the excipient and the osmotic pressure regulator is adopted in the prescription, such that the stability of the compound 1 lyophilized preparation is accidentally improved, the storage stability is improved even if the compound 1 lyophilized preparation is stored at 40 DEG C, the impurity generation is reduced, and the storage period is prolonged; compared with a common injection freeze-drying preparation with the preservation temperature required to be 20-25 DEG C, the product has the advantage that the tolerance at a higher temperature is improved. Meanwhile, the content of impurities after standing for 8 hours after redissolution is also low, and the standing time of the freeze-dried preparation after redissolution can be prolonged.

Description

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 schizophrenia patients 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 , 5-HT3 and dopamine D2 receptors, etc., and each CINV preventive drug usually blocks a certain type of receptor. Therefore, compared with setrons that block only 5-HT3 receptors or pitans that block NK1 receptors, compound 1 can act on multiple vomiting-related receptors, has a very noteworthy antiemetic effect, and has obvious clinical advantages.

[0005] At present, the marketed products of Compound 1 are mainly administered by oral (PO) route, with few intramuscular injections (IM) and no injection routes 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 drug via PO is generally significantly slower than that via injection.

[0007] In terms of efficacy and compliance, when used for the treatment of nausea and vomiting, drugs administered by PO may be excreted with vomiting before they are fully absorbed and take effect, affecting the clinical effect; some preparations may even have a certain bitterness and irritation, causing nausea and vomiting. For patients with dysphagia, such as the elderly and children, injection is recommended.

[0008] The route of administration of the Compound 1 freeze-dried powder injection product currently marketed overseas is intramuscular injection, and the storage temperature requirement in the U.S. instructions is 20°C to 25°C. If the stability of the product can be improved so that it can be stored at a higher temperature (such as below 30°C), it will be more conducive to its storage and circulation quality assurance during the shelf life.

[0009] Compound 1 is a poorly soluble and easily degradable drug, especially easy to hydrolyze, and it is very difficult to develop it into a liquid preparation, so it is considered to be prepared into a lyophilized powder injection. CN 1028429C mentions a lyophilized powder injection product using mannitol as a diluent, but after the applicant prepared the lyophilized powder injection according to the prescription provided by it, the study found that the compound 1 in the powder still degraded rapidly during the storage process and was unstable.

[0010] During the injection process, excessively high or low osmotic pressure of the drug solution can cause some adverse reactions, such as hemolysis, irritation, phlebitis, etc. The lyophilized powder injection product of Compound 1 that has been marketed is not an isotonic solution after reconstitution according to the instructions, and is clinically limited to intramuscular injection; since Compound 1 is easily hydrolyzed, the prescription design of the lyophilized powder injection product on the market has slight defects, so the drug solution after reconstitution of the lyophilized powder must be used as soon as possible, and the requirement for the use time is relatively strict.

[0011] Therefore, there is a great clinical demand for developing an injection preparation 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 a variety of clinical treatment needs. Summary of the invention

[0012] The purpose of the present invention is to provide a lyophilized preparation and an 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; and combined with the optimization of the lyophilization process, the moisture content of the lyophilized preparation (lyophilized powder) is reduced, and it is not easy to shrink and collapse.

[0013] The object of the present invention is achieved through the following technical solutions:

[0014] A lyophilized preparation comprising compound 1, an excipient and an osmotic pressure regulator;

[0015] The compound 1 has a structure as shown in Formula 1:

[0016]

[0017] The excipient is one or more of lactose, sucrose or trehalose, or a hydrate 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 great influence on the accessibility of the lyophilization process and the lyophilization effect.

[0024] The lyophilized preparation also 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 part 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 or 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 Fonetupitant.

[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, 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, 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, diphenhydramine 5-25 mg.

[0045] The active ingredients contained in the lyophilized preparation are 2 to 20 mg of compound 1 and 0.1 to 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 4.0-6.5; the concentration of compound 1 is 1-20 mg / mL, preferably 2-5 mg / mL.

[0049] The re-dissolution is to add a 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 to 830 mOsm / kg, preferably 230 to 500 mOsm / kg, and more preferably 260 to 330 mOsm / kg.

[0052] The diluent is water for injection, with a fixed volume of 2 to 8 mL, and the obtained injection has an osmotic pressure suitable for intravenous injection; other diluents other than water for injection are used, with a fixed volume of 10 to 50 mL, and the obtained 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: Keeping 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 the pH value is preferably adjusted to 3-7.

[0064] (3) Filtration and filling: Solution B is filtered using a microporous filtration 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 at 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 (lyophilized 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 1.5-25% (w / v), particularly preferably 1.5-10% (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, the present invention has the following advantages and beneficial effects:

[0075] 1. The present invention uses a combination of "excipients (lactose, sucrose or trehalose) plus an osmotic pressure regulator" in the prescription, which unexpectedly improves the stability of the lyophilized preparation of compound 1, improves the storage stability even when stored at 40°C, reduces the generation of impurities, and prolongs the storage period. Compared with the storage temperature requirement of 20-25°C for general injectable lyophilized preparations, this product improves its tolerance at higher temperatures (40°C), which is more conducive to its quality assurance for storage and circulation during the shelf life. At the same time, the impurity content after being placed for 8 hours after reconstitution is also low, which can prolong 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, and has a faster onset of effect, meeting the needs of clinical emergency situations.

[0078] 4. The formulation process provided by the present invention has 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] Figure 1 to Figure 27 The following are the appearance pictures of the freeze-dried products obtained from the prescriptions in Tables 13 and 14. DETAILED DESCRIPTION

[0080] The present invention is further described in detail below in conjunction with 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 General Rules of Part IV of the 2020 Pharmacopoeia, <0832 Determination of Water>, the volumetric titration method of the first method (Fischer method).

[0083] Compound 1 content detection method: Take an appropriate amount of lyophilized preparation (equivalent to 10 mg of compound 1), add 2 mL of water for injection to reconstitute, add diluent (acetonitrile and water, volume ratio 4:6) to quantitatively dilute to make a solution containing about 0.2 mg / mL of compound 1 per 1 mL as the sample solution. Chromatographic conditions: high performance liquid chromatograph (Agilent); chromatographic 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 lyophilized preparation (equivalent to 10 mg of compound 1), add 2 mL of water for injection to reconstitute, add diluent (acetonitrile and water, volume ratio 4:6) to quantitatively dilute to make a solution containing about 0.4 mg / mL of compound 1 per 1 mL as the sample solution. Chromatographic conditions: high performance liquid chromatograph (Agilent); chromatographic 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, 4.6mm×250mm, 5μm; flow rate: 1.0mL / min; detection wavelength: 288nm; injection volume: 10μL; mobile phase: acetonitrile-phosphate buffer (60mmol / 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] Prescription Code Comparison sample 1 2 3 Dosage of Compound 1 1.25g 1.25g 1.25g 1.25g Type and dosage of excipients Lactose monohydrate 6.5g Lactose monohydrate 6.5g Sucrose 6.5g Trehalose 6.5g Sodium chloride dosage 0 0.32g 0.32g 0.32g Tartaric acid dosage 0.4375g 0.4375g 0.4375g 0.4375g

[0092] 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 freeze-dried according to the following process.

[0093] Preparation process of freeze-dried preparations:

[0094] (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.

[0095] (2) Dissolving 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.

[0096] (3) Adjusting the volume: Transfer the solution obtained in step (2) into a 250 mL volumetric flask, add water for injection and adjust the volume to 250 mL to obtain Solution B.

[0097] (4) Filtration and filling: The fixed volume drug solution is sterile filtered. It is filtered twice using a microporous filter membrane made of PES material with a pore size of 0.22 μm. The filtered drug solution is filled into a vial with a filling volume of 2 mL.

[0098] (5) Freeze drying: using a freezing process of the prior art, such as the freezing process disclosed in CN 1537007A, specifically: freezing the vial containing the drug solution at -45°C for 3 h, and then drying the frozen sample in a freeze drying device at an air pressure of less than 125 mTorr for the first time (also called primary drying) at -25°C for 20.5 h, and then drying it for the second time at 40°C (heating rate 0.3°C / min) for 12 h to obtain a freeze-dried powder (freeze-dried preparation).

[0099] (6) Nitrogen filling, plugging and capping: The container containing the freeze-dried powder is filled with nitrogen, plugged with a rubber plug, and then capped to obtain the finished product.

[0100] Stability study of the freeze-dried preparation obtained:

[0101] After the obtained lyophilized powder was placed at 40°C for 0 day, 3 months and 6 months, 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 impurities were tested. The results are shown in Tables 2 to 5:

[0102] Table 2: Impurity Content after Reconstitution of Compound 1 Lyophilized Preparation

[0103]

[0104] Note: ND means not detected; <RL means less than the reporting limit of 0.05%; the same below.

[0105] Table 3: Impurity Content after Reconstitution of Ziprasidone Lyophilized Preparation

[0106]

[0107] Table 4: Impurity Content after Reconstitution of Aripiprazole Lyophilized Preparation

[0108]

[0109] Table 5: Impurity Content after Reconstitution of Nicergoline Lyophilized Preparation

[0110]

[0111] 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 improves the stability of the lyophilized preparation of Compound 1 and reduces the generation of impurities.

[0112] 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.

[0113] It can be seen that the scheme of the present invention with "excipient (lactose, sucrose, or trehalose) + osmotic pressure regulator" has a 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 does not play a role in improving stability.

[0114] The tartaric acid in prescriptions 1 to 3 in Table 1 was replaced with the same amount of hydrochloric acid, citric acid or acetic acid to obtain prescriptions 1' (cosolvent hydrochloric acid), prescription 2' (cosolvent citric acid) and prescription 3' (cosolvent acetic acid), and freeze-dried powders were prepared by the same process. The freeze-dried powders obtained from prescriptions 1' to 3' were placed at 40°C for 0 days, 3 months and 6 months, and 2 mL of injection water was added to each vial for reconstitution. After preparing the sample solution, the impurities were tested, and the results are shown in Table 6:

[0115] Table 6: Impurity content of compound 1 lyophilized formulation after reconstitution

[0116]

[0117] As can be seen from Table 6, after being placed at 40°C for 3 months and 6 months, the amount of impurities generated in each formulation of Compound 1 is still significantly less than that of the control sample. At the same time, there is no significant difference in the total impurities of Formulations 1 to 3 and Formulations 1' to 3', indicating that the cosolvent in the present invention is not the main factor in improving the stability of the formulation of Compound 1.

[0118] Other property parameters of the lyophilized preparation of Compound 1 are shown in Table 7 (in this application, the data on storage temperature and time are not clear, all refer to the test after lyophilization):

[0119] Table 7: Property parameters of compound 1 lyophilized powder

[0120]

[0121] As shown in Table 7, after being placed at 40°C for 3 months, the main drug content and moisture content of each prescription did not change significantly. It can be seen that the storage process did not have much effect on the main drug content and moisture content.

[0122] Take one bottle of the control sample in Table 1 and the 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.

[0123] Take one bottle of the control sample in Table 1 and the lyophilized powder of prescriptions 1, 2, and 3, 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.

[0124] 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.

[0125] Take one bottle of freeze-dried powder of the control sample and prescriptions 1, 2, and 3, and reconstitute them with water for injection, 0.9% sodium chloride or 5% glucose as diluent (2 mL). After leaving for 0, 2, 4, 8, and 24 hours, the impurity content is tested, as shown in Table 8, Table 9, and Table 10:

[0126] Table 8: Impurity content of lyophilized powder after reconstitution with water for injection

[0127]

[0128] Table 9: Impurity content of lyophilized powder after reconstitution with 0.9% sodium chloride diluent

[0129]

[0130] Table 10: Impurity content of lyophilized powder after reconstitution with 5% glucose diluent

[0131]

[0132] 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 re-dissolution, but the impurity content increases significantly 8 hours after re-dissolution.

[0133] In various dilution solutions, the impurity content after reconstitution between prescriptions 1, 2 and 3 is not much different; 8 hours after reconstitution, the total impurity content is still at a relatively low level (less than 0.2%). Therefore, based on the comparative samples, the requirements for the storage time after reconstitution can be relaxed for prescriptions 1, 2 and 3.

[0134] 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 solution) had almost no effect on the amount of impurities produced.

[0135] Example 2

[0136] Based on the freeze-drying process in Table 1 and Example 1, the pH value of the freeze-dried preparation preparation process step (2) was changed, and the obtained freeze-dried preparation was placed at 40° C. for 3 months and 6 months, and then 2 mL of injection water was added to each vial for reconstitution, and the impurities were detected. The results are shown in Table 11:

[0137] Table 11: Effect of pH value of formulations 1 to 3 on impurities

[0138]

[0139] In the stability study in Table 11, the 0-day impurity content of each prescription sample was less than the reporting limit.

[0140] As shown in Table 11, within the range of pH value of 4.0 to 6.5, the stability of the freeze-dried preparations of Compound 1 (Formulation 1 to Formulation 3) is very good, and the amount of impurities generated is significantly lower than that of the control sample. When the pH value of the preparation of the control sample is adjusted to below 5.0 and placed at 40°C for 6 months, the content of impurity B exceeds the acceptable standard (≤0.30%).

[0141] Example 3

[0142] On the basis of Table 1, the dosage of osmotic pressure regulator and excipient were changed, and the freeze-drying process was the same as in Example 1.

[0143] Study on stability of freeze-dried preparations:

[0144] The obtained 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. The results are shown in Tables 12 and 13:

[0145] Table 12: Changes in impurities in freeze-dried preparations with different osmotic pressure regulator dosages after storage at 40°C

[0146]

[0147] In the stability study in Table 12, the 0-day impurity content of each formulation sample was less than the reporting limit.

[0148] When the dosage of the osmotic pressure regulator was 0.1 part of compound 1 (formulation 1-1), the impurity B of the lyophilized preparation increased rapidly at 40°C, exceeding the acceptable standard (≤0.30%).

[0149] 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.

[0150] Table 13: Changes in impurities and appearance of freeze-dried preparations with different excipient dosages after storage at 40°C

[0151]

[0152] In the stability study in Table 13, the 0-day impurity content of each prescription sample was less than the reporting limit.

[0153] As can be seen from Table 13, relative to 1 part of compound 1, the amount of 4 to 60 parts of excipients has no effect on stability and the impurity content is low.

[0154] However, the freezing process conditions of the prior art have a low temperature and a low drying rate. The drying time of 20.5 hours is not enough for the sample to complete one-time drying, resulting in more samples with collapsed appearance. Moreover, a lower primary drying temperature and a longer drying time will increase energy consumption.

[0155] Example 4

[0156] The freeze-drying process of step (5) of Example 1 is adjusted to specifically include the following steps:

[0157] 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 vacuum degree of the plate layer is 15~20Pa; secondary drying is drying at 40℃ (heating for 4 hours) for 10 hours, and the vacuum degree of the plate layer is 15Pa.

[0158] 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.

[0159] Table 14: Appearance of lyophilized formulations with different excipient dosages

[0160] Prescription Code Freeze-dried product appearance Prescription Code Freeze-dried product appearance 2-1 Fig.16 2-9 (i.e., Table 1 Prescription 1) Fig. 22 2-2 Fig.17 2-10 (i.e. prescription 1-8) Fig.23 2-3 Fig.18 2-11 Fig.24 2-4 and Fig.13 approximate 2-12 Fig.25 2-5 Fig.19 2-13 and Fig.13 approximate 2-6 and Fig.13 approximate 2-14 and Fig.13 approximate 2-7 Fig. 20 2-15 Fig.26 2-8 Fig.21 2-16 Fig. 27

[0161] After process adjustment, the appearance of most formulations did not shrink or collapse, and the stability results were basically consistent with Table 12.

[0162] 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 (prescriptions 2-4, 2-6, 2-13, 2-14) under the same pre-freezing conditions is poor, the primary drying rate is fast, and the bottle spray phenomenon is easy to occur, which will lead to content loss and may affect the sealing; 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.

[0163] When the dosage of the osmotic pressure regulator is too high (such as in prescription 2-16, the dosage of sodium chloride is 2.5 parts relative to 1 part of compound 1), bubbling appears on the sample surface when freeze-dried under the same conditions. It is necessary to lower the primary drying temperature and extend the primary drying time.

[0164] Therefore, in addition to stability, taking into account the accessibility of the freezing process and the appearance requirements of the lyophilized 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.

[0165] Example 5

[0166] A lyophilized preparation, in addition to Compound 1, also contains other antiemetic active ingredients. The liquid formulation is shown in Table 15. The preparation process refers to Example 1, and the filling volume is adjusted as needed.

[0167] Table 15: Liquid formulation of compound preparation containing compound 1

[0168]

[0169] The freeze-drying process is the same as in Example 1.

[0170] 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, and the impurity situation of compound 1 was tested. The results are shown in Table 16.

[0171] Table 16: Changes in impurities of compound 1 after storage at 40°C in the compound lyophilized preparation

[0172]

[0173] As shown in Table 16, after the composite preparation was placed at 40°C for 3 months, the impurity content of compound 1 remained at a very low level, reflecting good storage stability.

[0174] 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 equivalent replacement methods and are included in the protection scope 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 one or more of lactose, sucrose or trehalose, or a hydrate 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 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.

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).

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